title: FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss.
abstract: The mechanism by which pharmacologic administration of the hormone FGF21 increases energy expenditure to cause weight loss in obese animals is unknown. Here we report that FGF21 acts centrally to exert its effects on energy expenditure and body weight in obese mice. Using tissue-specific knockout mice, we show that βKlotho, the obligate coreceptor for FGF21, is required in the nervous system for these effects. FGF21 stimulates sympathetic nerve activity to brown adipose tissue through a mechanism that depends on the neuropeptide corticotropin-releasing factor. Our findings provide an unexpected mechanistic explanation for the strong pharmacologic effects of FGF21 on energy expenditure and weight loss in obese animals.
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Bryn M
authors.initials: BM
authors.lastname: Owen
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Xunshan
authors.initials: X
authors.lastname: Ding
authors.affiliation: Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Morgan
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Katie Colbert
authors.initials: KC
authors.lastname: Coate
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Angie L
authors.initials: AL
authors.lastname: Bookout
authors.affiliation: Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Kamal
authors.initials: K
authors.lastname: Rahmouni
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: steven.kliewer@utsouthwestern.edu.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Kliewer
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: davo.mango@utsouthwestern.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Mangelsdorf
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D007031:Hypothalamus / Q000378:metabolism; D000090265:Klotho Proteins; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000378:metabolism; D022722:Thermogenesis / Q000235:genetics; D015431:Weight Loss / Q000187:drug effects*
chemical_list: C418622:Klb protein, mouse; D008565:Membrane Proteins; D012333:RNA, Messenger; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D003346:Corticotropin-Releasing Hormone; D000090265:Klotho Proteins