Olga Ilkayeva

Journal Article J Appl Physiol (1985) · September 1, 2024 Physical activity, including structured exercise, is associated with favorable health-related chronic disease outcomes. Although there is evidence of various molecular pathways that affect these responses, a comprehensive molecular map of these molecular r ... Full text Link to item Cite

The mitochondrial multi-omic response to exercise training across rat tissues.

Journal Article Cell Metab · June 4, 2024 Mitochondria have diverse functions critical to whole-body metabolic homeostasis. Endurance training alters mitochondrial activity, but systematic characterization of these adaptations is lacking. Here, the Molecular Transducers of Physical Activity Consor ... Full text Link to item Cite

Targeted Metabolomic Profiling of Dapagliflozin in Heart Failure With Preserved Ejection Fraction: The PRESERVED-HF Trial.

Journal Article JACC Heart Fail · June 2024 BACKGROUND: Although sodium glucose co-transporter 2 inhibitors (SGLT2is) improve heart failure (HF)-related symptoms and outcomes in HF with preserved ejection fraction (HFpEF), underlying mechanisms remain unclear. In HF with reduced EF, dapagliflozin al ... Full text Link to item Cite

Metabolomic profiling during ex situ normothermic perfusion before heart transplantation defines patterns of substrate utilization and correlates with markers of allograft injury.

Conference J Heart Lung Transplant · May 2024 BACKGROUND: Cardiac metabolism is altered in heart failure and ischemia-reperfusion injury states. We hypothesized that metabolomic profiling during ex situ normothermic perfusion before heart transplantation (HT) would lend insight into myocardial substra ... Full text Link to item Cite

Metabolomic and genetic architecture of gestational diabetes subtypes.

Journal Article Diabetologia · May 2024 AIMS/HYPOTHESIS: Physiological gestational diabetes mellitus (GDM) subtypes that may confer different risks for adverse pregnancy outcomes have been defined. The aim of this study was to characterise the metabolome and genetic architecture of GDM subtypes ... Full text Link to item Cite

Sexual dimorphism and the multi-omic response to exercise training in rat subcutaneous white adipose tissue.

Journal Article Nat Metab · May 2024 Subcutaneous white adipose tissue (scWAT) is a dynamic storage and secretory organ that regulates systemic homeostasis, yet the impact of endurance exercise training (ExT) and sex on its molecular landscape is not fully established. Utilizing an integrativ ... Full text Link to item Cite

Temporal dynamics of the multi-omic response to endurance exercise training.

Journal Article Nature · May 2024 Regular exercise promotes whole-body health and prevents disease, but the underlying molecular mechanisms are incompletely understood1-3. Here, the Molecular Transducers of Physical Activity Consortium4 profiled the temporal transcriptome, proteome, metabo ... Full text Link to item Cite

Optical imaging reveals chemotherapy-induced metabolic reprogramming of residual disease and recurrence.

Journal Article Sci Adv · April 5, 2024 Fewer than 20% of triple-negative breast cancer patients experience long-term responses to mainstay chemotherapy. Resistant tumor subpopulations use alternative metabolic pathways to escape therapy, survive, and eventually recur. Here, we show in vivo, lon ... Full text Link to item Cite

Prevotella copri and microbiota members mediate the beneficial effects of a therapeutic food for malnutrition.

Journal Article Nat Microbiol · April 2024 Microbiota-directed complementary food (MDCF) formulations have been designed to repair the gut communities of malnourished children. A randomized controlled trial demonstrated that one formulation, MDCF-2, improved weight gain in malnourished Bangladeshi ... Full text Link to item Cite

Racial Differences in Vaginal Fluid Metabolites and Association with Systemic Inflammation Markers among Ovarian Cancer Patients: A Pilot Study.

Journal Article Cancers (Basel) · March 23, 2024 The vaginal microbiome differs by race and contributes to inflammation by directly producing or consuming metabolites or by indirectly inducing host immune response, but its potential contributions to ovarian cancer (OC) disparities remain unclear. In this ... Full text Link to item Cite

Sex Differences in Branched-chain Amino Acid and Tryptophan Metabolism and Pathogenesis of Youth-onset Type 2 Diabetes.

Journal Article J Clin Endocrinol Metab · March 15, 2024 OBJECTIVES: Insulin resistance is associated with elevations in plasma branched-chain amino acids (BCAAs). BCAAs compete with aromatic amino acids including tryptophan for uptake into β cells. To explore relationships between BCAAs and tryptophan metabolis ... Full text Link to item Cite

Chronic exercise improves hepatic acylcarnitine handling.

Journal Article iScience · March 15, 2024 Exercise mediates tissue metabolic function through direct and indirect adaptations to acylcarnitine (AC) metabolism, but the exact mechanisms are unclear. We found that circulating medium-chain acylcarnitines (AC) (C12-C16) are lower in active/endurance t ... Full text Link to item Cite

Metabolite signature of diabetes remission in individuals with obesity undergoing weight loss interventions.

Journal Article Obesity (Silver Spring) · February 2024 OBJECTIVE: This observational study investigated metabolomic changes in individuals with type 2 diabetes (T2D) after weight loss. We hypothesized that metabolite changes associated with T2D-relevant phenotypes are signatures of improved health. METHODS: Fa ... Full text Link to item Cite

Circulating metabolic profile in idiopathic pulmonary fibrosis: data from the IPF-PRO Registry.

Journal Article Respir Res · January 25, 2024 BACKGROUND: The circulating metabolome, reflecting underlying cellular processes and disease biology, has not been fully characterized in patients with idiopathic pulmonary fibrosis (IPF). We evaluated whether circulating levels of metabolites correlate wi ... Full text Link to item Cite

APOL1-mediated monovalent cation transport contributes to APOL1-mediated podocytopathy in kidney disease.

Journal Article J Clin Invest · January 16, 2024 Two coding variants of apolipoprotein L1 (APOL1), called G1 and G2, explain much of the excess risk of kidney disease in African Americans. While various cytotoxic phenotypes have been reported in experimental models, the proximal mechanism by which G1 and ... Full text Open Access Link to item Cite

Catabolism of fats and branched-chain amino acids in children with Type 1 diabetes: Association with glycaemic control and total daily insulin dose.

Journal Article Endocrinol Diabetes Metab · November 2023 OBJECTIVE: Hyperglycaemia in Type 1 diabetes (T1D) results from an absolute insulin deficiency. However, insulin resistance (IR) may exacerbate glycaemic instability in T1D and contribute to long-term cardiovascular complications. We previously showed that ... Full text Link to item Cite

Mitochondrial metabolites predict adverse cardiovascular events in individuals with diabetes.

Journal Article JCI Insight · September 8, 2023 Metabolic mechanisms underlying the heterogeneity of major adverse cardiovascular (CV) event (MACE) risk in individuals with type 2 diabetes mellitus (T2D) remain unclear. We hypothesized that circulating metabolites reflecting mitochondrial dysfunction pr ... Full text Link to item Cite

Metabolic factors associated with incident fracture among older adults with type 2 diabetes mellitus: a nested case-control study.

Journal Article Osteoporos Int · July 2023 UNLABELLED: Older adults with type 2 diabetes mellitus have an increased risk of fracture despite a paradoxically higher average bone mineral density. This study identified additional markers of fracture risk in this at-risk population. Non-esterified fatt ... Full text Open Access Link to item Cite

Maternal and Cord Blood Serum Metabolite Associations with Childhood Adiposity and Body Composition Outcomes.

Journal Article Metabolites · June 13, 2023 Maternal metabolites influence the size of newborns independently of maternal body mass index (BMI) and glycemia, highlighting the importance of maternal metabolism on offspring outcomes. This study examined associations of maternal metabolites during preg ... Full text Link to item Cite

Acetyl-CoA carboxylase 1 is a suppressor of the adipocyte thermogenic program.

Journal Article Cell Rep · May 30, 2023 Disruption of adipocyte de novo lipogenesis (DNL) by deletion of fatty acid synthase (FASN) in mice induces browning in inguinal white adipose tissue (iWAT). However, adipocyte FASN knockout (KO) increases acetyl-coenzyme A (CoA) and malonyl-CoA in additio ... Full text Link to item Cite

Molecular Transducers of Physical Activity Consortium (MoTrPAC): human studies design and protocol.

The mitochondrial multi-omic response to exercise training across rat tissues.

Targeted Metabolomic Profiling of Dapagliflozin in Heart Failure With Preserved Ejection Fraction: The PRESERVED-HF Trial.

Metabolomic profiling during ex situ normothermic perfusion before heart transplantation defines patterns of substrate utilization and correlates with markers of allograft injury.

Metabolomic and genetic architecture of gestational diabetes subtypes.

Sexual dimorphism and the multi-omic response to exercise training in rat subcutaneous white adipose tissue.

Temporal dynamics of the multi-omic response to endurance exercise training.

Optical imaging reveals chemotherapy-induced metabolic reprogramming of residual disease and recurrence.

Prevotella copri and microbiota members mediate the beneficial effects of a therapeutic food for malnutrition.

Racial Differences in Vaginal Fluid Metabolites and Association with Systemic Inflammation Markers among Ovarian Cancer Patients: A Pilot Study.

Sex Differences in Branched-chain Amino Acid and Tryptophan Metabolism and Pathogenesis of Youth-onset Type 2 Diabetes.

Chronic exercise improves hepatic acylcarnitine handling.

Metabolite signature of diabetes remission in individuals with obesity undergoing weight loss interventions.

Circulating metabolic profile in idiopathic pulmonary fibrosis: data from the IPF-PRO Registry.

APOL1-mediated monovalent cation transport contributes to APOL1-mediated podocytopathy in kidney disease.

Catabolism of fats and branched-chain amino acids in children with Type 1 diabetes: Association with glycaemic control and total daily insulin dose.

Mitochondrial metabolites predict adverse cardiovascular events in individuals with diabetes.

Metabolic factors associated with incident fracture among older adults with type 2 diabetes mellitus: a nested case-control study.

Maternal and Cord Blood Serum Metabolite Associations with Childhood Adiposity and Body Composition Outcomes.

Acetyl-CoA carboxylase 1 is a suppressor of the adipocyte thermogenic program.

Association of Maternal Metabolites and Metabolite Networks with Newborn Outcomes in a Multi-Ancestry Cohort.

Journal Article Metabolites · March 31, 2023 The in utero environment is important for newborn size at birth, which is associated with childhood adiposity. We examined associations between maternal metabolite levels and newborn birthweight, sum of skinfolds (SSF), and cord C-peptide in a multinationa ... Full text Link to item Cite

De novo lipogenesis fuels adipocyte autophagosome and lysosome membrane dynamics.

Journal Article Nat Commun · March 13, 2023 Adipocytes robustly synthesize fatty acids (FA) from carbohydrate through the de novo lipogenesis (DNL) pathway, yet surprisingly DNL contributes little to their abundant triglyceride stored in lipid droplets. This conundrum raises the hypothesis that adip ... Full text Link to item Cite

Fitm2 is required for ER homeostasis and normal function of murine liver.

Journal Article J Biol Chem · March 2023 The endoplasmic reticulum (ER)-resident protein fat storage-inducing transmembrane protein 2 (FIT2) catalyzes acyl-CoA cleavage in vitro and is required for ER homeostasis and normal lipid storage in cells. The gene encoding FIT2 is essential for the viabi ... Full text Link to item Cite

Branched-chain α-keto acids and glutamate/glutamine: Biomarkers of insulin resistance in childhood obesity.

