The short term goal is to understand how fat cells are created in vivo and what determines their metabolic phenotype, with a long term goal of manipulating adipocyte phenotypes for therapeutic benefit. During the past funding cycle our laboratory established several important principles of in vivo adipogenesis that provide a foundation for further investigation. Specifically, we have shown that adipogenesis occurs in well-defined tissue niches and involves critical interactions among stromal cell populations that include committed progenitors, resident immune cells, and vascular cells. The renewal application will build upon these observations by further deconstructing specific adipogenic niches that generate therapeutically beneficial phenotypes.
The first aim will deconstruct the adipogenic niche in classic brown adipose tissue by providing a comprehensive and unbiased identification of BAT stromal cell types using the emerging technologies of single cell RNA-sequencing (scRNA-seq) and single molecule fluorescence in situ hybridization (smFISH). In complementary mechanistic experiments, we will determine how ?1-adrenergic receptors control recruitment of brown adipocyte progenitors and proliferation of resident macrophages and endothelial cells. These experiments will also determine whether cyclic AMP-dependent neogenesis is a general property of preadipocytes in subcutaneous and visceral fat, using a novel chemogenetic approach.
The second aim will investigate the origins and functions of distinct anabolic and catabolic adipocytes within subcutaneous adipose tissue. We will first establish whether catabolic and anabolic phenotypes can be derived from a single progenitor using a novel clonal tracing technology. Next, we will use scRNA-seq and smFISH to determine the temporal stability of these phenotypes in vivo. In addition, we will directly determine whether the putative metabolic phenotypes separately mediate lipid oxidation/turnover and synthesis using stable isotope tracing. Finally, we will investigate molecular mechanisms of phenotype selection and stability using a novel cell reporter line. Overall, the proposed work will provide the first comprehensive, unbiased, and systematic analysis of cell types that comprise BAT and ingAT. We will deconstruct cellular interactions and mechanisms guiding brown adipocyte recruitment in vivo. This work will also investigate the new, unexpected metabolic flexibility of subcutaneous adipocytes using innovative cellular and molecular approaches. Together, this work will greatly advance our understanding of cellular and metabolic plasticity of adipogenic niches, and will guide therapeutic efforts for establishing and maintaining beneficial cellular phenotypes.
Adipose tissue remodeling is an emerging therapeutic strategy for treatment of obesity-related disorders like diabetes. Nonetheless, the mechanisms that recruit and maintain beneficial adipocyte phenotypes are poorly understood. This proposal will use innovative single cell technologies to identify all of the cellular types that contribute to therapeutic remodeling. We will then examine the interactions of these cell types in robust mouse models and test specific mechanisms that drive the appearance of beneficial adipocyte phenotypes. In addition, we will investigate unexpected metabolic heterogeneity of subcutaneous adipocytes, which will include functional, cellular and molecular analyses in vivo and in vitro. The long term goal of this project is to guide strategies for expanding metabolically desirable adipocyte phenotypes for treating obesity-related disorders.
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