Obesity is a well-established risk factor for a number of diseases, including type 2 diabetes and coronary heart disease. While weight loss is the most effective treatment of type 2 diabetes, current methods for reducing weight are typically insufficient for long-term weight loss. The mission of AdipoGenix, Inc. is to discover, develop, and license novel therapeutics acting at the level of the fat cell for the treatment of obesity and related disorders. Targets for use in drug discovery in the area of obesity are lacking, particularly at the level of the fat cell. Ideal targets are specific to the cell in question. In adipose tissue this would translate to differentiation-specific and depot-specific targets, especially those prominent in visceral adipocytes or preadipocytes, since the accumulation of visceral (mesenteric and omental) fat carries a greater risk of morbidity and mortality than peripherally distributed (subcutaneous) fat. Adipocytes are known to secrete a number of factors having autocrine, paracrine, and/or endocrine functions, and in many instances these factors are secreted at considerably different levels by preadipocytes. These secretion factors may represent valid targets in drug discovery, through either an interference with their natural function, or through modulation of their secretion levels. We will therefore identify targets through the comprehensive detection of depot- and differentiation-dependent secreted proteins and peptides using human adipocytes and preadipocytes from omental, mesenteric, and subcutaneous depots. We will use HPLC to compare protein and peptide secretion levels between each cell type and depot. We will test the effects of several exogenous agents relevant to obesity on the secretion levels of proteins and peptides that meet certain criteria across patient populations. Through the work proposed here, we expect to identify targets that are secreted in a depot- and differentiation-specific manner for subsequent use in the development of assays designed to measure secretion levels. This work will therefore produce commercially viable targets, assays, and eventual lead compounds for development into anti-obesity drugs.