Journal Article Endocrinol Diabetes Metab · January 2023 OBJECTIVES: Insulin resistance (IR) in adolescents with obesity is associated with a sex-dependent metabolic 'signature' comprising the branched-chain amino acids (BCAAs), glutamate/glutamine, C3/C5 acylcarnitines and uric acid. Here, we compared the level ... Full text Link to item Cite

Tryptophan Metabolism and Neurodegeneration: Longitudinal Associations of Kynurenine Pathway Metabolites with Cognitive Performance and Plasma Alzheimer's Disease and Related Dementias Biomarkers in the Duke Physical Performance Across the LifeSpan Study.

Journal Article J Alzheimers Dis · 2023 BACKGROUND: The kynurenine pathway (KP) comprises a family of tryptophan-derived metabolites that some studies have reported are associated with poorer cognitive performance and an increased risk of Alzheimer's disease and related dementias (ADRD). OBJECTI ... Full text Open Access Link to item Cite

KLF15 controls brown adipose tissue transcriptional flexibility and metabolism in response to various energetic demands.

Journal Article iScience · November 18, 2022 Brown adipose tissue (BAT) is a specialized metabolic organ responsible for non-shivering thermogenesis. Recently, its activity has been shown to be critical in systemic metabolic health through its utilization and consumption of macronutrients. In the fac ... Full text Link to item Cite

A Randomized Controlled Trial of Mobile Health Intervention in Patients With Heart Failure and Diabetes.

Journal Article J Card Fail · November 2022 BACKGROUND: Mobile health (mHealth) platforms can affect health behaviors but have not been rigorously tested in randomized trials. OBJECTIVES: We sought to evaluate the effectiveness of a pragmatic mHealth intervention in patients with heart failure (HF) ... Full text Link to item Cite

Maternal Exercise and Paternal Exercise Induce Distinct Metabolite Signatures in Offspring Tissues.

Journal Article Diabetes · October 1, 2022 That maternal and paternal exercise improve the metabolic health of adult offspring is well established. Tissue and serum metabolites play a fundamental role in the health of an organism, but how parental exercise affects offspring tissue and serum metabol ... Full text Link to item Cite

Tirzepatide induces a thermogenic-like amino acid signature in brown adipose tissue.

Journal Article Mol Metab · October 2022 OBJECTIVES: Tirzepatide, a dual GIP and GLP-1 receptor agonist, delivered superior glycemic control and weight loss compared to selective GLP-1 receptor (GLP-1R) agonism in patients with type 2 diabetes (T2D). These results have fueled mechanistic studies ... Full text Link to item Cite

Paradoxical activation of transcription factor SREBP1c and de novo lipogenesis by hepatocyte-selective ATP-citrate lyase depletion in obese mice.

Journal Article J Biol Chem · October 2022 Hepatic steatosis associated with high-fat diet, obesity, and type 2 diabetes is thought to be the major driver of severe liver inflammation, fibrosis, and cirrhosis. Cytosolic acetyl CoA (AcCoA), a central metabolite and substrate for de novo lipogenesis ... Full text Link to item Cite

In vivo metabolic imaging identifies lipid vulnerability in a preclinical model of Her2+/Neu breast cancer residual disease and recurrence.

Journal Article NPJ Breast Cancer · September 26, 2022 Recurrent cancer cells that evade therapy is a leading cause of death in breast cancer patients. This risk is high for women showing an overexpression of human epidermal growth factor receptor 2 (Her2). Cells that persist can rely on different substrates f ... Full text Link to item Cite

Metabolomic Profiling of the Effects of Dapagliflozin in Heart Failure With Reduced Ejection Fraction: DEFINE-HF.

Journal Article Circulation · September 13, 2022 BACKGROUND: Sodium-glucose cotransporter-2 inhibitors are foundational therapy in patients with heart failure with reduced ejection fraction (HFrEF), but underlying mechanisms of benefit are not well defined. We sought to investigate the relationships betw ... Full text Link to item Cite

Altered branched-chain α-keto acid metabolism is a feature of NAFLD in individuals with severe obesity.

Journal Article JCI Insight · August 8, 2022 Hepatic de novo lipogenesis is influenced by the branched-chain α-keto acid dehydrogenase (BCKDH) kinase (BCKDK). Here, we aimed to determine whether circulating levels of the immediate substrates of BCKDH, the branched-chain α-keto acids (BCKAs), and hepa ... Full text Link to item Cite

A precision medicine approach to stress testing using metabolomics and microribonucleic acids.

Journal Article Per Med · July 2022 Both transcriptomics and metabolomics hold promise for identifying acute coronary syndrome (ACS) but they have not been used in combination, nor have dynamic changes in levels been assessed as a diagnostic tool. We assessed integrated analysis of periphera ... Full text Link to item Cite

A Multidimensional Bioinformatic Platform for the Study of Human Response to Surgery.

Journal Article Ann Surg · June 1, 2022 OBJECTIVE: To design and establish a prospective biospecimen repository that integrates multi-omics assays with clinical data to study mechanisms of controlled injury and healing. BACKGROUND: Elective surgery is an opportunity to understand both the system ... Full text Link to item Cite

Statin therapy inhibits fatty acid synthase via dynamic protein modifications.

Journal Article Nat Commun · May 10, 2022 Statins are a class of drug widely prescribed for the prevention of cardiovascular disease, with pleiotropic cellular effects. Statins inhibit HMG-CoA reductase (HMGCR), which converts the metabolite HMG-CoA into mevalonate. Recent discoveries have shown H ... Full text Link to item Cite

Metabolomics analysis identifies a lipidomic profile in treatment-naïve juvenile dermatomyositis patients vs healthy control subjects.

Journal Article Rheumatology (Oxford) · April 11, 2022 OBJECTIVES: To perform an exploratory study to identify a JDM serum metabolic profile that differs from healthy controls (HCs) and responds to immunosuppressive treatment. METHODS: Blood was collected from 9 HCs and 10 patients diagnosed with probable (n = ... Full text Link to item Cite

Deglutarylation of glutaryl-CoA dehydrogenase by deacylating enzyme SIRT5 promotes lysine oxidation in mice.

Journal Article J Biol Chem · April 2022 A wide range of protein acyl modifications has been identified on enzymes across various metabolic processes; however, the impact of these modifications remains poorly understood. Protein glutarylation is a recently identified modification that can be none ... Full text Link to item Cite

Nicotinamide riboside supplementation confers marginal metabolic benefits in obese mice without remodeling the muscle acetyl-proteome.

Journal Article iScience · January 21, 2022 Nicotinamide riboside supplements (NRS) have been touted as a nutraceutical that promotes cardiometabolic and musculoskeletal health by enhancing nicotinamide adenine dinucleotide (NAD+) biosynthesis, mitochondrial function, and/or the activities of NAD-de ... Full text Link to item Cite

Evaluating immune response and metabolic related biomarkers pre-allogenic hematopoietic stem cell transplant in acute myeloid leukemia.

Journal Article PLoS One · 2022 Although hematopoietic stem cell transplantation (HCT) is the only curative treatment for acute myeloid leukemia (AML), it is associated with significant treatment related morbidity and mortality. There is great need for predictive biomarkers associated wi ... Full text Link to item Cite

Ildr1 gene deletion protects against diet-induced obesity and hyperglycemia.

Journal Article PLoS One · 2022 OBJECTIVE: Immunoglobulin-like Domain-Containing Receptor 1 (ILDR1) is expressed on nutrient sensing cholecystokinin-positive enteroendocrine cells of the gastrointestinal tract and it has the unique ability to induce fat-mediated CCK secretion. However, t ... Full text Link to item Cite

Urine tricarboxylic acid cycle signatures of early-stage diabetic kidney disease.

Journal Article Metabolomics · December 20, 2021 INTRODUCTION: Urine tricarboxylic acid (TCA) cycle organic anions (OAs) are elevated in diabetes and may be biomarkers for diabetic kidney disease (DKD) progression. OBJECTIVES: We assessed associations of 10 urine TCA cycle OAs with estimated glomerular f ... Full text Open Access Link to item Cite

NADH inhibition of SIRT1 links energy state to transcription during time-restricted feeding.

Journal Article Nat Metab · December 2021 In mammals, circadian rhythms are entrained to the light cycle and drive daily oscillations in levels of NAD+, a cosubstrate of the class III histone deacetylase sirtuin 1 (SIRT1) that associates with clock transcription factors. Although NAD+ also partici ... Full text Link to item Cite

Maternal Metabolites Associated With Gestational Diabetes Mellitus and a Postpartum Disorder of Glucose Metabolism.

Journal Article J Clin Endocrinol Metab · October 21, 2021 CONTEXT: Gestational diabetes is associated with a long-term risk of developing a disorder of glucose metabolism. However, neither the metabolic changes characteristic of gestational diabetes in a large, multi-ancestry cohort nor the ability of metabolic c ... Full text Link to item Cite

Transmethylamine-N-Oxide Is Associated With Diffuse Cardiac Fibrosis in People Living With HIV.

Journal Article J Am Heart Assoc · August 17, 2021 Background People living with HIV are at increased risk of developing diastolic dysfunction, heart failure, and sudden cardiac death, all of which have been characterized by higher levels of myocardial fibrosis. Transmethylamine-N-oxide (TMAO), a dietary g ... Full text Link to item Cite

Circulating long chain acylcarnitines and outcomes in diabetic heart failure: an HF-ACTION clinical trial substudy.

Journal Article Cardiovasc Diabetol · August 3, 2021 BACKGROUND: Whether differences in circulating long chain acylcarnitines (LCAC) are seen in heart failure (HF) patients with and without diabetes mellitus (DM), and whether these biomarkers report on exercise capacity and clinical outcomes, remains unknown ... Full text Link to item Cite

BCAA Supplementation in Mice with Diet-induced Obesity Alters the Metabolome Without Impairing Glucose Homeostasis.

Journal Article Endocrinology · July 1, 2021 Circulating branched chain amino acid (BCAA) levels are elevated in obese humans and genetically obese rodents. However, the relationship of BCAAs to insulin resistance in diet-induced obese mice, a commonly used model to study glucose homeostasis, is stil ... Full text Link to item Cite

Impact of lifestyle Intervention on branched-chain amino acid catabolism and insulin sensitivity in adolescents with obesity.

Journal Article Endocrinol Diabetes Metab · July 2021 UNLABELLED: Insulin resistance in adolescents with obesity associates with a sex-dependent metabolic 'signature' comprising branched-chain amino acids (BCAAs), glutamate and C3/C5 acylcarnitines (C3/C5), implicating altered flux through BCAA catabolic path ... Full text Link to item Cite

Effect of Bicarbonate on Net Acid Excretion, Blood Pressure, and Metabolism in Patients With and Without CKD: The Acid Base Compensation in CKD Study.

Journal Article Am J Kidney Dis · July 2021 RATIONALE & OBJECTIVE: Patients with CKD are at elevated risk of metabolic acidosis due to impaired net acid excretion (NAE). Identifying early markers of acidosis may guide prevention in chronic kidney disease (CKD). This study compared NAE in participant ... Full text Link to item Cite

Early-life mitochondrial DNA damage results in lifelong deficits in energy production mediated by redox signaling in Caenorhabditis elegans.

Journal Article Redox Biol · July 2021 The consequences of damage to the mitochondrial genome (mtDNA) are poorly understood, although mtDNA is more susceptible to damage resulting from some genotoxicants than nuclear DNA (nucDNA), and many environmental toxicants target the mitochondria. Report ... Full text Link to item Cite

Feeding diversified protein sources exacerbates hepatic insulin resistance via increased gut microbial branched-chain fatty acids and mTORC1 signaling in obese mice.

