Fibroblast growth factors (FGFs) 19 and 21 are related hormones that have emerged as promising drug candidates for the treatment of metabolic syndrome. Pharmacologically, both FGF19 and FGF21 increase energy expenditure, cause weight loss and improve glucose tolerance, insulin sensitivity and lipid parameters in rodent models of metabolic disease. FGF21 has similar beneficial effects in obese monkeys and in patients with type 2 diabetes. However, the tissues and molecular mechanisms through which FGF19 and FGF21 exert their beneficial effects remain to be determined. In this proposal, we explore the basis for their effects on energy expenditure, weight loss, insulin sensitivity and glycemia. Based on work from our laboratory and others, we hypothesize that FGF19 and FGF21 act directly on the hypothalamus and dorsal-vagal complex in the nervous system to stimulate sympathetic outflow to brown and white adipose tissue depots; and on brown and white adipose tissue to stimulate glucose uptake, fatty acid synthesis and mobilization, and thermogenic gene expression. The net effect of this two-pronged mechanism is increased energy expenditure and weight loss and improved insulin sensitivity. In addition, we hypothesize that FGF19 acts directly on liver to stimulate glycogen synthesis and to suppress gluconeogenesis, which contributes to its beneficial glycemic effects. We propose to test this hypothesis by using diet-induced obese mice in which -Klotho, a cell surface protein that serves as an obligate co-receptor for both FGF19 and FGF21, is selectively eliminated in the nervous system, adipose tissue or liver. Treatment and evaluation of these different tissue-specific -Klotho knockout mouse models in conjunction with complementary in vitro studies with isolated white and brown adipocytes will provide important insights into the tissues and molecular mechanisms whereby FGF19 and FGF21 mediate their pharmacologic effects. We anticipate that these studies will provide important insights into FGF19 and FGF21's mechanism of action and help guide the generation of more efficacious FGF19 and FGF21-based drugs for treating metabolic disease.
While the hormones FGF19 and FGF21 have powerful beneficial effects in obese animals, including increased energy expenditure and weight loss and improved insulin sensitivity, their mechanism of action is poorly understood. The proposed studies will provide important insights into the tissues and molecular pathways whereby FGF19 and FGF21 mediate their powerful metabolic effects and aid in the design of more efficacious clinical derivatives.
| Patton, John B; Bonne-Année, Sandra; Deckman, Jessica et al. (2018) Methylprednisolone acetate induces, and ?7-dafachronic acid suppresses, Strongyloides stercoralis hyperinfection in NSG mice. Proc Natl Acad Sci U S A 115:204-209 |
| Song, Parkyong; Zechner, Christoph; Hernandez, Genaro et al. (2018) The Hormone FGF21 Stimulates Water Drinking in Response to Ketogenic Diet and Alcohol. Cell Metab 27:1338-1347.e4 |
| Katafuchi, Takeshi; Holland, William L; Kollipara, Rahul K et al. (2018) PPAR?-K107 SUMOylation regulates insulin sensitivity but not adiposity in mice. Proc Natl Acad Sci U S A 115:12102-12111 |
| Lan, Tian; Morgan, Donald A; Rahmouni, Kamal et al. (2017) FGF19, FGF21, and an FGFR1/?-Klotho-Activating Antibody Act on the Nervous System to Regulate Body Weight and Glycemia. Cell Metab 26:709-718.e3 |
| Coate, Katie C; Hernandez, Genaro; Thorne, Curtis A et al. (2017) FGF21 Is an Exocrine Pancreas Secretagogue. Cell Metab 25:472-480 |
| Albarqi, Mennatallah M Y; Stoltzfus, Jonathan D; Pilgrim, Adeiye A et al. (2016) Regulation of Life Cycle Checkpoints and Developmental Activation of Infective Larvae in Strongyloides stercoralis by Dafachronic Acid. PLoS Pathog 12:e1005358 |
| Youm, Yun-Hee; Horvath, Tamas L; Mangelsdorf, David J et al. (2016) Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution. Proc Natl Acad Sci U S A 113:1026-31 |
| Talukdar, Saswata; Owen, Bryn M; Song, Parkyong et al. (2016) FGF21 Regulates Sweet and Alcohol Preference. Cell Metab 23:344-9 |
| Katafuchi, Takeshi; Esterházy, Daria; Lemoff, Andrew et al. (2015) Detection of FGF15 in plasma by stable isotope standards and capture by anti-peptide antibodies and targeted mass spectrometry. Cell Metab 21:898-904 |
| Kliewer, Steven A; Mangelsdorf, David J (2015) Bile Acids as Hormones: The FXR-FGF15/19 Pathway. Dig Dis 33:327-31 |
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