P311 mediated adipogenesis, adipocyte plasticity and metabolic regulation

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Summary One third of the US population is clinically obese, a condition which increases the risk for chronic diseases like type 2 diabetes mellitus (DM), heart disease and cancers. Adipocyte dysfunction (AD) is cardinal feature of metabolic dysregulation and increases the risk for developing insulin resistance (IR), DM, and hypertension. Along with adipocyte hypertrophy, macrophage infiltration of white adipose tissue (WAT) is associated with the pathophysiology of obesity, AD and IR, albeit the underlying molecular mechanisms are uncharacterized. We were first to show the presence of P311 in WAT, brown adipose tissue (BAT) and beige adipose tissue. The WAT of P311 knockout (KO) mice has fewer resident macrophages and decreased cellular dynamics, including decreased autophagy and apoptosis. This is potentially leading to adipocyte hypertrophy that in turn causes hyperglycemia due to age- and genetic ablation-mediated P311 expression leading to overworked and exhausted adipocytes in P311 KOs or low P311 expressing adipocytes compared to wild types. As studies are limited, resident macrophages could alter adipocyte function early in adipose tissue development, a novel mechanism requiring exploration. We will also explore key adipocyte cellular processes of apoptosis and autophagy/lipophagy, which may affect adipocyte turnover in the WAT of P311 KO mice, leading to adipocyte hypertrophy and dysfunction, and thus metabolic deregulation. The proposed project will test the central hypothesis that age- and genetic ablation-mediated P311 levels play a key role in white, brown and beige adipocyte development, plasticity and function, as well as in metabolic regulation. Further, we will investigate the role of P311 in cellular processes (i.e., WAT browning and BAT whitening) and its effect on adipocyte function and glycemic control, as P311 KO mice are hyperglycemic. We will also evaluate the ability of P311 to modulate adipose biology and metabolic regulation through PPAR and UCP1 regulation; and myo1C binding to GLUT4. We will develop adipocyte-specific P311 KO conditional mice using novel CRISPR technology to evaluate the adipocyte-specific P311 roles. The current project will thereby establish P311 as a new player in adipocyte biology and metabolic regulation. Our experimental strategy will incorporate transgenic animals using classic cell biology, molecular biology, biochemical, immunoassays and imaging methods studies. Our findings will enhance the understanding of P311 mediated fat cell development and function and fat mass expansion. Our ongoing studies indicate that P311 potentially regulates metabolism through adipocyte dynamics, function and plasticity (a novel approach to targeting metabolic disorders through browning of WAT); regulating resident and infiltrating macrophages; and controlling adipocyte cellular processes. These studies are new and do not overlap with existing funding.