Journal Article Nat Commun · June 7, 2021 Animal models of human diseases are classically fed purified diets that contain casein as the unique protein source. We show that provision of a mixed protein source mirroring that found in the western diet exacerbates diet-induced obesity and insulin resi ... Full text Link to item Cite

Gut microbiome contributions to altered metabolism in a pig model of undernutrition.

Journal Article Proc Natl Acad Sci U S A · May 25, 2021 The concept that gut microbiome-expressed functions regulate ponderal growth has important implications for infant and child health, as well as animal health. Using an intergenerational pig model of diet restriction (DR) that produces reduced weight gain, ... Full text Link to item Cite

Urine and Plasma Metabolome of Healthy Adults Consuming the DASH (Dietary Approaches to Stop Hypertension) Diet: A Randomized Pilot Feeding Study.

Journal Article Nutrients · May 22, 2021 We aimed to identify plasma and urine metabolites altered by the Dietary Approaches to Stop Hypertension (DASH) diet in a post-hoc analysis of a pilot feeding trial. Twenty adult participants with un-medicated hypertension consumed a Control diet for one w ... Full text Link to item Cite

Branched-chain α-ketoacids are preferentially reaminated and activate protein synthesis in the heart.

Journal Article Nat Commun · March 15, 2021 Branched-chain amino acids (BCAA) and their cognate α-ketoacids (BCKA) are elevated in an array of cardiometabolic diseases. Here we demonstrate that the major metabolic fate of uniformly-13C-labeled α-ketoisovalerate ([U-13C]KIV) in the heart is reaminati ... Full text Link to item Cite

The Pediatric Obesity Microbiome and Metabolism Study (POMMS): Methods, Baseline Data, and Early Insights.

Journal Article Obesity (Silver Spring) · March 2021 OBJECTIVE: The purpose of this study was to establish a biorepository of clinical, metabolomic, and microbiome samples from adolescents with obesity as they undergo lifestyle modification. METHODS: A total of 223 adolescents aged 10 to 18 years with BMI ≥9 ... Full text Open Access Link to item Cite

Metabolites and diabetes remission after weight loss.

Journal Article Nutr Diabetes · February 24, 2021 There is marked heterogeneity in the response to weight loss interventions with regards to weight loss amount and metabolic improvement. We sought to identify biomarkers predictive of type 2 diabetes remission and amount of weight loss in individuals with ... Full text Link to item Cite

Muscle Krüppel-like factor 15 regulates lipid flux and systemic metabolic homeostasis.

Journal Article J Clin Invest · February 15, 2021 Skeletal muscle is a major determinant of systemic metabolic homeostasis that plays a critical role in glucose metabolism and insulin sensitivity. By contrast, despite being a major user of fatty acids, and evidence that muscular disorders can lead to abno ... Full text Link to item Cite

Multiple metabolic changes mediate the response of Caenorhabditis elegans to the complex I inhibitor rotenone.

Journal Article Toxicology · January 15, 2021 Rotenone, a mitochondrial complex I inhibitor, has been widely used to study the effects of mitochondrial dysfunction on dopaminergic neurons in the context of Parkinson's disease. Although the deleterious effects of rotenone are well documented, we found ... Full text Link to item Cite

A phase 2 trial of the somatostatin analog pasireotide to prevent GI toxicity and acute GVHD in allogeneic hematopoietic stem cell transplant.

Journal Article PLoS One · 2021 BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HCT) is an often curative intent treatment, however it is associated with significant gastrointestinal (GI) toxicity and treatment related mortality. Graft-versus-host disease is a significant ... Full text Link to item Cite

Branched-Chain Amino Acid Catabolism and Cardiopulmonary Function Following Acute Maximal Exercise Testing in Adolescents.

Journal Article Front Cardiovasc Med · 2021 Background: To provide energy for cardiopulmonary function and maintenance of blood glucose, acute aerobic exercise induces lipolysis, fatty acid oxidation (FAO), glycolysis, and glycogenolysis/gluconeogenesis. These adaptations are mediated by increases i ... Full text Link to item Cite

Metabolic and physiological effects of high intensity interval training in patients with knee osteoarthritis: A pilot and feasibility study.

Journal Article Osteoarthr Cartil Open · December 2020 OBJECTIVE: To examine the feasibility of a 6-week high intensity interval training (HIIT) program in patients with symptomatic knee osteoarthritis (OA). A secondary aim was to evaluate the change in whole-body metabolism. DESIGN: In a single-arm interventi ... Full text Link to item Cite

Muscle-Liver Trafficking of BCAA-Derived Nitrogen Underlies Obesity-Related Glycine Depletion.

Journal Article Cell Rep · November 10, 2020 Glycine levels are inversely associated with branched-chain amino acids (BCAAs) and cardiometabolic disease phenotypes, but biochemical mechanisms that explain these relationships remain uncharted. Metabolites and genes related to BCAA metabolism and nitro ... Full text Link to item Cite

Nutritional modulation of heart failure in mitochondrial pyruvate carrier-deficient mice.

Journal Article Nat Metab · November 2020 The myocardium is metabolically flexible; however, impaired flexibility is associated with cardiac dysfunction in conditions including diabetes and heart failure. The mitochondrial pyruvate carrier (MPC) complex, composed of MPC1 and MPC2, is required for ... Full text Link to item Cite

FIT2 is an acyl-coenzyme A diphosphatase crucial for endoplasmic reticulum homeostasis.

Journal Article J Cell Biol · October 5, 2020 The endoplasmic reticulum is a cellular hub of lipid metabolism, coordinating lipid synthesis with continuous changes in metabolic flux. Maintaining ER lipid homeostasis despite these fluctuations is crucial to cell function and viability. Here, we identif ... Full text Link to item Cite

Biomarkers Associated with Physical Resilience After Hip Fracture.

Journal Article J Gerontol A Biol Sci Med Sci · September 25, 2020 BACKGROUND: Clinically similar older adults demonstrate variable responses to health stressors, heterogeneity attributable to differences in physical resilience. However, molecular mechanisms underlying physical resilience are unknown. We previously derive ... Full text Link to item Cite

Metabolomic and genetic associations with insulin resistance in pregnancy.

Journal Article Diabetologia · September 2020 AIMS/HYPOTHESIS: Our study aimed to integrate maternal metabolic and genetic data related to insulin sensitivity during pregnancy to provide novel insights into mechanisms underlying pregnancy-induced insulin resistance. METHODS: Fasting and 1 h serum samp ... Full text Link to item Cite

Molecular Transducers of Physical Activity Consortium (MoTrPAC): Mapping the Dynamic Responses to Exercise.

Journal Article Cell · June 25, 2020 Exercise provides a robust physiological stimulus that evokes cross-talk among multiple tissues that when repeated regularly (i.e., training) improves physiological capacity, benefits numerous organ systems, and decreases the risk for premature mortality. ... Full text Link to item Cite

Preliminary evidence of effects of potassium chloride on a metabolomic path to diabetes and cardiovascular disease.

Journal Article Metabolomics · June 18, 2020 INTRODUCTION: Low potassium intake can affect cardiovascular disease (CVD) risk and cardiometabolic risk factors. OBJECTIVE: We hypothesize that potassium chloride (KCl) supplementation can improve cardiovascular risk metabolomic profile. METHODS: In this ... Full text Link to item Cite

Macrophage Metabolism of Apoptotic Cell-Derived Arginine Promotes Continual Efferocytosis and Resolution of Injury.

Journal Article Cell Metab · March 3, 2020 Continual efferocytic clearance of apoptotic cells (ACs) by macrophages prevents necrosis and promotes injury resolution. How continual efferocytosis is promoted is not clear. Here, we show that the process is optimized by linking the metabolism of engulfe ... Full text Link to item Cite

TASK-1 and TASK-3 channels modulate pressure overload-induced cardiac remodeling and dysfunction.

Journal Article Am J Physiol Heart Circ Physiol · March 1, 2020 Tandem pore domain acid-sensitive K+ (TASK) channels are present in cardiac tissue; however, their contribution to cardiac pathophysiology is not well understood. Here, we investigate the role of TASK-1 and TASK-3 in the pathogenesis of cardiac dysfunction ... Full text Link to item Cite

Dietary branched-chain amino acid restriction alters fuel selection and reduces triglyceride stores in hearts of Zucker fatty rats.

Journal Article Am J Physiol Endocrinol Metab · February 1, 2020 Elevations in circulating levels of branched-chain amino acids (BCAAs) are associated with a variety of cardiometabolic diseases and conditions. Restriction of dietary BCAAs in rodent models of obesity lowers circulating BCAA levels and improves whole-anim ... Full text Link to item Cite

SIRT6 Promotes Hepatic Beta-Oxidation via Activation of PPARα.

Journal Article Cell Rep · December 17, 2019 The pro-longevity enzyme SIRT6 regulates various metabolic pathways. Gene expression analyses in SIRT6 heterozygotic mice identify significant decreases in PPARα signaling, known to regulate multiple metabolic pathways. SIRT6 binds PPARα and its response e ... Full text Link to item Cite

Cord Blood Metabolomics: Association With Newborn Anthropometrics and C-Peptide Across Ancestries.

Journal Article J Clin Endocrinol Metab · October 1, 2019 CONTEXT: Newborn adiposity is associated with childhood obesity. Cord blood metabolomics is one approach that can be used to understand early-life contributors to adiposity and insulin resistance. OBJECTIVE: To determine the association of cord blood metab ... Full text Link to item Cite

Dietary Sugars Alter Hepatic Fatty Acid Oxidation via Transcriptional and Post-translational Modifications of Mitochondrial Proteins.

Journal Article Cell Metab · October 1, 2019 Dietary sugars, fructose and glucose, promote hepatic de novo lipogenesis and modify the effects of a high-fat diet (HFD) on the development of insulin resistance. Here, we show that fructose and glucose supplementation of an HFD exert divergent effects on ... Full text Link to item Cite

BCAA catabolism in brown fat controls energy homeostasis through SLC25A44.

Journal Article Nature · August 2019 Branched-chain amino acid (BCAA; valine, leucine and isoleucine) supplementation is often beneficial to energy expenditure; however, increased circulating levels of BCAA are linked to obesity and diabetes. The mechanisms of this paradox remain unclear. Her ... Full text Link to item Cite

Modification of messenger RNA by 2'-O-methylation regulates gene expression in vivo.

Journal Article Nat Commun · July 30, 2019 Epitranscriptomic modifications of mRNA are important regulators of gene expression. While internal 2'-O-methylation (Nm) has been discovered on mRNA, questions remain about its origin and function in cells and organisms. Here, we show that internal Nm mod ... Full text Open Access Link to item Cite

Effects of microbiota-directed foods in gnotobiotic animals and undernourished children.

Journal Article Science · July 12, 2019 To examine the contributions of impaired gut microbial community development to childhood undernutrition, we combined metabolomic and proteomic analyses of plasma samples with metagenomic analyses of fecal samples to characterize the biological state of Ba ... Full text Link to item Cite

Cellular energetics and mitochondrial uncoupling in canine aging.

Journal Article Geroscience · April 2019 The first domesticated companion animal, the dog, is currently represented by over 190 unique breeds. Across these numerous breeds, dogs have exceptional variation in lifespan (inversely correlated with body size), presenting an opportunity to discover lon ... Full text Link to item Cite

Maternal metabolites during pregnancy are associated with newborn outcomes and hyperinsulinaemia across ancestries.

Journal Article Diabetologia · March 2019 AIMS/HYPOTHESIS: We aimed to determine the association of maternal metabolites with newborn adiposity and hyperinsulinaemia in a multi-ethnic cohort of mother-newborn dyads. METHODS: Targeted and non-targeted metabolomics assays were performed on fasting a ... Full text Link to item Cite

Age-Related Adverse Inflammatory and Metabolic Changes Begin Early in Adulthood.

