Role of Acylated Ghrelin in Adipose Tissue Metabolism and Investigation of Its Interaction with O-GlcNAc Transferase

Adipose tissue is an endocrine organ that plays, besides its pivotal role in energy storage, a principal role in the whole-body metabolic homeostasis. Acylated ghrelin exerts major effects on intermediate metabolism and energy homeostasis. While the effects of acylated ghrelin in metabolic tissues like liver and skeletal muscle are at least in part known, those are still to be discovered and largely unknown. This study aimed at investigating the role of acylated ghrelin in adipose tissue metabolism, and identifying possible mediators for the acylated ghrelin effect. We reported in this study that sustained acylated ghrelin treatment lowers insulin sensitivity in the visceral adipose tissue in vivo, in both physiological conditions and in a rodent model of inflammation and wasting by surgically induced-CKD, and in vitro in 3T3L1 differentiated adipocytes. In parallel with lowering insulin sensitivity, AG treatment lowered the mitochondrial function in physiological conditions without altering the redox state and cytokine profile, while in systemic inflammation conditions, AG selectively improved the proinflammatory cytokine profile by lowering TNFα levels without exerting significant effects on redox state and mitochondrial function. O-GlcNAcylation is a non-canonical glycolisation post-translational dynamic modification (PTM) that resulted in the attachment of O-linked N-acetylglucosamine (O-GlcNAc) moieties to Ser and Thr residues of cellular proteins. O-GlcNAc transferase, OGT, is the enzyme that adds O-GlcNAc to the targets. We reported in our study that OGT levels in the visceral adipose tissue are upregulated by AG treatment in vivo, both healthy and systemic inflamed rats, not in vitro suggesting that OGT upregulation upon AG treatment is regulated by non-adipose tissue mechanism. In the last part of the study, we reported in vitro using 3T3L1 and human differentiated adipocytes that OGT alters the adipocytes sensitivity to the AG treatment, and AG administration to OGT-silenced adipocytes in starvation conditions improved the insulin sensitivity of the adipocytes suggesting potential therapeutic effect for metabolic syndrome still needs to be validated in vivo by transgenic mice knocked for OGT expression in the adipose tissue.