MODULATION OF ADIPOSE TISSUE METABOLISM BY UNACYLATED GHRELIN AND ITS RELEVANCE IN OBESITY

Adipose tissue is a multi-functional organ with metabolic implication far beyond its role in energy storage, therefore its relevance in obesity and consequent metabolic dysregulation has been largely investigated. Ghrelin is a gastric hormone whose circulating levels are predominantly in the unacylated form (UnAG). While the acylated form was first characterized for its important effects on energy balance, UnAG has recently shown to be independently involved in several metabolic functions, including a role as positive modulator of oxidative stress, inflammation and insulin sensitivity in skeletal muscle. However, to date, very little is known about UnAG effects in adipose tissue, another important metabolic organ. The current study proposes to investigate UnAG implications in rodents adipose tissue metabolism by testing 1) 4-day of UnAG sustained exogenous administration on healthy rats and 2) transgenic systemic overexpression of UnAG in mice treated with standard or high-fat diet (HFD). Complexively our results showed that in healthy rodents, UnAG does not modify mitochondrial activity, antioxidant systems and inflammatory state but it decreases insulin sensitivity in both models of UnAG administration or overexpression. Interestingly though, in obese mice UnAG systemic overexpression, the hormone was found to prevent alterations of mitochondrial function and dynamics, redox state and inflammatory response. Consistently, UnAG also improved insulin sensitivity of obese mice, and finally prevented HFD-related adipocytes enlargement with lower actin remodeling. In support of these in vivo results, clinical analyses in humans showed that UnAG circulating levels decrease in elderly overweight-obese individuals compared to lean and are predictive of 5-year mucle mass independently from BMI. Consistently, in a general population cohort fat-to-mass ratio was negatively correlated to UnAG levels, independently from BMI and other metabolic variables. Globally, our findings in animal and human studies suggest UnAG as a novel modulator of adipose tissue metabolism with important implications in obesity pathogenesis, suggesting UnAG as a potential candidate for further studies aiming to contrast obesity and obesity-associated metabolic complications.