Journal Article J Gerontol A Biol Sci Med Sci · February 15, 2019 Aging is characterized by deleterious immune and metabolic changes, but the onset of these changes is unknown. We measured immune and metabolic biomarkers in adults beginning at age 30. To our knowledge, this is the first study to evaluate these biomarkers ... Full text Open Access Link to item Cite

Respiratory Phenomics across Multiple Models of Protein Hyperacylation in Cardiac Mitochondria Reveals a Marginal Impact on Bioenergetics.

Journal Article Cell Rep · February 5, 2019 Acyl CoA metabolites derived from the catabolism of carbon fuels can react with lysine residues of mitochondrial proteins, giving rise to a large family of post-translational modifications (PTMs). Mass spectrometry-based detection of thousands of acyl-PTMs ... Full text Link to item Cite

A Mitochondrial Progesterone Receptor Increases Cardiac Beta-Oxidation and Remodeling.

Journal Article J Endocr Soc · February 1, 2019 Progesterone is primarily a pregnancy-related hormone, produced in substantial quantities after ovulation and during gestation. Traditionally known to function via nuclear receptors for transcriptional regulation, there is also evidence of nonnuclear actio ... Full text Open Access Link to item Cite

Plasma MicroRNAs in Established Rheumatoid Arthritis Relate to Adiposity and Altered Plasma and Skeletal Muscle Cytokine and Metabolic Profiles.

Journal Article Front Immunol · 2019 Background: MicroRNAs have been implicated in the pathogenesis of rheumatoid arthritis (RA), obesity, and altered metabolism. Although RA is associated with both obesity and altered metabolism, expression of RA-related microRNA in the setting of these card ... Full text Link to item Cite

Type-2-Diabetes Alters CSF but Not Plasma Metabolomic and AD Risk Profiles in Vervet Monkeys.

Journal Article Front Neurosci · 2019 Epidemiological studies suggest that individuals with type 2 diabetes (T2D) have a twofold to fourfold increased risk for developing Alzheimer's disease (AD), however, the exact mechanisms linking the two diseases are unknown. In both conditions, the major ... Full text Link to item Cite

Cord Blood Metabolites Associated with Newborn Adiposity and Hyperinsulinemia.

Journal Article J Pediatr · December 2018 OBJECTIVE: To evaluate the association between cord blood amino acid and acylcarnitine profiles and measures of adiposity and hyperinsulinemia in healthy newborns. STUDY DESIGN: A cross-sectional study of 118 full-term infants born to mothers without gesta ... Full text Link to item Cite

Adverse Effects of Fenofibrate in Mice Deficient in the Protein Quality Control Regulator, CHIP.

Journal Article J Cardiovasc Dev Dis · August 15, 2018 We previously reported how the loss of CHIP expression (Carboxyl terminus of Hsc70-Interacting Protein) during pressure overload resulted in robust cardiac dysfunction, which was accompanied by a failure to maintain ATP levels in the face of increased ener ... Full text Link to item Cite

Improvement in insulin resistance after gastric bypass surgery is correlated with a decline in plasma 2-hydroxybutyric acid.

Journal Article Surg Obes Relat Dis · August 2018 BACKGROUND: Gastric bypass surgery for weight reduction often corrects dysglycemia in diabetic patients, but a full understanding of the underlying biochemical pathways continues to be investigated. OBJECTIVES: To explore the effects of weight loss by surg ... Full text Link to item Cite

N6-methyladenosine contributes to cellular phenotype in a genetically-defined model of breast cancer progression.

Journal Article Oncotarget · July 27, 2018 The mRNA modification N6-methyladenosine (m6A) is involved in many post-transcriptional regulatory processes including mRNA stability and translational efficiency. However, it is also imperative to correlate these processes with phenotypic outputs during c ... Full text Link to item Cite

Remodeling of the Acetylproteome by SIRT3 Manipulation Fails to Affect Insulin Secretion or β Cell Metabolism in the Absence of Overnutrition.

Journal Article Cell Rep · July 3, 2018 SIRT3 is a nicotinamide adenine dinucleotide (NAD+)-dependent mitochondrial protein deacetylase purported to influence metabolism through post-translational modification of metabolic enzymes. Fuel-stimulated insulin secretion, which involves mitochondrial ... Full text Link to item Cite

Dietary Patterns among Asian Indians Living in the United States Have Distinct Metabolomic Profiles That Are Associated with Cardiometabolic Risk.

Journal Article J Nutr · July 1, 2018 BACKGROUND: Recent studies, primarily in non-Hispanic whites, suggest that dietary patterns have distinct metabolomic signatures that may influence disease risk. However, evidence in South Asians, a group with unique dietary patterns and a high prevalence ... Full text Open Access Link to item Cite

The BCKDH Kinase and Phosphatase Integrate BCAA and Lipid Metabolism via Regulation of ATP-Citrate Lyase.

Journal Article Cell Metab · June 5, 2018 Branched-chain amino acids (BCAA) are strongly associated with dysregulated glucose and lipid metabolism, but the underlying mechanisms are poorly understood. We report that inhibition of the kinase (BDK) or overexpression of the phosphatase (PPM1K) that r ... Full text Link to item Cite

Physiological mechanisms of sustained fumagillin-induced weight loss.

Journal Article JCI Insight · March 8, 2018 Current obesity interventions suffer from lack of durable effects and undesirable complications. Fumagillin, an inhibitor of methionine aminopeptidase-2, causes weight loss by reducing food intake, but with effects on weight that are superior to pair-feedi ... Full text Link to item Cite

Metabolites predict cardiovascular disease events in persons living with HIV: a pilot case-control study.

Journal Article Metabolomics · March 2018 INTRODUCTION: Persons living with HIV (PLWH) are at higher risk for cardiovascular disease (CVD) events than uninfected persons. Current risk-stratification methods to define PLWH at highest risk for CVD events are lacking. METHODS: Using tandem flow injec ... Full text Link to item Cite

Kruppel-like factor 15 is required for the cardiac adaptive response to fasting.

Journal Article PLoS One · 2018 Cardiac metabolism is highly adaptive in response to changes in substrate availability, as occur during fasting. This metabolic flexibility is essential to the maintenance of contractile function and is under the control of a group of select transcriptiona ... Full text Link to item Cite

Temporal dynamics of liver mitochondrial protein acetylation and succinylation and metabolites due to high fat diet and/or excess glucose or fructose.

Journal Article PLoS One · 2018 Dietary macronutrient composition alters metabolism through several mechanisms, including post-translational modification (PTM) of proteins. To connect diet and molecular changes, here we performed short- and long-term feeding of mice with standard chow di ... Full text Link to item Cite

Metabolomic analysis of insulin resistance across different mouse strains and diets.

Journal Article J Biol Chem · November 24, 2017 Insulin resistance is a major risk factor for many diseases. However, its underlying mechanism remains unclear in part because it is triggered by a complex relationship between multiple factors, including genes and the environment. Here, we used metabolomi ... Full text Link to item Cite

Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling.

Journal Article J Clin Invest · November 1, 2017 Overconsumption of high-fat diet (HFD) and sugar-sweetened beverages are risk factors for developing obesity, insulin resistance, and fatty liver disease. Here we have dissected mechanisms underlying this association using mice fed either chow or HFD with ... Full text Link to item Cite

Perinatal western-type diet and associated gestational weight gain alter postpartum maternal mood.

Journal Article Brain Behav · October 2017 INTRODUCTION: The role of perinatal diet in postpartum maternal mood disorders, including depression and anxiety, remains unclear. We investigated whether perinatal consumption of a Western-type diet (high in fat and branched-chain amino acids [BCAA]) and ... Full text Link to item Cite

N6-methyladenosine is required for the hypoxic stabilization of specific mRNAs.

Journal Article RNA · September 2017 Post-transcriptional regulation of mRNA during oxygen deprivation, or hypoxia, can affect the survivability of cells. Hypoxia has been shown to increase stability of a subset of ischemia-related mRNAs, including VEGF. RNA binding proteins and miRNAs have b ... Full text Link to item Cite

Sildenafil Treatment in Heart Failure With Preserved Ejection Fraction: Targeted Metabolomic Profiling in the RELAX Trial.

Journal Article JAMA Cardiol · August 1, 2017 IMPORTANCE: Phosphodiesterase-5 inhibition with sildenafil compared with a placebo had no effect on the exercise capacity or clinical status of patients with heart failure with preserved ejection fraction (HFpEF) in the PhosphodiesteRasE-5 Inhibition to Im ... Full text Link to item Cite

Targeted Metabolomics Demonstrates Distinct and Overlapping Maternal Metabolites Associated With BMI, Glucose, and Insulin Sensitivity During Pregnancy Across Four Ancestry Groups.

Journal Article Diabetes Care · July 2017 OBJECTIVE: We used targeted metabolomics in pregnant mothers to compare maternal metabolite associations with maternal BMI, glycemia, and insulin sensitivity. RESEARCH DESIGN AND METHODS: Targeted metabolomic assays of clinical metabolites, amino acids, an ... Full text Link to item Cite

Maternal BMI and Glycemia Impact the Fetal Metabolome.

Journal Article Diabetes Care · July 2017 OBJECTIVE: We used targeted metabolomics to determine associations of maternal BMI and glucose levels with cord blood metabolites and associations of cord blood metabolites with newborn birth weight and adiposity in mother-offspring dyads. RESEARCH DESIGN ... Full text Link to item Cite

Interrupted Glucagon Signaling Reveals Hepatic α Cell Axis and Role for L-Glutamine in α Cell Proliferation.

Journal Article Cell Metab · June 6, 2017 Decreasing glucagon action lowers the blood glucose and may be useful therapeutically for diabetes. However, interrupted glucagon signaling leads to α cell proliferation. To identify postulated hepatic-derived circulating factor(s) responsible for α cell p ... Full text Link to item Cite

SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion.

Journal Article Cell Metab · April 4, 2017 Sirtuins are NAD+-dependent protein deacylases that regulate several aspects of metabolism and aging. In contrast to the other mammalian sirtuins, the primary enzymatic activity of mitochondrial sirtuin 4 (SIRT4) and its overall role in metabolic control h ... Full text Link to item Cite

A Class of Reactive Acyl-CoA Species Reveals the Non-enzymatic Origins of Protein Acylation.

Journal Article Cell Metab · April 4, 2017 The mechanisms underlying the formation of acyl protein modifications remain poorly understood. By investigating the reactivity of endogenous acyl-CoA metabolites, we found a class of acyl-CoAs that undergo intramolecular catalysis to form reactive interme ... Full text Link to item Cite

Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages.

Journal Article J Biol Chem · March 17, 2017 The immunity-related GTPases (IRGs) are a family of proteins that are induced by interferon (IFN)-γ and play pivotal roles in immune and inflammatory responses. IRGs ostensibly function as dynamin-like proteins that bind to intracellular membranes and prom ... Full text Link to item Cite

Associations of maternal BMI and insulin resistance with the maternal metabolome and newborn outcomes.

Journal Article Diabetologia · March 2017 AIMS/HYPOTHESIS: Maternal obesity increases the risk for large-for-gestational-age birth and excess newborn adiposity, which are associated with adverse long-term metabolic outcomes in offspring, probably due to effects mediated through the intrauterine en ... Full text Link to item Cite

Plasma acylcarnitines are associated with pulmonary hypertension.

Journal Article Pulm Circ · March 2017 Quantifying metabolic derangements in pulmonary hypertension (PH) by plasma metabolomics could identify biomarkers useful for diagnosis and treatment. The objective of this paper is to test the hypotheses that circulating metabolites are differentially exp ... Full text Link to item Cite

Mixture model normalization for non-targeted gas chromatography/mass spectrometry metabolomics data.

