The Regulation and Metabolic Effects of gp130 Cytokines in Human White Adipose Ti

Lsu Pennington Biomedical Research Ctr, Baton Rouge LA

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Abstract

DESCRIPTION (provided by applicant): Obesity, characterized by excessive adiposity, is a risk factor for many metabolic pathologies, such as Type 2 Diabetes mellitus (T2DM). Numerous studies have shown that adipose tissue distribution may be a greater predictor of metabolic health. Upper-body fat is commonly associated with complications of obesity, while lower-body fat may be protective. However, the factors and mechanisms that govern white adipose tissue (AT) depot expansion have not been elucidated. Published studies have highlighted the effects of gp130 cytokines, specifically cardiotrophin-1 (CT-1) and oncostatin M (OSM), on the function of murine adipocytes in vitro and rodent WAT in vivo. Our novel preliminary data reveal that CT-1 and OSM are differentially expressed in human AT depots and that AT-derived gp130 cytokine production is altered in obesity. Our preliminary data also strongly suggest that elevated OSM expression in human AT correlates with global insulin resistance. The research objective for the proposed project is to collect and analyze human samples and physiological data from 3 completed and on-going clinical studies [Cellular Dynamics of Fat Distribution (R01-DK090607); Fat Cell Size and Overfeeding(R01-DK060412); and Effect of Bariatric Surgery and Weights Loss on Energy Metabolism and Insulin Sensitivity (Ethicon Endo-Surgery, Inc. Grant #25404)- all PI: Ravussin, E)] to investigate how the production of gp130 cytokines from divergent human AT depots is modulated by obesity and metabolic health status and to assess the influence of these cytokines on insulin sensitivity. We hypothesize that CT-1 and OSM production and secretion are modulated by depot and adiposity and highly correlate with systemic insulin resistance. In addition, we propose that CT-1 and OSM can directly affect insulin action in human adipocytes. These studies will fill a critical void in the literature by assessing the novel actions of the gp130 family in human AT. Importantly, Dr. White will learn and implement new methods in clinical research that are necessary to become a translational investigator. Pennington Biomedical Research Center, with its vast array of research facilities, will provide a nurturing learning environment for the candidate to successfully complete the aims and objectives of the application. The training in this research project will also set the stage fo future analyses to investigate mechanisms that control regional adipose tissue growth and distribution that may be important as pharmacological targets for body weight regulation- which is the candidate's long-term research goal. The objective of the NIDDK K01 award is to facilitate the career development of the candidate through training from experienced mentors and implementation of the proposed research project. The PI has assembled an outstanding mentoring team comprised of experienced investigators that will all provide instruction and expertise to her research interests and contribute to her path to independence. Overall, this application will promote Dr. White's long-term goal of becoming an independent, well-funded translational investigator of adipose tissue biology.