Obesity is a major contributor to the epidemic of metabolic diseases including dyslipidemia, cardiovascular disease, and type II diabetes. Numerous studies suggest that increasing energy expenditure can effectively decrease body weight. However, no current therapeutic compounds safely or selectively activate energy expenditure. The endocrine hormone fibroblast growth factor 21 (FGF21) decreases body weight during obesity by increasing energy expenditure without affecting physical activity. Moreover, FGF21 potently decreases both fat and body mass in obese animals and human patients. However, the mechanism for FGF21-mediated increases in energy expenditure has not been identified. Work from our lab and others have demonstrated that FGF21 acts in the central nervous system to promote weight loss. In addition, several lines of evidence suggest that FGF21 requires intact signaling from the adipose-derived hormone, leptin, to elicit its full effects on driving weight loss. Finally, our preliminary data demonstrates that the obligate FGF21 co- receptor, ?-klotho, is expressed in the arcuate nucleus (ARC) and ventromedial hypothalamus (VMH), primary sites of leptin action in the brain, and that leptin activates signaling in ?-klotho-expressing cells in the VMH and ARC. Thus, we hypothesize that FGF21 signals, at least in part, to leptin-sensitive cells in the VMH and/or ARC to modulate energy expenditure. This proposal employs novel genetic mouse models, chemogenetic manipulation of neurons, and pharmacological approaches to investigate the crosstalk between FGF21 and leptin signaling in the central control of energy homeostasis. Through these studies we aim to identify novel therapeutic targets for the treatment of obesity and obesity-associated disorders.

Public Health Relevance

The proposed research aims at understanding a novel hormonal pathway that regulates body weight and metabolic flexibility with the ultimate goal to develop new treatments for obesity and obesity-associated diseases. Specifically, this proposal examines endocrine crosstalk between leptin and FGF21 signaling and evaluates the contribution of leptin signaling in the energy expending effects of FGF21.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK106104-06A1
Application #
10118923
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Cooke, Brad
Project Start
2015-07-15
Project End
2024-07-31
Budget Start
2020-09-20
Budget End
2021-07-31
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Iowa
Department
Pharmacology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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