Abstract

Aside from energy storage, the adipose tissue (AT) communicates to distant organs, including the heart, through endocrine mechanisms influenced by the metabolic status. We tested the hypothesis that modifications of AT during obesity modulates cardiac hypertrophy and fibrosis via AT endocrine communication, and that increasing the pool of beige (brown-like) adipocytes by stimulating adipocyte beta-3 adrenergic receptor (β3AR), prevents AT remodeling and remotely protects against cardiac remodeling. C57Bl/6J mice were fed a high-fat (50%) + sucrose (12%) diet (HF-S) or a control diet during 5 months. Cardiac remodeling was assessed by serial echocardiography and histomorphometric analysis, and metabolism by glucose and insulin tolerance tests. Browning and inflammation were measured by multiplex IHC and RTqPCR. Circulating extracellular vesicle were characterized by surface markers and electron microscopy. HF-S diet during 5 months produces significant weight gain and insulino-resistance in C57Bl/6J mice, together with inflammation of both the visceral and inguinal AT, expression of TNFα and IL6 as well as reduction of brown/beige adipocyte markers. HF-S diet produced cardiac hypertrophy and interstitial fibrosis as well as initial signs of left ventricular diastolic dysfunction (increased E/A and left atrial dimensions; increased left ventricular mass/tibial length, lung weight but unchanged ejection fraction). Osmotic minipump infusion of the β3AR agonist, CL-316 243 (CL) significantly attenuated weight gain and corrected insulin resistance in HF-S - fed mice. In lean mice, CL produced browning of both visceral and subcutaneous AT and increased the expression of beige/brown markers isolated adipocytes. Extracellular vesicles isolated from AT of obese mice superfused on isolated cardiac myocytes produced myocyte hypertrophy. Conversely, microvesicles isolated from AT of CL-treated mice attenuated the hypertrophy of phenylephrine-treated cardiac myocytes in culture. HF-S-fed C57Bl/6J mice recapitulate key features of obesity-related metabolic and cardiac remodeling, which can be reproduced with their circulating extracellular vesicles superfused on cardiac myocytes in vitro. The latter is reversed by activation of the B3AR that induces browning of AT and composition of their extracellular vesicles.