Examining Mechanisms and Functional Significance of Adiponectin Stimulated Autophagy in Cardiometabolic Diseases

Unbalanced energy intake over expenditure causes obesity, and the prevalence and incidences of obesity have increased over last decades. People with obesity have a cluster of metabolic co-morbidities called metabolic syndrome which substantially increase the risk of diabetes and cardiovascular diseases. The pathophysiological mechanisms underlying metabolic syndrome are multifaceted and one contributing factor is altered adipokines profiles. Adiponectin is the most abundant adipokine in the circulation and a low serum adiponectin level is implicated in multiple diseases. Adiponectin acts on various tissues by improving energy metabolism and conferring protective effects. Majority of studies suggest adiponectins beneficial effects are mediated through AMPK signaling. AMPK is a master regulator of energy metabolism and activated upon low energy status. AMPK activates multiple cellular process to generate energy including autophagy. Autophagy is a conserved catabolic process which confers an adaptive force against stresses by mobilizing energy sources and preventing toxin accumulation. The studies presented here investigating molecular mechanism underlying adiponectins pleotropic effects, particularly focusing on its relation to autophagy. In the first study, the effects of iron overload on autophagy in skeletal muscle were observed. Iron toxicity is associated with reduced circulating adiponectin level and increased the diabetes mellitus incidences. Chronic iron overload altered the autophagy regulatory signaling mTOR, which impaired autophagy lysosome reformation, a novel late stage autophagy process crucial for insulin sensitivity. In the second and third studies, the changes in cardiac autophagy following pressure overload or myocardial infarction were monitored in mice lacking adiponectin. Adiponectin deficient mice exhibited exaggerated cardiac remodeling with evidence of autophagy impairments. With an advanced live-animal imaging system, a lower autophagy activity was observed in adiponectin knockout mice hearts after stresses. Cell culture experiments further validated that adiponectin directly stimulated autophagy flux and protected cardiomyocytes from cell death. Taken together, the studies described here highlight that adiponectin is an important regulator of autophagy in skeletal muscle and hearts, and adiponectin signaling is a potential therapeutic target to modulate autophagy rates.