Abstract 312: Cardiomyocyte-secreted Signaling Factors Modulate Adipocyte Differentiation And Function
Gresham, KS; Koch, WJ
Published in: Circulation Research
Heart failure (HF) alters cardiomyocyte metabolism by altering energy substrate utilization and mitochondrial function, which has potential implications for global metabolic health. Recent studies demonstrated that cardiomyocyte-released signaling factors communicate with peripheral organ systems to alter metabolic function and that signaling pathways activated by HF control the release of these factors. However, the identity of these factors is still under investigation. Conditioned media (CM) collected from neonatal rat ventricular myocytes (NRVMs) was used to treat 3T3-L1 pre-adipocytes to 1) identify signaling molecules released by cardiomyocytes that could regulate global metabolic function and 2) determine how HF signaling pathways alter their release. NRVM-CM slowed adipocyte differentiation as measured by lipid accumulation using the fluorescent probe BODIPY 493/503 (57±8% decrease in normalized fluorescence compared to control media) and reduced the expression of adipocyte-related proteins. NRVM CM treatment also increased basal mitochondrial oxygen consumption (78 ± 3 vs 62±4 pmol/min) and maximal respiration (270±12 vs 220 ± 16 pmol/min) in mature adipocytes. CM protein fractionation revealed that released-factor activity was retained in >100kDa fractions and this activity was abolished by trypsin digestion, suggesting a novel, high-MW cardiomyocyte-released signaling protein that targets adipocytes. To determine if NRVM-released factor activity is altered by HF signaling, the ability of G-protein kinase 2 (GRK2, upregulated by HF) signaling activity to alter NRVM-released factor activity was investigated. GRK2 overexpression in NRVMs increased the activity of this released-factor as measured by further decreased 3T3-L1 differentiation (lipid accumulation measured by BODIPY fluorescence was 70±8% compared to CM from GFP-overexpressing NRVMs), while overexpression of the GRK2 inhibitor βARKct increased adipocyte differentiation (140±13% compared to control NRVM-CM). These results suggest a novel, high-MW cardiomyocyte-released signaling protein under the control of HF signaling pathways communicates with adipocytes to alter adipose tissue function and potentially alter global metabolic function.
