Mechanisms of human adipose tissue development and impact of diabetes

Univ Of Massachusetts Med Sch Worcester, Worcester MA

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Abstract

ABSTRACT The distribution of adipose tissue among central and lower body depots is a major predictor of Type 2 Diabetes (T2D) and cardio metabolic disease risk. However, the mechanisms that control regional adipose tissue development, and how each depot differentially impacts systemic metabolism, are not well understood. The goal of this proposal is to elucidate these mechanisms by leveraging powerful new approaches to generate functional adipose tissue in mice from mesenchymal progenitor cells derived from human adipose tissue. During the past budget period, we obtained and characterized progenitor cells from the abdominal (ABD) and gluteo-femoral (GLU) depots from individuals with normal glucose tolerance (NGT) or with T2D. We now seek to use these cells to elucidate mechanisms by which these adipose depots develop, selectively impact systemic metabolism, and influence T2D pathogenesis. We propose the following specific aims: Aim 1. We will test the hypothesis that functionally distinct adipose depots will be generated from progenitor cells from ABD or GLU depots from subjects with NGT or T2D, and that these depots will differentially impact systemic metabolic homeostasis in the mouse host. These “human” adipose depots will be generated in two mouse models of insulin resistance: first, in the well-characterized NSG mouse on a high-fat diet, and second, in a newly developed model lacking endogenous adipose tissue due to knockout of the BSCL2 lipodystrophy gene, in which all functional adipocytes will be from human origin. This will provide exceptional sensitivity to detect the selective effects of each depot on mouse metabolic parameters. Aim 2. In vitro, progenitor cells from subjects with T2D display an impaired commitment to the adipogenic fate. We will test the hypothesis that this impairment is due to enhanced WNT signaling, which in the prior budget period we have found to be a critical determinant of mesenchymal progenitor adipogenic differentiation. We will measure WNT signaling directly and compare the developmental trajectory of progenitor cells from NGT and T2D subjects using newly discovered markers for each developmental fate. Aim 3. We will define the specific WNT ligands operating across the human adipocyte differentiation trajectory, and their impact on the development and function of adipose tissue in vivo. Using CRISPR-Cas9, we will selectively knockout each of the WNT ligands expressed at distinct points during human adipocyte differentiation from progenitor cells and assess the impact on tissue development in-vivo. Defining the role of the WNT pathway in human adipose tissue development will help understand the basis for the strong genetic association between T2D risk and polymorphisms in TCF7L2, a critical element of the WNT pathway. It will also provide a framework to explore targeting of adipose tissue WNT ligands as a potential therapeutic strategy in T2D.