@article{6dade8345832466d842a1fb490909f22,
title = "Pharmacological FGF21 signals to glutamatergic neurons to enhance leptin action and lower body weight during obesity",
abstract = "Objective: Fibroblast growth factor 21 (FGF21) is a peripherally-derived endocrine hormone that acts on the central nervous system (CNS) to regulate whole body energy homeostasis. Pharmacological administration of FGF21 promotes weight loss in obese animal models and human subjects with obesity. However, the central targets mediating these effects are incompletely defined. Methods: To explore the mechanism for FGF21's effects to lower body weight, we pharmacologically administer FGF21 to genetic animal models lacking the obligate FGF21 co-receptor, β-klotho (KLB), in either glutamatergic (Vglut2-Cre) or GABAergic (Vgat-Cre) neurons. In addition, we abolish FGF21 signaling to leptin receptor (LepR-Cre) positive cells. Finally, we examine the synergistic effects of FGF21 and leptin to lower body weight and explore the importance of physiological leptin levels in FGF21-mediated regulation of body weight. Results: Here we show that FGF21 signaling to glutamatergic neurons is required for FGF21 to modulate energy expenditure and promote weight loss. In addition, we demonstrate that FGF21 signals to leptin receptor-expressing cells to regulate body weight, and that central leptin signaling is required for FGF21 to fully stimulate body weight loss during obesity. Interestingly, co-administration of FGF21 and leptin synergistically leads to robust weight loss. Conclusions: These data reveal an important endocrine crosstalk between liver- and adipose-derived signals which integrate in the CNS to modulate energy homeostasis and body weight regulation.",
keywords = "Adipose, Betaklotho, FGF21, Glutamatergic, Leptin, Liver, Neurons, Synergy",
author = "Claflin, {Kristin E.} and Sullivan, {Andrew I.} and Naber, {Meghan C.} and Flippo, {Kyle H.} and Morgan, {Donald A.} and Neff, {Tate J.} and Jensen-Cody, {Sharon O.} and Zhiyong Zhu and Zingman, {Leonid V.} and Kamal Rahmouni and Potthoff, {Matthew J.}",
note = "Funding Information: We thank Dr. Birgitte Andersen (Novo Nordisk) for providing FGF21 protein, Dr. Justin Grobe (Medical College of Wisconsin) for analytical expertise, and Dr. Lucas BonDurant for data collection and project support. This work was funded by the National Institutes of Health R01DK106104 (M.J.P.), R01AA027654 (M.J.P.), T32 HL007121 (K.E.C.), F32 DK117510 (K.E.C.), T32 DK112751 (K.H.F.), F31 DK117515 (S.O.J.), Veterans Affairs Merit Review Program I01BX004634 (M.J.P.), and the University of Iowa Carver College of Medicine (M.J.P). The authors would like to acknowledge use of the University of Iowa Central Microscopy Research Facility, the University of Iowa Metabolic Phenotyping Core and the Genomics Division of the Iowa Institute of Human Genetics. Funding Information: We thank Dr. Birgitte Andersen (Novo Nordisk) for providing FGF21 protein, Dr. Justin Grobe (Medical College of Wisconsin) for analytical expertise, and Dr. Lucas BonDurant for data collection and project support. This work was funded by the National Institutes of Health R01DK106104 (M.J.P.), R01AA027654 (M.J.P.), T32 HL007121 (K.E.C.), F32 DK117510 (K.E.C.), T32 DK112751 (K.H.F.), F31 DK117515 (S.O.J.), Veterans Affairs Merit Review Program I01BX004634 (M.J.P.), and the University of Iowa Carver College of Medicine (M.J.P). The authors would like to acknowledge use of the University of Iowa Central Microscopy Research Facility, the University of Iowa Metabolic Phenotyping Core and the Genomics Division of the Iowa Institute of Human Genetics. Publisher Copyright: {\textcopyright} 2022",
year = "2022",
month = oct,
day = "1",
doi = "10.1016/j.molmet.2022.101564",
language = "English",
volume = "64",
journal = "Molecular Metabolism",
issn = "2212-8778",
publisher = "Elsevier GmbH",
}