Journal Article BMC Bioinformatics · February 2, 2017 BACKGROUND: Metabolomics offers a unique integrative perspective for health research, reflecting genetic and environmental contributions to disease-related phenotypes. Identifying robust associations in population-based or large-scale clinical studies dema ... Full text Link to item Cite

Prior Dietary Practices and Connections to a Human Gut Microbial Metacommunity Alter Responses to Diet Interventions.

Journal Article Cell Host Microbe · January 11, 2017 Ensuring that gut microbiota respond consistently to prescribed dietary interventions, irrespective of prior dietary practices (DPs), is critical for effective nutritional therapy. To address this, we identified DP-associated gut bacterial taxa in individu ... Full text Link to item Cite

HIV-1 Envelope Mimicry of Host Enzyme Kynureninase Does Not Disrupt Tryptophan Metabolism.

Journal Article J Immunol · December 15, 2016 The HIV-1 envelope protein (Env) has evolved to subvert the host immune system, hindering viral control by the host. The tryptophan metabolic enzyme kynureninase (KYNU) is mimicked by a portion of the HIV Env gp41 membrane proximal region (MPER) and is cro ... Full text Link to item Cite

Enhanced GLUT4-Dependent Glucose Transport Relieves Nutrient Stress in Obese Mice Through Changes in Lipid and Amino Acid Metabolism.

Journal Article Diabetes · December 2016 Impaired GLUT4-dependent glucose uptake is a contributing factor in the development of whole-body insulin resistance in obese patients and obese animal models. Previously, we demonstrated that transgenic mice engineered to express the human GLUT4 gene unde ... Full text Link to item Cite

Effects of a gut pathobiont in a gnotobiotic mouse model of childhood undernutrition.

Journal Article Sci Transl Med · November 23, 2016 To model how interactions among enteropathogens and gut microbial community members contribute to undernutrition, we colonized gnotobiotic mice fed representative Bangladeshi diets with sequenced bacterial strains cultured from the fecal microbiota of two ... Full text Link to item Cite

N6-Methyladenosine in Flaviviridae Viral RNA Genomes Regulates Infection.

Journal Article Cell Host Microbe · November 9, 2016 The RNA modification N6-methyladenosine (m6A) post-transcriptionally regulates RNA function. The cellular machinery that controls m6A includes methyltransferases and demethylases that add or remove this modification, as well as m6A-binding YTHDF proteins t ... Full text Link to item Cite

Arsenite Uncouples Mitochondrial Respiration and Induces a Warburg-Like Effect in Caenorhabditis elegans.

Journal Article Toxicol Sci · November 2016 Full text Link to item Cite

Lipids Reprogram Metabolism to Become a Major Carbon Source for Histone Acetylation.

Journal Article Cell Rep · November 1, 2016 Cells integrate nutrient sensing and metabolism to coordinate proper cellular responses to a particular nutrient source. For example, glucose drives a gene expression program characterized by activating genes involved in its metabolism, in part by increasi ... Full text Link to item Cite

From the Cover: Arsenite Uncouples Mitochondrial Respiration and Induces a Warburg-like Effect in Caenorhabditis elegans.

Journal Article Toxicol Sci · August 2016 Millions of people worldwide are chronically exposed to arsenic through contaminated drinking water. Despite decades of research studying the carcinogenic potential of arsenic, the mechanisms by which arsenic causes cancer and other diseases remain poorly ... Full text Open Access Link to item Cite

Plasma amino acid concentrations are independently associated with adverse outcomes in heart failure and preserved ejection fraction: prognostic utility of amino acid profiles in HFpEF

Conference European Heart Journal · August 1, 2016 Link to item Cite

Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure.

Journal Article J Am Heart Assoc · July 29, 2016 BACKGROUND: Metabolic impairment is an important contributor to heart failure (HF) pathogenesis and progression. Dysregulated metabolic pathways remain poorly characterized in patients with HF and preserved ejection fraction (HFpEF). We sought to determine ... Full text Open Access Link to item Cite

Hepatic mTORC1 Opposes Impaired Insulin Action to Control Mitochondrial Metabolism in Obesity.

Journal Article Cell Rep · July 12, 2016 Dysregulated mitochondrial metabolism during hepatic insulin resistance may contribute to pathophysiologies ranging from elevated glucose production to hepatocellular oxidative stress and inflammation. Given that obesity impairs insulin action but paradoxi ... Full text Link to item Cite

Branched-chain amino acid restriction in Zucker-fatty rats improves muscle insulin sensitivity by enhancing efficiency of fatty acid oxidation and acyl-glycine export.

Journal Article Mol Metab · July 2016 OBJECTIVE: A branched-chain amino acid (BCAA)-related metabolic signature is strongly associated with insulin resistance and predictive of incident diabetes and intervention outcomes. To better understand the role that this metabolite cluster plays in obes ... Full text Link to item Cite

Metabolic Networks and Metabolites Underlie Associations Between Maternal Glucose During Pregnancy and Newborn Size at Birth.

Journal Article Diabetes · July 2016 Maternal metabolites and metabolic networks underlying associations between maternal glucose during pregnancy and newborn birth weight and adiposity demand fuller characterization. We performed targeted and nontargeted gas chromatography/mass spectrometry ... Full text Link to item Cite

Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure.

Journal Article Circulation · May 24, 2016 BACKGROUND: Although metabolic reprogramming is critical in the pathogenesis of heart failure, studies to date have focused principally on fatty acid and glucose metabolism. Contribution of amino acid metabolic regulation in the disease remains understudie ... Full text Link to item Cite

Research Resource: Roles for Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CaMKK2) in Systems Metabolism.

Journal Article Mol Endocrinol · May 2016 A number of epidemiological studies have implicated calcium (Ca(2+)) signaling as a major factor in obesity that contributes to aberrant systems metabolism. Somewhat paradoxically, obesity correlates with decreased circulating Ca(2+) levels, leading to inc ... Full text Link to item Cite

Integrated Regulation of Hepatic Lipid and Glucose Metabolism by Adipose Triacylglycerol Lipase and FoxO Proteins.

Journal Article Cell Rep · April 12, 2016 Metabolism is a highly integrated process that is coordinately regulated between tissues and within individual cells. FoxO proteins are major targets of insulin action and contribute to the regulation of gluconeogenesis, glycolysis, and lipogenesis in the ... Full text Link to item Cite

Sialylated Milk Oligosaccharides Promote Microbiota-Dependent Growth in Models of Infant Undernutrition.

Journal Article Cell · February 25, 2016 Identifying interventions that more effectively promote healthy growth of children with undernutrition is a pressing global health goal. Analysis of human milk oligosaccharides (HMOs) from 6-month-postpartum mothers in two Malawian birth cohorts revealed t ... Full text Link to item Cite

The Gut Microbiota Modulates Energy Metabolism in the Hibernating Brown Bear Ursus arctos.

Journal Article Cell Rep · February 23, 2016 Hibernation is an adaptation that helps many animals to conserve energy during food shortage in winter. Brown bears double their fat depots during summer and use these stored lipids during hibernation. Although bears seasonally become obese, they remain me ... Full text Link to item Cite

Prognostic Implications of Long-Chain Acylcarnitines in Heart Failure and Reversibility With Mechanical Circulatory Support.

Journal Article J Am Coll Cardiol · January 26, 2016 BACKGROUND: Heart failure (HF) is characterized by perturbations in energy homeostasis and metabolism. The reversibility and prognostic value of circulating markers associated with these changes remain unclear. OBJECTIVES: This study sought to describe the ... Full text Link to item Cite

The Acetyl Group Buffering Action of Carnitine Acetyltransferase Offsets Macronutrient-Induced Lysine Acetylation of Mitochondrial Proteins.

Journal Article Cell Rep · January 12, 2016 Lysine acetylation (AcK), a posttranslational modification wherein a two-carbon acetyl group binds covalently to a lysine residue, occurs prominently on mitochondrial proteins and has been linked to metabolic dysfunction. An emergent theory suggests mitoch ... Full text Link to item Cite

Metabolic profiling in Prader-Willi syndrome and nonsyndromic obesity: sex differences and the role of growth hormone.

Journal Article Clin Endocrinol (Oxf) · December 2015 OBJECTIVES: To identify metabolic factors controlling appetite and insulin sensitivity in PWS and assess effects of GH treatment. METHODS: We compared amino acids, fatty acids and acylcarnitines in GH-treated and untreated PWS children and obese and lean c ... Full text Open Access Link to item Cite

Impact of combined resistance and aerobic exercise training on branched-chain amino acid turnover, glycine metabolism and insulin sensitivity in overweight humans.

Journal Article Diabetologia · October 2015 AIMS/HYPOTHESES: Obesity is associated with decreased insulin sensitivity (IS) and elevated plasma branched-chain amino acids (BCAAs). The purpose of this study was to investigate the relationship between BCAA metabolism and IS in overweight (OW) individua ... Full text Link to item Cite

Isocitrate-to-SENP1 signaling amplifies insulin secretion and rescues dysfunctional β cells.

Journal Article J Clin Invest · October 1, 2015 Insulin secretion from β cells of the pancreatic islets of Langerhans controls metabolic homeostasis and is impaired in individuals with type 2 diabetes (T2D). Increases in blood glucose trigger insulin release by closing ATP-sensitive K+ channels, depolar ... Full text Link to item Cite

ACLY and ACC1 Regulate Hypoxia-Induced Apoptosis by Modulating ETV4 via α-ketoglutarate.

Journal Article PLoS Genet · October 2015 In order to propagate a solid tumor, cancer cells must adapt to and survive under various tumor microenvironment (TME) stresses, such as hypoxia or lactic acidosis. To systematically identify genes that modulate cancer cell survival under stresses, we perf ... Full text Open Access Link to item Cite

Long-chain Acylcarnitines Reduce Lung Function by Inhibiting Pulmonary Surfactant.

Journal Article J Biol Chem · September 25, 2015 The role of mitochondrial energy metabolism in maintaining lung function is not understood. We previously observed reduced lung function in mice lacking the fatty acid oxidation enzyme long-chain acyl-CoA dehydrogenase (LCAD). Here, we demonstrate that lon ... Full text Link to item Cite

Carnitine Acetyltransferase Mitigates Metabolic Inertia and Muscle Fatigue during Exercise.

Journal Article Cell Metab · July 7, 2015 Acylcarnitine metabolites have gained attention as biomarkers of nutrient stress, but their physiological relevance and metabolic purpose remain poorly understood. Short-chain carnitine conjugates, including acetylcarnitine, derive from their corresponding ... Full text Link to item Cite

Isoprenylcysteine carboxylmethyltransferase regulates mitochondrial respiration and cancer cell metabolism.

Journal Article Oncogene · June 2015 Isoprenylcysteine carboxylmethyltransferase (Icmt) catalyzes the last of the three-step posttranslational protein prenylation process for the so-called CaaX proteins, which includes many signaling proteins, such as most small GTPases. Despite extensive stu ... Full text Link to item Cite

HIF-1 Alpha Regulates the Response of Primary Sarcomas to Radiation Therapy through a Cell Autonomous Mechanism.

Journal Article Radiat Res · June 2015 Hypoxia is a major cause of radiation resistance, which may predispose to local recurrence after radiation therapy. While hypoxia increases tumor cell survival after radiation exposure because there is less oxygen to oxidize damaged DNA, it remains unclear ... Full text Link to item Cite

Muscle-Specific Overexpression of PGC-1α Does Not Augment Metabolic Improvements in Response to Exercise and Caloric Restriction.

