Type 2 diabetes is an increasingly prevalent disease posing great burdens to healthcare, in which obesity and adipose tissue (AT) dysfunction are central components of disease progression. Impairment of insulin signaling and inflammation in AT can trigger insulin resistance but an improved understanding of metabolic dysfunction during disease progression is necessary to identify novel targets for therapeutics. G-protein pathway suppressor 2 (GPS2) plays an important role as a mediator of lipid metabolism and inflammatory responses, both processes regulating insulin resistance, but GPS2 exact function in AT remains unknown. These data suggest GPS2 in AT plays an important role in systemic regulation of metabolic homeostasis and dissecting GPS2 function in AT is therefore critical for understanding how metabolic and inflammatory pathways are inter-regulated during the development of insulin resistance. These studies describe the characterization of the adipocyte-specific GPS2 knockout (GPS2-AKO) mouse model. A novel layer of regulation in the insulin signaling cascade was identified, based on ubiquitin conjugating enzyme E2N (Ubc13)-mediated K63 ubiquitination of protein kinase B (AKT). GPS2 was found to be a negative regulator of this pathway through inhibition of Ubc13. Loss of GPS2 promoted AKT hyperubiquitination and activation and enhanced insulin signaling in adipocytes, a mechanism conserved in other cell types. Phenotypic characterization of GPS2-AKO mice showed they developed increased body weight and AT mass when fed chow diet. The white AT (WAT) was characterized by adipocyte hypertrophy, a result of impaired lipolysis and increased lipogenesis. Similarly, brown AT (BAT) acquired a WAT phenotype caused by increased lipid accumulation from compromised lipolysis and defective mitochondrial biogenesis. Despite significant increases in adiposity, GPS2-AKO mice had improved systemic insulin sensitivity due to enhanced insulin signaling and lipid storage capacity. Observations indicated GPS2-AKO mice on high fat diet (HFD) became excessively obese and inflamed, yet displayed reduced peripheral tissue lipid deposition and remained metabolically healthy. This work describes how GPS2 modulates systemic metabolism by regulating insulin signaling, lipid storage capacity, mitochondrial biogenesis and inflammation. Dissecting GPS2 function in AT provides insight into points of regulatory convergence among pathways connecting AT to systemic metabolic regulation, helping to uncover innovative targets for the treatment of metabolic disorders
