title: Central action of FGF19 reduces hypothalamic AGRP/NPY neuron activity and improves glucose metabolism.
abstract: Tight control of glucose excursions has been a long-standing goal of treatment for patients with type 2 diabetes mellitus in order to ameliorate the morbidity and mortality associated with hyperglycemia. Fibroblast growth factor (FGF) 19 is a hormone-like enterokine released postprandially that emerged as a potential therapeutic agent for metabolic disorders, including diabetes and obesity. Remarkably, FGF19 treatment has hypoglycemic actions that remain potent in models of genetic and acquired insulin resistance. Here, we provided evidence that the central nervous system responds to FGF19 administered in the periphery. Then, in two mouse models of insulin resistance, leptin-deficiency and high-fat diet feeding, third intra-cerebro-ventricular infusions of FGF19 improved glycemic status, reduced insulin resistance and potentiated insulin signaling in the periphery. In addition, our study highlights a new mechanism of central FGF19 action, involving the suppression of AGRP/NPY neuronal activity. Overall, our work unveils novel regulatory pathways induced by FGF19 that will be useful in the design of novel strategies to control diabetes in obesity.
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Marcelin
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Young-Hwan
authors.initials: YH
authors.lastname: Jo
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Schwartz
authors.affiliation: Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19122, USA ; Department of Pathophysiology, Kunming Medical University, Kunming, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19122, USA.
authors.forename: Nae J
authors.initials: NJ
authors.lastname: Dun
authors.affiliation: Phoenix Pharmaceuticals, Inc., Burlingame, CA 94010, USA.
authors.forename: Rong-Ming
authors.initials: RM
authors.lastname: Lyu
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Clémence
authors.initials: C
authors.lastname: Blouet
authors.affiliation: Phoenix Pharmaceuticals, Inc., Burlingame, CA 94010, USA.
authors.forename: Jaw K
authors.initials: JK
authors.lastname: Chang
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Streamson
authors.initials: S
authors.lastname: Chua
keywords: AGRP/NPY neurons; Diabetes; FGF19; Obesity