Journal Article Diabetes · May 2015 This study used mice with muscle-specific overexpression of PGC-1α, a transcriptional coactivator that promotes mitochondrial biogenesis, to determine whether increased oxidative potential facilitates metabolic improvements in response to lifestyle modific ... Full text Link to item Cite

Metabolomic analysis reveals altered skeletal muscle amino acid and fatty acid handling in obese humans.

Journal Article Obesity (Silver Spring) · May 2015 OBJECTIVE: Investigate the effects of obesity and high-fat diet (HFD) exposure on fatty acid oxidation and TCA cycle intermediates and amino acids in skeletal muscle to better characterize energy metabolism. METHODS: Plasma and skeletal muscle metabolomic ... Full text Link to item Cite

Metabolomic analysis reveals altered skeletal muscle amino acid and fatty acid handling in obese humans

Journal Article Obesity · May 1, 2015 Objective Investigate the effects of obesity and high-fat diet (HFD) exposure on fatty acid oxidation and TCA cycle intermediates and amino acids in skeletal muscle to better characterize energy metabolism. Methods Plasma and skeletal muscle metabolomic pr ... Full text Cite

CAPER is vital for energy and redox homeostasis by integrating glucose-induced mitochondrial functions via ERR-α-Gabpa and stress-induced adaptive responses via NF-κB-cMYC.

Journal Article PLoS Genet · April 2015 Ever since we developed mitochondria to generate ATP, eukaryotes required intimate mito-nuclear communication. In addition, since reactive oxygen species are a cost of mitochondrial oxidative phosphorylation, this demands safeguards as protection from thes ... Full text Link to item Cite

Erratum: Sex differences in biomarkers associated with insulin resistance in obese adolescents: Metabolomic profiling and principal components analysis (Journal of Clinical Endocrinology and Metabolism (2014) 99 (4730-4739) DOI: 10.1210/jc.2014-2080)

Journal Article Journal of Clinical Endocrinology and Metabolism · April 1, 2015 Full text Cite

Metabolomic Profiling Identifies Biomarkers of Mitochondrial Function in Heart Failure with Preserved versus Reduced Ejection Fraction

Conference Journal of the American College of Cardiology · March 2015 Full text Cite

Metabolomic Profiling Identifies Biomarkers Predicting Adverse Outcomes in Patients with Heart Failure with Preserved Ejection Fraction

Conference Journal of the American College of Cardiology · March 2015 Full text Cite

Neuronal CRTC-1 governs systemic mitochondrial metabolism and lifespan via a catecholamine signal.

Journal Article Cell · February 26, 2015 Low energy states delay aging in multiple species, yet mechanisms coordinating energetics and longevity across tissues remain poorly defined. The conserved energy sensor AMP-activated protein kinase (AMPK) and its corresponding phosphatase calcineurin modu ... Full text Link to item Cite

Cardiomyocyte glucagon receptor signaling modulates outcomes in mice with experimental myocardial infarction.

Journal Article Mol Metab · February 2015 OBJECTIVE: Glucagon is a hormone with metabolic actions that maintains normoglycemia during the fasting state. Strategies enabling either inhibition or activation of glucagon receptor (Gcgr) signaling are being explored for the treatment of diabetes or obe ... Full text Link to item Cite

Cardiomyocyte glucagon receptor signaling modulates outcomes in mice with experimental myocardial infarction

Journal Article Molecular Metabolism · February 1, 2015 Objective: Glucagon is a hormone with metabolic actions that maintains normoglycemia during the fasting state. Strategies enabling either inhibition or activation of glucagon receptor (Gcgr) signaling are being explored for the treatment of diabetes or obe ... Full text Cite

Compartmentalized acyl-CoA metabolism in skeletal muscle regulates systemic glucose homeostasis.

Journal Article Diabetes · January 2015 The impaired capacity of skeletal muscle to switch between the oxidation of fatty acid (FA) and glucose is linked to disordered metabolic homeostasis. To understand how muscle FA oxidation affects systemic glucose, we studied mice with a skeletal muscle-sp ... Full text Link to item Cite

Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation.

Journal Article J Clin Invest · January 2015 Activation of CD4+ T cells results in rapid proliferation and differentiation into effector and regulatory subsets. CD4+ effector T cell (Teff) (Th1 and Th17) and Treg subsets are metabolically distinct, yet the specific metabolic differences that modify T ... Full text Open Access Link to item Cite

Comparison of proteomic and metabolomic profiles of mutants of the mitochondrial respiratory chain in Caenorhabditis elegans.

Journal Article Mitochondrion · January 2015 Single-gene mutations that disrupt mitochondrial respiratory chain function in Caenorhabditis elegans change patterns of protein expression and metabolites. Our goal was to develop useful molecular fingerprints employing adaptable techniques to recognize m ... Full text Link to item Cite

Dynamic Metabolite Profiling in an Archaeon Connects Transcriptional Regulation to Metabolic Consequences.

Journal Article PLoS One · 2015 Previous work demonstrated that the TrmB transcription factor is responsible for regulating the expression of many enzyme-coding genes in the hypersaline-adapted archaeon Halobacterium salinarum via a direct interaction with a cis-regulatory sequence in th ... Full text Link to item Cite

Acyl-CoA thioesterase-2 facilitates mitochondrial fatty acid oxidation in the liver.

Journal Article J Lipid Res · December 2014 Acyl-CoA thioesterase (Acot)2 localizes to the mitochondrial matrix and hydrolyses long-chain fatty acyl-CoA into free FA and CoASH. Acot2 is expressed in highly oxi-dative tissues and is poised to modulate mitochondrial FA oxidation (FAO), yet its biologi ... Full text Link to item Cite

Sex differences in biomarkers associated with insulin resistance in obese adolescents: metabolomic profiling and principal components analysis.

Journal Article J Clin Endocrinol Metab · December 2014 OBJECTIVE: Obesity and insulin resistance (IR) predispose to type 2 diabetes mellitus. Yet only half of obese adolescents have IR and far fewer progress to type 2 diabetes mellitus. We hypothesized that amino acid and fatty acid metabolites may serve as bi ... Full text Link to item Cite

Androgens regulate prostate cancer cell growth via an AMPK-PGC-1α-mediated metabolic switch.

Journal Article Oncogene · November 6, 2014 Prostate cancer is the most commonly diagnosed malignancy among men in industrialized countries, accounting for the second leading cause of cancer-related deaths. Although we now know that the androgen receptor (AR) is important for progression to the dead ... Full text Link to item Cite

Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism.

Journal Article Cell Metab · November 4, 2014 Circulating branched-chain amino acid (BCAA) levels are elevated in obesity/diabetes and are a sensitive predictor for type 2 diabetes. Here we show in rats that insulin dose-dependently lowers plasma BCAA levels through induction of hepatic protein expres ... Full text Link to item Cite

Downregulation of carnitine acyl-carnitine translocase by miRNAs 132 and 212 amplifies glucose-stimulated insulin secretion.

Journal Article Diabetes · November 2014 We previously demonstrated that micro-RNAs (miRNAs) 132 and 212 are differentially upregulated in response to obesity in two mouse strains that differ in their susceptibility to obesity-induced diabetes. Here we show the overexpression of miRNAs 132 and 21 ... Full text Link to item Cite

Metabolite signatures of exercise training in human skeletal muscle relate to mitochondrial remodelling and cardiometabolic fitness.

Journal Article Diabetologia · November 2014 AIMS/HYPOTHESIS: Targeted metabolomic and transcriptomic approaches were used to evaluate the relationship between skeletal muscle metabolite signatures, gene expression profiles and clinical outcomes in response to various exercise training interventions. ... Full text Link to item Cite

Energy metabolic reprogramming in the hypertrophied and early stage failing heart: a multisystems approach.

Journal Article Circ Heart Fail · November 2014 BACKGROUND: An unbiased systems approach was used to define energy metabolic events that occur during the pathological cardiac remodeling en route to heart failure (HF). METHODS AND RESULTS: Combined myocardial transcriptomic and metabolomic profiling were ... Full text Link to item Cite

Treatment with the 3-ketoacyl-CoA thiolase inhibitor trimetazidine does not exacerbate whole-body insulin resistance in obese mice.

Journal Article J Pharmacol Exp Ther · June 2014 There is a growing need to understand the underlying mechanisms involved in the progression of cardiovascular disease during obesity and diabetes. Although inhibition of fatty acid oxidation has been proposed as a novel approach to treat ischemic heart dis ... Full text Link to item Cite

Mechanical unloading promotes myocardial energy recovery in human heart failure.

Journal Article Circ Cardiovasc Genet · June 2014 BACKGROUND: Impaired bioenergetics is a prominent feature of the failing heart, but the underlying metabolic perturbations are poorly understood. METHODS AND RESULTS: We compared metabolomic, gene transcript, and protein data from 6 paired samples of faili ... Full text Link to item Cite

Obesity and lipid stress inhibit carnitine acetyltransferase activity.

Journal Article J Lipid Res · April 2014 Carnitine acetyltransferase (CrAT) is a mitochondrial matrix enzyme that catalyzes the interconversion of acetyl-CoA and acetylcarnitine. Emerging evidence suggests that this enzyme functions as a positive regulator of total body glucose tolerance and musc ... Full text Link to item Cite

Lysine glutarylation is a protein posttranslational modification regulated by SIRT5.

Journal Article Cell Metab · April 1, 2014 We report the identification and characterization of a five-carbon protein posttranslational modification (PTM) called lysine glutarylation (Kglu). This protein modification was detected by immunoblot and mass spectrometry (MS), and then comprehensively va ... Full text Link to item Cite

Caffeine stimulates hepatic lipid metabolism by the autophagy-lysosomal pathway in mice.

Journal Article Hepatology · April 2014 UNLABELLED: Caffeine is one of the world's most consumed drugs. Recently, several studies showed that its consumption is associated with lower risk for nonalcoholic fatty liver disease (NAFLD), an obesity-related condition that recently has become the majo ... Full text Link to item Cite

Targeted metabolomics connects thioredoxin-interacting protein (TXNIP) to mitochondrial fuel selection and regulation of specific oxidoreductase enzymes in skeletal muscle.

Journal Article J Biol Chem · March 21, 2014 Thioredoxin-interacting protein (TXNIP) is an α-arrestin family member involved in redox sensing and metabolic control. Growing evidence links TXNIP to mitochondrial function, but the molecular nature of this relationship has remained poorly defined. Herei ... Full text Link to item Cite

BMI, RQ, diabetes, and sex affect the relationships between amino acids and clamp measures of insulin action in humans.

Journal Article Diabetes · February 2014 Previous studies have used indirect measures of insulin sensitivity to link circulating amino acids with insulin resistance and identify potential biomarkers of diabetes risk. Using direct measures (i.e., hyperinsulinemic-euglycemic clamps), we examined th ... Full text Link to item Cite

Phosphoproteomic profiling of human myocardial tissues distinguishes ischemic from non-ischemic end stage heart failure.

Journal Article PLoS One · 2014 The molecular differences between ischemic (IF) and non-ischemic (NIF) heart failure are poorly defined. A better understanding of the molecular differences between these two heart failure etiologies may lead to the development of more effective heart fail ... Full text Open Access Link to item Cite

SIRT5 regulates the mitochondrial lysine succinylome and metabolic networks.

Journal Article Cell Metab · December 3, 2013 Reversible posttranslational modifications are emerging as critical regulators of mitochondrial proteins and metabolism. Here, we use a label-free quantitative proteomic approach to characterize the lysine succinylome in liver mitochondria and its regulati ... Full text Link to item Cite

Circadian clock NAD+ cycle drives mitochondrial oxidative metabolism in mice.

