Obesity is the leading cause of chronic illness and premature death in the United States. The goal of this proposal is to further our understanding of how obesity develops and how obesity causes metabolic disease. In particular we will investigate an area that we developed during the last funding cycle - the regulation of adipocyte mitochondrial biogenesis and metabolism by Wnt signaling. Exposure of cultured adipocytes to Wnt3a activates signaling pathways and increases expression of mitochondrial regulators, such as peroxisome proliferator-activated receptor-? coactivator 1? (Pgc1?), mitochondrial transcription factor A (Tfam) and nuclear respiratory factors (Nrfs). In addition, Wnt3a regulates lysine acetylation of a subset of mitochondrial proteins including citrate synthase, whose activity increases with Wnt treatment. Based on these data, we propose experiments to test the hypotheses that regulation of posttranslational modifications on mitochondrial proteins mediates effects of Wnt3a on oxidative metabolism, and that it is Wnt11 that initiates endogenous Wnt signaling in this context. We have found that inhibition of Wnt signaling by secreted frizzled-related protein 5 (SFRP5), which is induced in adipose tissue with obesity, is required for adipocytes to hypertrophy in response to an obesigenic diet, and we propose to use our novel animal models to extend the roles of SFRP5 and Wnt signaling in adipose tissue biology. To test these hypotheses we propose the following specific aims: 1) to investigate mechanisms by which expression of SFRP5 in adipocytes regulates adipocyte hypertrophy and the development of obesity, and 2) to determine mechanisms by which Wnt signaling stimulates mitochondria biogenesis and metabolism. These studies will greatly advance our understanding of the mechanisms that control adipocyte metabolism. Importantly this work will resolve for the field the conflicting data on the regulation and functional roles of Sfrp5 in adipose tissue and glucose homeostasis/insulin sensitivity. Our results will also further our mechanistic understanding of how Wnt signaling regulates oxidative metabolism through acetylation and activity of mitochondrial proteins in adipocytes and with obesity. These findings may also shed light on similar regulatory processes of Wnt signaling on mitochondrial function in liver and muscle. Thus, insights gained from the successful completion of proposed studies will be crucial for our understanding of adipose tissue physiology and the development of obesity and associated metabolic complications.

Public Health Relevance

Obesity and the myriad of associated health consequences such as type 2 diabetes and cancers are an enormous health problem for the United States population. The proposed research will greatly advance our understanding of how nutrients are utilized and released by adipocytes, and novel factors that control this process. Thus, insights gained from the successful completion of proposed studies will be crucial for our understanding of adipose tissue physiology and the development of obesity and associated metabolic complications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK062876-14
Application #
9513519
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Haft, Carol R
Project Start
2003-02-01
Project End
2019-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
14
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Physiology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Bagchi, Devika P; Forss, Isabel; Mandrup, Susanne et al. (2018) SnapShot: Niche Determines Adipocyte Character II. Cell Metab 27:266-266.e1
Ge, Chunxi; Zhao, Guisheng; Li, BinBin et al. (2018) Genetic inhibition of PPAR? S112 phosphorylation reduces bone formation and stimulates marrow adipogenesis. Bone 107:1-9
Li, Ziru; Hardij, Julie; Bagchi, Devika P et al. (2018) Development, regulation, metabolism and function of bone marrow adipose tissues. Bone 110:134-140
Bagchi, Devika P; Forss, Isabel; Mandrup, Susanne et al. (2018) SnapShot: Niche Determines Adipocyte Character I. Cell Metab 27:264-264.e1
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Chen, Yii-Shyuan; Wu, Rui; Yang, Xiaosong et al. (2016) Inhibiting DNA methylation switches adipogenesis to osteoblastogenesis by activating Wnt10a. Sci Rep 6:25283

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