World-wide rates of obesity have reached epidemic proportions. In the United States alone 30% of the population is overweight and 30% is obese, contributing to an excess mortality of 300,000 deaths a year. Significant consequences of obesity include Type II diabetes and non-alcoholic fatty liver disease. Rates of Type II diabetes are rising in adults and worryingly, Type II is now also seen in adolescent patients. Despite the morbidity and mortality of obesity, few useful therapeutic agents have emerged and many current therapies used to treat diabetes induce additional weight gain. Fibroblast growth-fact 21 (FGF21) when administered pharmacologically to mice, has multiple beneficial effects including: improved glucose tolerance, activation of brown adipose tissue, browning of white adipose tissue, weight loss and anti-fibrotic and anti-inflammatory effects in the liver. Recent data suggest that beneficial effects are also seen in humans and thus FGF21 is considered a promising drug target. We found that in rodents FGF21 plays a role in browning of white adipose tissue in response to cold which is associated with beneficial metabolic consequences. Furthermore treatment with FGF21 mimics many of the effects of cold exposure. At least some of these effects are mediated by direct action through the central nervous system (CNS). We also found that FGF21 has anti- fibrotic and anti-inflammatory effects in the liver. However there are several significant uncertainties regarding it's mechanisms of action. In this proposal we will use an integrative physiologic approach to elucidate the effects of FGF21 on white adipose tissue, brown adipose tissue and liver. Many of the beneficial metabolic effects of FGF21 occur in an intact animal and cannot be reproduced in isolated tissue culture models. We believe that FGF21 integrates signals from the liver, brain and fat, and in the process of communicating between these 3 tissues, acts as a master regulator of whole body metabolism. We are particularly focused on distinguishing between effects mediated by the brain. We will focus on CNS mediated effects on the peripheral targets BAT, WAT & liver. We will also examine the differential effects of several potential downstream mediators. These include the fat derived hormone adiponectin and the mitochondrial-associated uncoupling protein 1 (UCP-1), an important mediator of increased energy expenditure, that can be activated through multiple pathways. We predict that FGF21 effects, such as weight loss and improved glucose homeostasis, depend on the ability of FGF21 to act in the CNS and activate browning through UCP-1. Other effects may reflect cell autonomous action on WAT, which may be mediated by adiponectin. Anti-inflammatory and anti- fibrotic effects on the liver will likely reflect direct ation on this tissue. We hope that with this physiologic approach we will be able to distinguish the integrative physiologic actions of FGF21 and uncover additional targetable systems for the therapy of metabolic disorders.

Public Health Relevance

Obesity and its comorbidities such as diabetes and fatty liver are major problems threatening the health of the US population and new effective therapies are needed. FGF21 is a hormone made in multiple tissues including fat and liver that acts to improve metabolism, especially related to diabetes. This grant focuses on the metabolic actions of FGF21 in the liver, brain and fat and the mechanisms mediating these actions, as such understanding is important for both developing treatments and preventing obesity and its consequences.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK028082-34
Application #
9022467
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Hyde, James F
Project Start
1981-03-01
Project End
2019-02-28
Budget Start
2016-03-01
Budget End
2017-02-28
Support Year
34
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
Desai, Bhavna N; Singhal, Garima; Watanabe, Mikiko et al. (2017) Fibroblast growth factor 21 (FGF21) is robustly induced by ethanol and has a protective role in ethanol associated liver injury. Mol Metab 6:1395-1406
Douris, Nicholas; Desai, Bhavna N; Fisher, Ffolliott M et al. (2017) Beta-adrenergic receptors are critical for weight loss but not for other metabolic adaptations to the consumption of a ketogenic diet in male mice. Mol Metab 6:854-862
Maratos-Flier, Eleftheria (2017) Fatty liver and FGF21 physiology. Exp Cell Res 360:2-5
Fisher, Ffolliott M; Kim, MiSung; Doridot, Ludivine et al. (2017) A critical role for ChREBP-mediated FGF21 secretion in hepatic fructose metabolism. Mol Metab 6:14-21
Singhal, Garima; Fisher, Ffolliott Martin; Chee, Melissa J et al. (2016) Fibroblast Growth Factor 21 (FGF21) Protects against High Fat Diet Induced Inflammation and Islet Hyperplasia in Pancreas. PLoS One 11:e0148252
Singhal, Garima; Douris, Nicholas; Fish, Alan J et al. (2016) Fibroblast growth factor 21 has no direct role in regulating fertility in female mice. Mol Metab 5:690-8
Fisher, Ffolliott Martin; Maratos-Flier, Eleftheria (2016) Understanding the Physiology of FGF21. Annu Rev Physiol 78:223-41
Domouzoglou, Eleni M; Naka, Katerina K; Vlahos, Antonios P et al. (2015) Fibroblast growth factors in cardiovascular disease: The emerging role of FGF21. Am J Physiol Heart Circ Physiol 309:H1029-38
Dushay, Jody R; Toschi, Elena; Mitten, Emilie K et al. (2015) Fructose ingestion acutely stimulates circulating FGF21 levels in humans. Mol Metab 4:51-7
Douris, Nicholas; Melman, Tamar; Pecherer, Jordan M et al. (2015) Adaptive changes in amino acid metabolism permit normal longevity in mice consuming a low-carbohydrate ketogenic diet. Biochim Biophys Acta 1852:2056-65

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