Journal Article Science · November 1, 2013 Circadian clocks are self-sustained cellular oscillators that synchronize oxidative and reductive cycles in anticipation of the solar cycle. We found that the clock transcription feedback loop produces cycles of nicotinamide adenine dinucleotide (NAD(+)) b ... Full text Link to item Cite

Glycerol-3-phosphate acyltransferase (GPAT)-1, but not GPAT4, incorporates newly synthesized fatty acids into triacylglycerol and diminishes fatty acid oxidation.

Journal Article J Biol Chem · September 20, 2013 Four glycerol-3-phosphate acyltransferase (GPAT) isoforms, each encoded by a separate gene, catalyze the initial step in glycerolipid synthesis; in liver, the major isoforms are GPAT1 and GPAT4. To determine whether each of these hepatic isoforms performs ... Full text Link to item Cite

Gut microbiota from twins discordant for obesity modulate metabolism in mice.

Journal Article Science · September 6, 2013 The role of specific gut microbes in shaping body composition remains unclear. We transplanted fecal microbiota from adult female twin pairs discordant for obesity into germ-free mice fed low-fat mouse chow, as well as diets representing different levels o ... Full text Link to item Cite

Effect of Roux-en-Y gastric bypass and laparoscopic adjustable gastric banding on branched-chain amino acid metabolism.

Journal Article Diabetes · August 2013 It has been hypothesized that a greater decline in circulating branched-chain amino acids (BCAAs) after weight loss induced by Roux-en-Y gastric bypass (RYGB) surgery than after calorie restriction alone has independent effects on glucose homeostasis, poss ... Full text Link to item Cite

Diminished acyl-CoA synthetase isoform 4 activity in INS 832/13 cells reduces cellular epoxyeicosatrienoic acid levels and results in impaired glucose-stimulated insulin secretion.

Journal Article J Biol Chem · July 26, 2013 Glucose-stimulated insulin secretion (GSIS) in pancreatic beta-cells is potentiated by fatty acids (FA). The initial step in the metabolism of intracellular FA is the conversion to acyl-CoA by long chain acyl-CoA synthetases (Acsls). Because the predominan ... Full text Link to item Cite

Ablation of dihydroceramide desaturase 1, a therapeutic target for the treatment of metabolic diseases, simultaneously stimulates anabolic and catabolic signaling.

Journal Article Mol Cell Biol · June 2013 The lipotoxicity hypothesis posits that obesity predisposes individuals to metabolic diseases because the oversupply of lipids to tissues not suited for fat storage leads to the accumulation of fat-derived molecules that impair tissue function. Means of co ... Full text Link to item Cite

Metabolomic profiling reveals a role for caspase-2 in lipoapoptosis.

Journal Article J Biol Chem · May 17, 2013 The accumulation of long-chain fatty acids (LCFAs) in non-adipose tissues results in lipid-induced cytotoxicity (or lipoapoptosis). Lipoapoptosis has been proposed to play an important role in the pathogenesis of several metabolic diseases, including non-a ... Full text Link to item Cite

Branched-chain amino acids alter neurobehavioral function in rats.

Journal Article Am J Physiol Endocrinol Metab · February 15, 2013 Recently, we have described a strong association of branched-chain amino acids (BCAA) and aromatic amino acids (AAA) with obesity and insulin resistance. In the current study, we have investigated the potential impact of BCAA on behavioral functions. We de ... Full text Link to item Cite

Ectopic lipid deposition and the metabolic profile of skeletal muscle in ovariectomized mice.

Journal Article Am J Physiol Regul Integr Comp Physiol · February 2013 Disruptions of ovarian function in women are associated with increased risk of metabolic disease due to dysregulation of peripheral glucose homeostasis in skeletal muscle. Our previous evidence suggests that alterations in skeletal muscle lipid metabolism ... Full text Link to item Cite

Research resource: tissue- and pathway-specific metabolomic profiles of the steroid receptor coactivator (SRC) family.

Journal Article Mol Endocrinol · February 2013 The rapidly growing family of transcriptional coregulators includes coactivators that promote transcription and corepressors that harbor the opposing function. In recent years, coregulators have emerged as important regulators of metabolic homeostasis, inc ... Full text Link to item Cite

Adipose-specific deletion of TFAM increases mitochondrial oxidation and protects mice against obesity and insulin resistance.

Journal Article Cell Metab · December 5, 2012 Obesity and type 2 diabetes are associated with mitochondrial dysfunction in adipose tissue, but the role for adipose tissue mitochondria in the development of these disorders is currently unknown. To understand the impact of adipose tissue mitochondria on ... Full text Link to item Cite

Skeletal muscle Nur77 expression enhances oxidative metabolism and substrate utilization.

Journal Article J Lipid Res · December 2012 Mitochondrial dysfunction has been implicated in the pathogenesis of type 2 diabetes. Identifying novel regulators of mitochondrial bioenergetics will broaden our understanding of regulatory checkpoints that coordinate complex metabolic pathways. We previo ... Full text Link to item Cite

Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility.

Journal Article Cell Metab · May 2, 2012 The concept of "metabolic inflexibility" was first introduced to describe the failure of insulin-resistant human subjects to appropriately adjust mitochondrial fuel selection in response to nutritional cues. This phenomenon has since gained increasing reco ... Full text Link to item Cite

Ablation of steroid receptor coactivator-3 resembles the human CACT metabolic myopathy.

Journal Article Cell Metab · May 2, 2012 Oxidation of lipid substrates is essential for survival in fasting and other catabolic conditions, sparing glucose for the brain and other glucose-dependent tissues. Here we show Steroid Receptor Coactivator-3 (SRC-3) plays a central role in long chain fat ... Full text Link to item Cite

Atypical antipsychotics rapidly and inappropriately switch peripheral fuel utilization to lipids, impairing metabolic flexibility in rodents.

Journal Article Schizophr Bull · January 2012 Patients taking atypical antipsychotics are frequented by serious metabolic (eg, hyperglycemia, obesity, and diabetes) and cardiac effects. Surprisingly, chronic treatment also appears to lower free fatty acids (FFAs). This finding is paradoxical because i ... Full text Link to item Cite

Mig-6 plays a critical role in the regulation of cholesterol homeostasis and bile acid synthesis.

Journal Article PLoS One · 2012 The disruption of cholesterol homeostasis leads to an increase in cholesterol levels which results in the development of cardiovascular disease. Mitogen Inducible Gene 6 (Mig-6) is an immediate early response gene that can be induced by various mitogens, s ... Full text Link to item Cite

Metabolomic profiling reveals mitochondrial-derived lipid biomarkers that drive obesity-associated inflammation.

Journal Article PLoS One · 2012 Obesity has reached epidemic proportions worldwide. Several animal models of obesity exist, but studies are lacking that compare traditional lard-based high fat diets (HFD) to "Cafeteria diets" (CAF) consisting of nutrient poor human junk food. Our previou ... Full text Link to item Cite

Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation.

Journal Article Proc Natl Acad Sci U S A · November 8, 2011 Stimulation of resting CD4(+) T lymphocytes leads to rapid proliferation and differentiation into effector (Teff) or inducible regulatory (Treg) subsets with specific functions to promote or suppress immunity. Importantly, Teff and Treg use distinct metabo ... Full text Link to item Cite

Autophagy is essential to suppress cell stress and to allow BCR-Abl-mediated leukemogenesis.

Journal Article Oncogene · April 21, 2011 Hematopoietic cells normally require cell extrinsic signals to maintain metabolism and survival. In contrast, cancer cells can express constitutively active oncogenic kinases such as BCR-Abl that promote these processes independent of extrinsic growth fact ... Full text Link to item Cite

Regulation of mitochondrial morphology by APC/CCdh1-mediated control of Drp1 stability.

Journal Article Mol Biol Cell · April 15, 2011 Homeostatic maintenance of cellular mitochondria requires a dynamic balance between fission and fusion, and controlled changes in morphology are important for processes such as apoptosis and cellular division. Interphase mitochondria have been described as ... Full text Link to item Cite

A high-fat diet elicits differential responses in genes coordinating oxidative metabolism in skeletal muscle of lean and obese individuals.

Journal Article J Clin Endocrinol Metab · March 2011 CONTEXT: In lean individuals, increasing dietary lipid can elicit an increase in whole body lipid oxidation; however, with obesity the capacity to respond to changes in substrate availability appears to be compromised. OBJECTIVE: To determine whether the r ... Full text Link to item Cite

Akt requires glucose metabolism to suppress puma expression and prevent apoptosis of leukemic T cells.

Journal Article J Biol Chem · February 18, 2011 The PI3K/Akt pathway is activated in stimulated cells and in many cancers to promote glucose metabolism and prevent cell death. Although inhibition of Akt-mediated cell survival may provide a means to eliminate cancer cells, this survival pathway remains i ... Full text Link to item Cite

The coactivator SRC-1 is an essential coordinator of hepatic glucose production.

Journal Article Cell Metab · December 1, 2010 Gluconeogenesis makes a major contribution to hepatic glucose production, a process critical for survival in mammals. In this study, we identify the p160 family member, SRC-1, as a key coordinator of the hepatic gluconeogenic program in vivo. SRC-1-null mi ... Full text Link to item Cite

Comprehensive Metabolic Analysis for Understanding of Disease

Journal Article · December 1, 2010 Comprehensive measurement of intermediary metabolites and changes in metabolic activity lead to the improved detection and understanding of diseases. Metabolomics is increasingly getting integrated with genomic and transcriptomic profiling methods. This ch ... Full text Cite

Metabolic profiling of muscle contraction in lean compared with obese rodents.

Journal Article Am J Physiol Regul Integr Comp Physiol · September 2010 Interest in the pathophysiological relevance of intramuscular triacylglycerol (IMTG) accumulation has grown from numerous studies reporting that abnormally high glycerolipid levels in tissues of obese and diabetic subjects correlate negatively with glucose ... Full text Link to item Cite

Adipose acyl-CoA synthetase-1 directs fatty acids toward beta-oxidation and is required for cold thermogenesis.

Journal Article Cell Metab · July 7, 2010 Long-chain acyl-CoA synthetase-1 (ACSL1) contributes 80% of total ACSL activity in adipose tissue and was believed to be essential for the synthesis of triacylglycerol. We predicted that an adipose-specific knockout of ACSL1 (Acsl1(A-/-)) would be lipodyst ... Full text Link to item Cite

Alterations in skeletal muscle fatty acid handling predisposes middle-aged mice to diet-induced insulin resistance.

Journal Article Diabetes · June 2010 OBJECTIVE: Although advanced age is a risk factor for type 2 diabetes, a clear understanding of the changes that occur during middle age that contribute to the development of skeletal muscle insulin resistance is currently lacking. Therefore, we sought to ... Full text Link to item Cite

The mitochondrial 2-oxoglutarate carrier is part of a metabolic pathway that mediates glucose- and glutamine-stimulated insulin secretion.

Journal Article J Biol Chem · May 28, 2010 Glucose-stimulated insulin secretion from pancreatic islet beta-cells is dependent in part on pyruvate cycling through the pyruvate/isocitrate pathway, which generates cytosolic alpha-ketoglutarate, also known as 2-oxoglutarate (2OG). Here, we have investi ... Full text Link to item Cite

Downregulation of adipose glutathione S-transferase A4 leads to increased protein carbonylation, oxidative stress, and mitochondrial dysfunction.

Journal Article Diabetes · May 2010 OBJECTIVE: Peripheral insulin resistance is linked to an increase in reactive oxygen species (ROS), leading in part to the production of reactive lipid aldehydes that modify the side chains of protein amino acids in a reaction termed protein carbonylation. ... Full text Link to item Cite

Insulin resistance is associated with a metabolic profile of altered protein metabolism in Chinese and Asian-Indian men.

