Project Summary: The pathogenesis of heart failure is linked to systemic metabolic dysfunction, a comorbidity likely involving peripheral organs, and resulting in insulin resistance in patients with and without diabetes. This study focuses on the reciprocal response of adipose tissue to pathological stress on the heart and will investigate how adipose tissue activity affects cardiac metabolic remodeling. This proposal originates from novel findings by each of the MPI laboratories. We have identified transient changes in adipose tissue plasticity during the pathogenesis of decompensated cardiac hypertrophy in response to pathological stress alone, absent any primary metabolic stress, such as diabetes, nutrient overload, or obesity. This finding and our unpublished data implicate cardiac natriuretic peptides (NP) as mediators of adipose activation and show that NPs are induced by a reduction in long chain fatty acid (LCFA) oxidation by the heart, even without pathological stress. Preliminary data reveal a profound, sex-specific array of early responses in white (WAT) and brown (BAT) adipose tissue activity to cardiac pressure overload that include beiging of WAT and induction of a lipolytic phenotype with cold exposure. While the cardiac responses to pathological stress include maladaptive remodeling of lipid metabolism, the effects of adipose plasticity on the cardiac lipid profile during the development of pathological hypertrophy are virtually unexplored. Thus, we hypothesize that: 1) the metabolic response of reduced fatty acid oxidation in the heart during pathological stress induces plasticity of WAT that is mediated by cardiac NPs in a sex-specific manner, distinct from β-adrenergic stimulation, with downstream effects on glucose tolerance; and 2) sustained beiging of WAT and activation of BAT confer cardioprotection against adverse cardiac metabolic remodeling. The research design supports three specific aims: 1. Elucidate effects of adipocyte adrenergic activation on WAT beiging, and responses of cardiac LCFA metabolism during TAC with adipose adrenergic activation and inhibition; 2. Determine whether adipose plasticity results from NP effects in direct response to TAC or from the metabolic shift of reduced LCFA oxidation in male and female mice; 3. Investigate a potential cardioprotective role of adipose browning on the lipid profile of failing hearts. The overall objectives are to: 1) determine the reciprocal metabolic responses between the pathologically stressed heart and adipose tissue via cardiac NP production and adipokine/lipokine release (namely 12,13-diHOME), respectively; 2) elucidate the consequences of sex differences in the responses of adipose tissue and myocardium to cardiac stress; and 3) explore the potential for WAT beiging or BAT activation to provide cardioprotection via metabolic signaling. The findings will contribute new insights into the adipose responses and contributions to metabolic remodeling of the heart durin...