title: An FGF21-adiponectin-ceramide axis controls energy expenditure and insulin action in mice.
abstract: FGF21, a member of the fibroblast growth factor (FGF) superfamily, has recently emerged as a regulator of metabolism and energy utilization. However, the exact mechanism(s) whereby FGF21 mediates its actions have not been elucidated. There is considerable evidence that insulin resistance may arise from aberrant accumulation of intracellular lipids in insulin-responsive tissues due to lipotoxicity. In particular, the sphingolipid ceramide has been implicated in this process. Here, we show that FGF21 rapidly and robustly stimulates adiponectin secretion in rodents while diminishing accumulation of ceramides in obese animals. Importantly, adiponectin-knockout mice are refractory to changes in energy expenditure and ceramide-lowering effects evoked by FGF21 administration. Moreover, FGF21 lowers blood glucose levels and enhances insulin sensitivity in diabetic Lep(ob/ob) mice and diet-induced obese (DIO) mice only when adiponectin is functionally present. Collectively, these data suggest that FGF21 is a potent regulator of adiponectin secretion and that FGF21 critically depends on adiponectin to exert its glycemic and insulin sensitizing effects.
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Holland
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Adams
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Brozinick
authors.forename: Hai H
authors.initials: HH
authors.lastname: Bui
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Miyauchi
authors.forename: Christine M
authors.initials: CM
authors.lastname: Kusminski
authors.forename: Steven M
authors.initials: SM
authors.lastname: Bauer
authors.forename: Mark
authors.initials: M
authors.lastname: Wade
authors.forename: Esha
authors.initials: E
authors.lastname: Singhal
authors.forename: Christine C
authors.initials: CC
authors.lastname: Cheng
authors.forename: Katherine
authors.initials: K
authors.lastname: Volk
authors.forename: Ming-Shang
authors.initials: MS
authors.lastname: Kuo
authors.forename: Ruth
authors.initials: R
authors.lastname: Gordillo
authors.forename: Alexei
authors.initials: A
authors.lastname: Kharitonenkov
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
mesh_terms: D052242:Adiponectin / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism*; D004032:Diet; D004734:Energy Metabolism / Q000502:physiology*; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology
chemical_list: D052242:Adiponectin; D001786:Blood Glucose; D002518:Ceramides; D007328:Insulin; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors