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Phillip James White

Assistant Professor in Medicine
Medicine, Endocrinology, Metabolism, and Nutrition

Selected Publications


Lipoprotein subclasses are associated with Hepatic steatosis: insights from the prospective multicenter imaging study for the evaluation of chest pain (PROMISE) clinical trial.

Journal Article Am J Prev Cardiol · June 2024 OBJECTIVES: To determine the relationship between lipoprotein particle size/number with hepatic steatosis (HS), given its association with traditional lipoproteins and coronary atherosclerosis. METHODS: Individuals with available CT data and blood samples ... Full text Link to item Cite

BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis.

Journal Article Cell · May 9, 2024 Brown adipose tissue (BAT) is best known for thermogenesis. Rodent studies demonstrated that enhanced BAT thermogenesis is tightly associated with increased energy expenditure, reduced body weight, and improved glucose homeostasis. However, human BAT is pr ... Full text Link to item Cite

Branched-chain amino acids in cardiovascular disease.

Journal Article Nat Rev Cardiol · February 2023 Research conducted in the past 15 years has yielded crucial insights that are reshaping our understanding of the systems physiology of branched-chain amino acid (BCAA) metabolism and the molecular mechanisms underlying the close relationship between BCAA h ... Full text Link to item Cite

HGFAC is a ChREBP-regulated hepatokine that enhances glucose and lipid homeostasis.

Journal Article JCI Insight · January 10, 2023 Carbohydrate response element-binding protein (ChREBP) is a carbohydrate-sensing transcription factor that regulates both adaptive and maladaptive genomic responses in coordination of systemic fuel homeostasis. Genetic variants in the ChREBP locus associat ... 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

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

Hepatic IRF3 fuels dysglycemia in obesity through direct regulation of Ppp2r1b.

Journal Article Sci Transl Med · March 23, 2022 Inflammation has profound but poorly understood effects on metabolism, especially in the context of obesity and nonalcoholic fatty liver disease (NAFLD). Here, we report that hepatic interferon regulatory factor 3 (IRF3) is a direct transcriptional regulat ... 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

Insulin action, type 2 diabetes, and branched-chain amino acids: A two-way street.

Journal Article Molecular metabolism · October 2021 BackgroundA strong association of obesity and insulin resistance with increased circulating levels of branched-chain and aromatic amino acids and decreased glycine levels has been recognized in human subjects for decades.Scope of reviewMo ... Full text 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

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

Metabolic flexibility via mitochondrial BCAA carrier SLC25A44 is required for optimal fever.

Journal Article eLife · May 2021 Importing necessary metabolites into the mitochondrial matrix is a crucial step of fuel choice during stress adaptation. Branched chain-amino acids (BCAAs) are essential amino acids needed for anabolic processes, but they are also imported into the mitocho ... Full text 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

Insights Into Metabolic Mechanisms and Their Application in the Treatment of NASH.

Journal Article Clin Liver Dis (Hoboken) · January 2021 Watch a video presentation of this article Answer questions and earn CME. ... 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

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

Lowering circulating apolipoprotein E levels improves aged bone fracture healing.

Journal Article JCI Insight · September 19, 2019 Age is a well-established risk factor for impaired bone fracture healing. Here, we identify a role for apolipoprotein E (ApoE) in age-associated impairment of bone fracture healing and osteoblast differentiation, and we investigate the mechanism by which A ... Full text Link to item Cite

Lipoprotein subclasses are associated with Hepatic steatosis: insights from the prospective multicenter imaging study for the evaluation of chest pain (PROMISE) clinical trial.

Journal Article Am J Prev Cardiol · June 2024 OBJECTIVES: To determine the relationship between lipoprotein particle size/number with hepatic steatosis (HS), given its association with traditional lipoproteins and coronary atherosclerosis. METHODS: Individuals with available CT data and blood samples ... Full text Link to item Cite

BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis.

Journal Article Cell · May 9, 2024 Brown adipose tissue (BAT) is best known for thermogenesis. Rodent studies demonstrated that enhanced BAT thermogenesis is tightly associated with increased energy expenditure, reduced body weight, and improved glucose homeostasis. However, human BAT is pr ... Full text Link to item Cite

Branched-chain amino acids in cardiovascular disease.

Journal Article Nat Rev Cardiol · February 2023 Research conducted in the past 15 years has yielded crucial insights that are reshaping our understanding of the systems physiology of branched-chain amino acid (BCAA) metabolism and the molecular mechanisms underlying the close relationship between BCAA h ... Full text Link to item Cite

HGFAC is a ChREBP-regulated hepatokine that enhances glucose and lipid homeostasis.

Journal Article JCI Insight · January 10, 2023 Carbohydrate response element-binding protein (ChREBP) is a carbohydrate-sensing transcription factor that regulates both adaptive and maladaptive genomic responses in coordination of systemic fuel homeostasis. Genetic variants in the ChREBP locus associat ... 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

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

Hepatic IRF3 fuels dysglycemia in obesity through direct regulation of Ppp2r1b.

Journal Article Sci Transl Med · March 23, 2022 Inflammation has profound but poorly understood effects on metabolism, especially in the context of obesity and nonalcoholic fatty liver disease (NAFLD). Here, we report that hepatic interferon regulatory factor 3 (IRF3) is a direct transcriptional regulat ... 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

Insulin action, type 2 diabetes, and branched-chain amino acids: A two-way street.

Journal Article Molecular metabolism · October 2021 BackgroundA strong association of obesity and insulin resistance with increased circulating levels of branched-chain and aromatic amino acids and decreased glycine levels has been recognized in human subjects for decades.Scope of reviewMo ... Full text 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

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

Metabolic flexibility via mitochondrial BCAA carrier SLC25A44 is required for optimal fever.

Journal Article eLife · May 2021 Importing necessary metabolites into the mitochondrial matrix is a crucial step of fuel choice during stress adaptation. Branched chain-amino acids (BCAAs) are essential amino acids needed for anabolic processes, but they are also imported into the mitocho ... Full text 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

Insights Into Metabolic Mechanisms and Their Application in the Treatment of NASH.

Journal Article Clin Liver Dis (Hoboken) · January 2021 Watch a video presentation of this article Answer questions and earn CME. ... 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

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

Lowering circulating apolipoprotein E levels improves aged bone fracture healing.

Journal Article JCI Insight · September 19, 2019 Age is a well-established risk factor for impaired bone fracture healing. Here, we identify a role for apolipoprotein E (ApoE) in age-associated impairment of bone fracture healing and osteoblast differentiation, and we investigate the mechanism by which A ... Full text Link to item Cite

Acute suppression of insulin resistance-associated hepatic miR-29 in vivo improves glycemic control in adult mice.

Journal Article Physiol Genomics · August 1, 2019 MicroRNAs (miRNAs) are important posttranscriptional regulators of metabolism and energy homeostasis. Dysregulation of certain miRNAs in the liver has been shown to contribute to the pathogenesis of Type 2 diabetes (T2D), in part by impairing hepatic insul ... 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 Cite

Loss of BCAA Catabolism during Carcinogenesis Enhances mTORC1 Activity and Promotes Tumor Development and Progression.

Journal Article Cell Metab · May 7, 2019 Tumors display profound changes in cellular metabolism, yet how these changes aid the development and growth of tumors is not fully understood. Here we use a multi-omic approach to examine liver carcinogenesis and regeneration, and find that progressive lo ... Full text Link to item Cite

Branched-chain amino acids in disease.

Journal Article Science · February 8, 2019 Full text Link to item Cite

MiR-29 Regulates de novo Lipogenesis in the Liver and Circulating Triglyceride Levels in a Sirt1-Dependent Manner.

Journal Article Front Physiol · 2019 MicroRNAs (miRNAs) are known regulators of lipid homeostasis. We recently demonstrated that miR-29 controls the levels of circulating cholesterol and triglycerides, but the mechanisms remained unknown. In the present study, we demonstrated that systemic de ... Full text 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 Featured Publication 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

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

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 Featured Publication 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

Impaired thermoregulation and beneficial effects of thermoneutrality in the 3×Tg-AD model of Alzheimer's disease.

Journal Article Neurobiol Aging · July 2016 The sharp rise in the incidence of Alzheimer's disease (AD) at an old age coincides with a reduction in energy metabolism and core body temperature. We found that the triple-transgenic mouse model of AD (3×Tg-AD) spontaneously develops a lower basal body t ... Full text 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

Age-dependent impairment of glucose tolerance in the 3xTg-AD mouse model of Alzheimer's disease.

Journal Article FASEB J · October 2015 Alzheimer's disease (AD) has been associated with type II diabetes (T2D) and obesity in several epidemiologic studies. To determine whether AD neuropathology can cause peripheral metabolic impairments, we investigated metabolic parameters in the triple-tra ... Full text Link to item Cite

Transgenic ω-3 PUFA enrichment alters morphology and gene expression profile in adipose tissue of obese mice: Potential role for protectins.

Journal Article Metabolism · June 2015 OBJECTIVE: Dietary administration of ω-3 polyunsaturated fatty acids (PUFA) is often associated with altered adipose tissue (AT) morphology and/or function in obese mice. Yet, it is unclear whether this is an indirect consequence of reduced weight gain or ... Full text Link to item Cite

Insulin reverses the high-fat diet-induced increase in brain Aβ and improves memory in an animal model of Alzheimer disease.

Journal Article Diabetes · December 2014 Defects in insulin production and signaling are suspected to share a key role in diabetes and Alzheimer disease (AD), two age-related pathologies. In this study, we investigated the interrelation between AD and diabetes using a high-fat diet (HFD) in a mou ... Full text Link to item Cite

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

Journal Article Cell Metab · November 4, 2014 Featured Publication 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

Protectin DX alleviates insulin resistance by activating a myokine-liver glucoregulatory axis.

Journal Article Nat Med · June 2014 Featured Publication We previously demonstrated that low biosynthesis of ω-3 fatty acid-derived proresolution mediators, termed protectins, is associated with an impaired global resolution capacity, inflammation and insulin resistance in obese high-fat diet-fed mice. These fin ... Full text Link to item Cite

Potential role of omega-3-derived resolution mediators in metabolic inflammation.

Journal Article Immunol Cell Biol · April 2014 In its most reduced form, metabolic inflammation can be best described as a maladaptive process that involves an integrated innate and acquired immune response to nutrient surplus. Although originally these events were thought to be restricted to the expan ... Full text Link to item Cite

Distinct patterns of tissue-specific lipid accumulation during the induction of insulin resistance in mice by high-fat feeding.

Journal Article Diabetologia · July 2013 AIMS/HYPOTHESIS: While it is well known that diet-induced obesity causes insulin resistance, the precise mechanisms underpinning the initiation of insulin resistance are unclear. To determine factors that may cause insulin resistance, we have performed a d ... Full text Link to item Cite

Differential effects of various fish proteins in altering body weight, adiposity, inflammatory status, and insulin sensitivity in high-fat-fed rats.

Journal Article Metabolism · August 2011 Mounting evidence suggests that the benefits of fish consumption are not limited to the well-appreciated effects of omega-3 fatty acids. We previously demonstrated that cod protein protects against the development of diet-induced insulin resistance. The go ... Full text Link to item Cite

Endotoxin mediated-iNOS induction causes insulin resistance via ONOO⁻ induced tyrosine nitration of IRS-1 in skeletal muscle.

Journal Article PLoS One · December 28, 2010 BACKGROUND: It is believed that the endotoxin lipopolysaccharide (LPS) is implicated in the metabolic perturbations associated with both sepsis and obesity (metabolic endotoxemia). Here we examined the role of inducible nitric oxide synthase (iNOS) in skel ... Full text Link to item Cite

Nitrosative modifications of protein and lipid signaling molecules by reactive nitrogen species.

Journal Article Am J Physiol Endocrinol Metab · December 2010 This review is the last of four review articles addressing covalent modifications of proteins and lipids. Two of the reviews in this series were previously published (15, 28) and dealt with modifications of signaling proteins by GlcNAcylation and serine ph ... Full text Link to item Cite

Transgenic restoration of long-chain n-3 fatty acids in insulin target tissues improves resolution capacity and alleviates obesity-linked inflammation and insulin resistance in high-fat-fed mice.

Journal Article Diabetes · December 2010 OBJECTIVE: The catabasis of inflammation is an active process directed by n-3 derived pro-resolving lipid mediators. We aimed to determine whether high-fat (HF) diet-induced n-3 deficiency compromises the resolution capacity of obese mice and thereby contr ... Full text Link to item Cite

Long-chain omega-3 fatty acids regulate bovine whole-body protein metabolism by promoting muscle insulin signalling to the Akt-mTOR-S6K1 pathway and insulin sensitivity.

Journal Article J Physiol · February 15, 2007 The ability of the skeletal musculature to use amino acids to build or renew constitutive proteins is gradually lost with age and this is partly due to a decline in skeletal muscle insulin sensitivity. Since long-chain omega-3 polyunsaturated fatty acids ( ... Full text Link to item Cite

Enhancing Recovery in Coronary Heart Disease (ENRICHD) study intervention: rationale and design.

Journal Article Psychosom Med · 2001 OBJECTIVE: Depression and low social support are risk factors for medical morbidity and mortality after acute MI. The ENRICHD study is a multicenter, randomized, controlled clinical trial of a cognitive-behavioral treatment for depression and low social su ... Link to item Cite