White and brown adipocytes not only play a central role in energy storage and combustion, but are also dynamic secretory cells that produce signaling molecules that link levels of energy stores to other vital physiological systems. Disruption of the signaling properties of adipocytes, as occurs in obesity, contributes to insulin resistance, type 2 diabetes, and other metabolic disorders. Fat cells have been estimated to secrete more than 1,000 polypeptides and microproteins and even large number of small molecule metabolites. The great majority of the adipocyte secretome has not been defined or characterized and addressing this gap in knowledge is the main goal of this collaborative, interdisciplinary team project. A major obstacle has been the lack of suitable technologies to quantitatively identify circulating proteins and metabolites, determine their cellular origin, and elucidate their function. Building on compelling preliminary data and key innovations from members of this team, we will generate the first encyclopedia of the white and brown adipocyte secretome in mouse models and humans. Specifically, we will (1) Generate an encyclopedia of the secretome of murine adipocytes, (2) Characterize the adipocyte secretome in response to physiological stress and in pathological states, (3) Characterize the adipose secretome in humans, and (4) Characterize the function of the adipocyte secretome. These studies, which span from basic biology to human subject investigation will only be possible by optimizing tools within diverse disciplines and at their intersection. This project has the potential to address questions central to the mission of the NIDDK such as the molecular basis for the links between obesity and type 2 diabetes and understanding whether the anti-diabetic benefits of brown fat are conveyed by secreted mediators. Our studies have the potential to identify new secreted mediators with roles in obesity, type 2 diabetes and metabolic diseases, catalyze the development of new technologies, provide a crucial new resource for researchers and clinicians, and lead to new biomarkers and therapies.

In modern times, excess calorie dense foods, sedentary lifestyle, and thermal comfort have contributed to an overexpansion of white fat and a paucity of brown fat, resulting in a dramatic increase in the prevalence of obesity, type 2 diabetes, and associated diseases. White and brown adipocytes have important secretory functions, but the full complement of mediators that can be secreted by fat cells and their underlying mechanism of action remain unknown. The goal of this collaborative, interdisciplinary team research proposal is to employ novel technologies to create an encyclopedia of the adipocyte secretome and to elucidate the function of novel mediators, providing a valuable resource for the field and generating biological insights that could facilitate the development of new therapies for obesity, type 2 diabetes, and metabolic diseases.