306-OR: Diet-Induced Hyperlipidation of Adiponectin Contributes to Adiponectin Dysfunction

With the noteworthy linear rise in the prevalence of obesity in the United States, adiponectin has swiftly garnered attention as a hormone protein of interest owing to its anti-diabetic, anti-insulin-resistant, and anti-inflammatory properties. Protein S-palmitoylation is a post-translational modification that has been implicated in a wide variety of diseases including cancer, neurodegenerative disorders, and metabolic disorders, supporting its critical role in regulating protein transport, localization, and cell survivability. As serum Adiponectin exists as multimers, the distribution of which differs under disease pathology and by sex, our current study seeks to elucidate the underlying mechanism regulating adiponectin’s cellular localization, function, and stability. Utilizing acyl resin-assisted capture, our current study indicates that Adiponectin undergoes protein S-palmitoylation. Intriguingly, male mice fed a high-fat diet (HFD) exhibited an 18-fold increase in protein S-palmitoylation in their adipose tissue compared to normal chow (NC) diet-fed controls. However, no significant difference was observed in the levels of adiponectin palmitoylation between female mice on HFD compared to NC controls. Similarly, palmitoylation of adiponectin was observed in the adipose tissues of men with a BMI classified as obese and the modification was undetected in lean individuals. Collectively, our findings suggest that adiponectin undergoes protein S-palmitoylation and that this modification is associated with obesity in males. Identifying protein S-palmitoylation of adiponectin as a post-translational modification and a key regulatory mechanism in the expression and function of this beneficial hormone could unveil a novel mechanism contributing to the obesity-induced down-regulation of adiponectin - a causal factor for insulin resistance and related metabolic disorders.