Obesity has become one of the most pressing public health issues of the current century. Unfortunately, tackling the high incidence of obesity is proving to be extremely difficult. The initial discovery of leptin, an adipocyte-derived hormone that acts on hypothalamic neurons to suppress appetite and regulate energy expenditure, raised hope for an obesity therapy. However, its therapeutic use is hampered by the development of leptin resistance in obese humans, a phenomenon for which the precise molecular mechanisms are not fully understood. Similarly, diabetes mellitus is characterized by insulin deficiency or resistance. Interestingly, endoplasmic reticulum (ER) stress is associated with obesity and implicated in leptin and insulin resistance in peripheral tissues and in the brain. Recent evidence suggests that a key site involved this stress response is the hypothalamus. Notably, arcuate POMC and NPY/AgRP neurons are key targets of leptin and insulin action. Moreover, normal melanocortin signaling is required for normal food intake, body weight, and euglycemia. Thus we hypothesize arcuate POMC and NPY/AgRP neurons are involved in this hypothalamic stress response. In the current proposal, we will extend prior observations. We will identify cellular mechanisms through which ER stress induces acute leptin and insulin resistance. We will also determine a role for ER stress in identified hypothalamic neurons to regulate metabolism.

Public Health Relevance

The proposed studies will greatly increase our understanding of the mechanisms underlying leptin and insulin resistance and obesity. The study findings will provide valuable information with which to develop treatment strategies for the prevention of obesity and diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK100699-05
Application #
9517006
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Hyde, James F
Project Start
2014-09-15
Project End
2019-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Gaykema, Ronald P; Newmyer, Brandon A; Ottolini, Matteo et al. (2017) Activation of murine pre-proglucagon-producing neurons reduces food intake and body weight. J Clin Invest 127:1031-1045
Kong, Xingxing; Williams, Kevin W; Liu, Tiemin (2017) Genetic Mouse Models: The Powerful Tools to Study Fat Tissues. Methods Mol Biol 1566:99-107
Yao, Ting; Deng, Zhuo; Gao, Yong et al. (2017) Ire1? in Pomc Neurons Is Required for Thermogenesis and Glycemia. Diabetes 66:663-673
Gao, Yong; Yao, Ting; Deng, Zhuo et al. (2017) TrpC5 Mediates Acute Leptin and Serotonin Effects via Pomc Neurons. Cell Rep 18:583-592
Shen, Wen-Jie; Yao, Ting; Kong, Xingxing et al. (2017) Melanocortin neurons: Multiple routes to regulation of metabolism. Biochim Biophys Acta Mol Basis Dis 1863:2477-2485
Mosialou, Ioanna; Shikhel, Steven; Liu, Jian-Min et al. (2017) MC4R-dependent suppression of appetite by bone-derived lipocalin 2. Nature 543:385-390
Sun, Jia; Gao, Yong; Yao, Ting et al. (2016) Adiponectin potentiates the acute effects of leptin in arcuate Pomc neurons. Mol Metab 5:882-91
Zhu, Yi; Gao, Yong; Tao, Caroline et al. (2016) Connexin 43 Mediates White Adipose Tissue Beiging by Facilitating the Propagation of Sympathetic Neuronal Signals. Cell Metab 24:420-433
Sohn, Jong-Woo; Oh, Youjin; Kim, Ki Woo et al. (2016) Leptin and insulin engage specific PI3K subunits in hypothalamic SF1 neurons. Mol Metab 5:669-79

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