Journal Article Diabetologia · April 2010 AIMS/HYPOTHESIS: Insulin resistance (IR) is associated with obesity, but can also develop in individuals with normal body weight. We employed comprehensive profiling methods to identify metabolic events associated with IR, while controlling for obesity. ME ... Full text Link to item Cite

Leptin therapy in insulin-deficient type I diabetes.

Journal Article Proc Natl Acad Sci U S A · March 16, 2010 In nonobese diabetic mice with uncontrolled type 1 diabetes, leptin therapy alone or combined with low-dose insulin reverses the catabolic state through suppression of hyperglucagonemia. Additionally, it mimics the anabolic actions of insulin monotherapy a ... Full text Link to item Cite

SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation.

Journal Article Nature · March 4, 2010 Sirtuins are NAD(+)-dependent protein deacetylases. They mediate adaptive responses to a variety of stresses, including calorie restriction and metabolic stress. Sirtuin 3 (SIRT3) is localized in the mitochondrial matrix, where it regulates the acetylation ... Full text Link to item Cite

Insulin resistance and altered systemic glucose metabolism in mice lacking Nur77.

Journal Article Diabetes · December 2009 OBJECTIVE: Nur77 is an orphan nuclear receptor with pleotropic functions. Previous studies have identified Nur77 as a transcriptional regulator of glucose utilization genes in skeletal muscle and gluconeogenesis in liver. However, the net functional impact ... Full text Link to item Cite

Comprehensive Metabolic Analysis for Understanding of Disease Mechanisms

Journal Article · December 1, 2009 Full text Cite

Activation of nuclear receptor CAR ameliorates diabetes and fatty liver disease.

Journal Article Proc Natl Acad Sci U S A · November 3, 2009 Constitutive androstane receptor CAR (NR1I3) has been identified as a central mediator of coordinate responses to xenobiotic and endobiotic stress. Here we use leptin-deficient mice (ob/ob) and ob/ob, CAR(-/-) double mutant mice to identify a metabolic rol ... Full text Link to item Cite

Metabolomics applied to diabetes research: moving from information to knowledge.

Journal Article Diabetes · November 2009 Full text Link to item Cite

Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control.

Journal Article J Biol Chem · August 21, 2009 In addition to its essential role in permitting mitochondrial import and oxidation of long chain fatty acids, carnitine also functions as an acyl group acceptor that facilitates mitochondrial export of excess carbons in the form of acylcarnitines. Recent e ... Full text Link to item Cite

Fasting-induced hepatic production of DHEA is regulated by PGC-1alpha, ERRalpha, and HNF4alpha.

Journal Article Mol Endocrinol · August 2009 The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha is involved in the coordinate induction of changes in gene expression in the liver that enable a homeostatic response to alterations in metabolic stat ... Full text Link to item Cite

Insulin-stimulated cardiac glucose oxidation is increased in high-fat diet-induced obese mice lacking malonyl CoA decarboxylase.

Journal Article Diabetes · August 2009 OBJECTIVE: Whereas an impaired ability to oxidize fatty acids is thought to contribute to intracellular lipid accumulation, insulin resistance, and cardiac dysfunction, high rates of fatty acid oxidation could also impair glucose metabolism and function. W ... Full text Link to item Cite

A Branched-Chain Amino Acid-Related Metabolic Signature that Differentiates Obese and Lean Humans and Contributes to Insulin Resistance (DOI:10.1016/j.cmet.2009.02.002)

Journal Article Cell Metabolism · May 14, 2009 Full text Cite

A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance.

Journal Article Cell Metab · April 2009 Metabolomic profiling of obese versus lean humans reveals a branched-chain amino acid (BCAA)-related metabolite signature that is suggestive of increased catabolism of BCAA and correlated with insulin resistance. To test its impact on metabolic homeostasis ... Full text Link to item Cite

Glucose metabolism as a target of histone deacetylase inhibitors.

Journal Article Mol Endocrinol · March 2009 The therapeutic efficacy of histone deacetylase inhibitors (HDACI) is generally attributed to their ability to alter gene expression secondary to their effects on the acetylation status of transcription factors and histones. However, because HDACIs exhibit ... Full text Link to item Cite

Metabolic profiling of PPARalpha-/- mice reveals defects in carnitine and amino acid homeostasis that are partially reversed by oral carnitine supplementation.

Journal Article FASEB J · February 2009 Peroxisome proliferator-activated receptor-alpha (PPARalpha) is a master transcriptional regulator of beta-oxidation and a prominent target of hypolipidemic drugs. To gain deeper insights into the systemic consequences of impaired fat catabolism, we used q ... Full text Link to item Cite

The STEDMAN project: biophysical, biochemical and metabolic effects of a behavioral weight loss intervention during weight loss, maintenance, and regain.

Journal Article OMICS · February 2009 The Study of the Effects of Diet on Metabolism and Nutrition (STEDMAN) Project uses comprehensive metabolic profiling to probe biochemical mechanisms of weight loss in humans. Measurements at baseline, 2 and 4 weeks, 6 and 12 months included diet, body com ... Full text Link to item Cite

Autophagy provides nutrients but can lead to Chop-dependent induction of Bim to sensitize growth factor-deprived cells to apoptosis.

Journal Article Mol Biol Cell · February 2009 Tissue homeostasis is controlled by the availability of growth factors, which sustain exogenous nutrient uptake and prevent apoptosis. Although autophagy can provide an alternate intracellular nutrient source to support essential basal metabolism of apopto ... Full text Link to item Cite

Insulin-stimulated cardiac glucose oxidation is increased in high-fat diet-induced obese mice lacking malonyl CoA decarboxylase (Diabetes (2009) 58, (1766-1775))

Journal Article Diabetes · 2009 Cite

Comprehensive Metabolic Analysis for Understanding of Disease Mechanisms

Chapter · November 11, 2008 Full text Cite

Silencing of cytosolic or mitochondrial isoforms of malic enzyme has no effect on glucose-stimulated insulin secretion from rodent islets.

Journal Article J Biol Chem · October 24, 2008 We have previously demonstrated a role for pyruvate cycling in glucose-stimulated insulin secretion (GSIS). Some of the possible pyruvate cycling pathways are completed by conversion of malate to pyruvate by malic enzyme. Using INS-1-derived 832/13 cells, ... Full text Link to item Cite

Chronic suppression of acetyl-CoA carboxylase 1 in beta-cells impairs insulin secretion via inhibition of glucose rather than lipid metabolism.

Journal Article J Biol Chem · May 23, 2008 Acetyl-CoA carboxylase 1 (ACC1) currently is being investigated as a target for treatment of obesity-associated dyslipidemia and insulin resistance. To investigate the effects of ACC1 inhibition on insulin secretion, three small interfering RNA (siRNA) dup ... Full text Link to item Cite

Genetic networks of liver metabolism revealed by integration of metabolic and transcriptional profiling.

Journal Article PLoS Genet · March 14, 2008 Although numerous quantitative trait loci (QTL) influencing disease-related phenotypes have been detected through gene mapping and positional cloning, identification of the individual gene(s) and molecular pathways leading to those phenotypes is often elus ... Full text Link to item Cite

Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance.

Journal Article Cell Metab · January 2008 Previous studies have suggested that insulin resistance develops secondary to diminished fat oxidation and resultant accumulation of cytosolic lipid molecules that impair insulin signaling. Contrary to this model, the present study used targeted metabolomi ... Full text Link to item Cite

Glycogen synthase kinase 3alpha and 3beta mediate a glucose-sensitive antiapoptotic signaling pathway to stabilize Mcl-1.

Journal Article Mol Cell Biol · June 2007 Glucose uptake and utilization are growth factor-stimulated processes that are frequently upregulated in cancer cells and that correlate with enhanced cell survival. The mechanism of metabolic protection from apoptosis, however, has been unclear. Here we i ... Full text Link to item Cite

Carnitine revisited: potential use as adjunctive treatment in diabetes.

Journal Article Diabetologia · April 2007 AIMS/HYPOTHESIS: This study examined the efficacy of supplemental L: -carnitine as an adjunctive diabetes therapy in mouse models of metabolic disease. We hypothesised that carnitine would facilitate fatty acid export from tissues in the form of acyl-carni ... Full text Link to item Cite

Chemical knockout of pantothenate kinase reveals the metabolic and genetic program responsible for hepatic coenzyme A homeostasis.

Journal Article Chem Biol · March 2007 Coenzyme A (CoA) is the major acyl group carrier in intermediary metabolism. Hopantenate (HoPan), a competitive inhibitor of the pantothenate kinases, was used to chemically antagonize CoA biosynthesis. HoPan dramatically reduced liver CoA and mice develop ... Full text Link to item Cite

Contraction of insulin-resistant muscle normalizes insulin action in association with increased mitochondrial activity and fatty acid catabolism.

Journal Article Am J Physiol Cell Physiol · February 2007 Acute exercise can reverse muscle insulin resistance, but the mechanism(s) of action are unknown. With the use of a hindlimb perfusion model, we have found that acute contraction restores insulin-stimulated glucose uptake in muscle of obese Zucker rats to ... Full text Link to item Cite

The mitochondrial citrate/isocitrate carrier plays a regulatory role in glucose-stimulated insulin secretion.

Journal Article J Biol Chem · November 24, 2006 Glucose-stimulated insulin secretion (GSIS) is mediated in part by glucose metabolism-driven increases in ATP/ADP ratio, but by-products of mitochondrial glucose metabolism also play an important role. Here we investigate the role of the mitochondrial citr ... Full text Link to item Cite

A pyruvate cycling pathway involving cytosolic NADP-dependent isocitrate dehydrogenase regulates glucose-stimulated insulin secretion.

Journal Article J Biol Chem · October 13, 2006 Glucose-stimulated insulin secretion (GSIS) from pancreatic islet beta-cells is central to control of mammalian fuel homeostasis. Glucose metabolism mediates GSIS in part via ATP-regulated K+ (KATP) channels, but multiple lines of evidence suggest particip ... Full text Link to item Cite

Compensatory responses to pyruvate carboxylase suppression in islet beta-cells. Preservation of glucose-stimulated insulin secretion.

Journal Article J Biol Chem · August 4, 2006 We have previously reported that glucose-stimulated insulin secretion (GSIS) is tightly correlated with pyruvate carboxylase (PC)-catalyzed anaplerotic flux into the tricarboxylic acid cycle and stimulation of pyruvate cycling activity. To further evaluate ... Full text Link to item Cite

Peroxisome proliferator-activated receptor-gamma co-activator 1alpha-mediated metabolic remodeling of skeletal myocytes mimics exercise training and reverses lipid-induced mitochondrial inefficiency.

Journal Article J Biol Chem · September 30, 2005 Peroxisome proliferator-activated receptor-gamma co-activator 1alpha (PGC1alpha) is a promiscuous co-activator that plays a key role in regulating mitochondrial biogenesis and fuel homeostasis. Emergent evidence links decreased skeletal muscle PGC1alpha ac ... Full text Link to item Cite

Mitochondrial glycerol-3-phosphate acyltransferase-1 is essential in liver for the metabolism of excess acyl-CoAs.

Journal Article J Biol Chem · July 8, 2005 In vitro studies suggest that the mitochondrial glycerol-3-phosphate acyltransferase-1 (mtGPAT1) isoform catalyzes the initial and rate-controlling step in glycerolipid synthesis and aids in partitioning acyl-CoAs toward triacylglycerol synthesis and away ... Full text Link to item Cite