Insulin resistance is a major contributor to the epidemic of metabolic diseases including dyslipidemia, hypertension and type 2 diabetes. According to the CDC, approximately 10% of U.S. adults have diabetes now and 33% are expected to have diabetes by 2050. Therefore, there is a serious demand for the development of new therapeutics to increase insulin sensitivity. Fibroblast growth factor 21 (FGF21) is an endocrine hormone that is a potent insulin sensitizer. Unlike other insulin sensitizers that indirectly improve insulin sensitivity by reducing ectopic lipid accumulation, FGF21 has the unique ability to directly enhance insulin sensitivity. We recently demonstrated that circulating FGF21 levels are produced from the liver during overfeeding and function to enhance insulin-stimulated glucose disposal in brown adipose tissue (BAT).
The aims of this grant are to 1) determine the contribution of FGF21 action on BAT to the insulin-sensitizing effects of FGF21, and 2) determine the mechanism by which FGF21 enhances insulin sensitivity in brown adipocytes. To accomplish these aims, we propose several experimental approaches.
In specific aim 1, we will utilize novel animal models to inactivate, reactivate or constitutively activate FGF21 signaling to specific adipose depots in vivo to access tissue-specific effects on insulin sensitivity.
In specific aim 2, we will examine the mechanism whereby FGF21 enhances insulin-stimulated glucose uptake in brown adipocytes. In addition, we will evaluate the contribution of insulin-stimulated glucose uptake in BAT to the glucose lowering effects of FGF21 in vivo. These studies are significant because they will provide new information on the mechanism of FGF21 action, and also provide fundamental insight into the mechanisms regulating whole-body glucose homeostasis.

Public Health Relevance

Fibroblast growth factor 21 (FGF21) is an endocrine hormone produced by the liver to regulate metabolic homeostasis. Our published and preliminary data support the hypothesis that FGF21 acts on brown adipose tissue (BAT) to enhance insulin-stimulated glucose uptake and whole-body glucose homeostasis. We will test this hypothesis by administering recombinant FGF21 protein to unique mouse models in which a) the obligate FGF21 co-receptor is inactivated or reactivated specifically in brown adipocytes, and b) insulin-stimulated glucose uptake is inactivated specifically in brown adipocytes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK106104-04S1
Application #
9706425
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Haft, Carol R
Project Start
2015-07-15
Project End
2020-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
4
Fiscal Year
2018
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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