MEDAG functions as an A-Kinase Anchoring Protein in adipocytes

Induction of catabolic adipocyte activity independent of mitochondrial uncoupling to induce energy expenditure has received increasing attention in the last few years. In this study, we identified Mesenteric Estrogen-Dependent Adipogenesis Gene (MEDAG), a poorly studied gene, as a promising therapeutic target for enhancing energy expenditure in adipocytes. We demonstrated that adipose MEDAG expression positively correlates with obesity and metabolic dysfunction in humans. Consistently, adipocyte-specific ablation of Medag in mice leads to increased energy expenditure, offering protection from diet-induced obesity. Mechanistically, we show that MEDAG functions as an A-kinase Anchoring Protein which can directly regulate Protein Kinase A (PKA) activity through a negative feedback loop, involving direct interaction with PKA leading to MEDAG phosphorylation and consequent feedback-finetuning of PKA activity. Specifically, direct interaction of MEDAG with the PKA-RIIβ subunit regulates the stability of PKA-RIIβ to prevent PKA hyperactivation. These findings establish the MEDAG as an attractive novel target to stimulate adipose energy expenditure and uncover the novel AKAP activity of MEDAG.