Central Fibroblast Growth Factor 21 Browns White Fat via Sympathetic Action in Male Mice.
Fibroblast growth factor 21 (FGF21) has multiple metabolic actions, including the induction of browning in white adipose tissue. Although FGF21 stimulated browning results from a direct interaction between FGF21 and the adipocyte, browning is typically associated with activation of the sympathetic nervous system through cold exposure. We tested the hypothesis that FGF21 can act via the brain, to increase sympathetic activity and induce browning, independent of cell-autonomous actions. We administered FGF21 into the central nervous system via lateral ventricle infusion into male mice and found that the central treatment increased norepinephrine turnover in target tissues that include the inguinal white adipose tissue and brown adipose tissue. Central FGF21 stimulated browning as assessed by histology, expression of uncoupling protein 1, and the induction of gene expression associated with browning. These effects were markedly attenuated when mice were treated with a β-blocker. Additionally, neither centrally nor peripherally administered FGF21 initiated browning in mice lacking β-adrenoceptors, demonstrating that an intact adrenergic system is necessary for FGF21 action. These data indicate that FGF21 can signal in the brain to activate the sympathetic nervous system and induce adipose tissue thermogenesis.
Division of Endocrinology (N.D., D.M.S., f.M.F., T.I.C., M.J.C., J.S.F., E.M.-F.), Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215-5491; Institute of Medical Physiology (D.M.S.), School of Medicine, University of Belgrade, 11000 Belgrade, Serbia; Department of Biology and Center for Obesity Reversal (N.L.N., E.Z., T.J.B.), Georgia State University, Atlanta, Georgia 30302-4010; and Diabetes Research (A.C.A., A.K.), Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285-0001.
Nicholas
N
Douris
Division of Endocrinology (N.D., D.M.S., f.M.F., T.I.C., M.J.C., J.S.F., E.M.-F.), Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215-5491; Institute of Medical Physiology (D.M.S.), School of Medicine, University of Belgrade, 11000 Belgrade, Serbia; Department of Biology and Center for Obesity Reversal (N.L.N., E.Z., T.J.B.), Georgia State University, Atlanta, Georgia 30302-4010; and Diabetes Research (A.C.A., A.K.), Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285-0001.
Darko M
DM
Stevanovic
Division of Endocrinology (N.D., D.M.S., f.M.F., T.I.C., M.J.C., J.S.F., E.M.-F.), Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215-5491; Institute of Medical Physiology (D.M.S.), School of Medicine, University of Belgrade, 11000 Belgrade, Serbia; Department of Biology and Center for Obesity Reversal (N.L.N., E.Z., T.J.B.), Georgia State University, Atlanta, Georgia 30302-4010; and Diabetes Research (A.C.A., A.K.), Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285-0001.
Ffolliott M
FM
Fisher
Division of Endocrinology (N.D., D.M.S., f.M.F., T.I.C., M.J.C., J.S.F., E.M.-F.), Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215-5491; Institute of Medical Physiology (D.M.S.), School of Medicine, University of Belgrade, 11000 Belgrade, Serbia; Department of Biology and Center for Obesity Reversal (N.L.N., E.Z., T.J.B.), Georgia State University, Atlanta, Georgia 30302-4010; and Diabetes Research (A.C.A., A.K.), Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285-0001.
Theodore I
TI
Cisu
Division of Endocrinology (N.D., D.M.S., f.M.F., T.I.C., M.J.C., J.S.F., E.M.-F.), Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215-5491; Institute of Medical Physiology (D.M.S.), School of Medicine, University of Belgrade, 11000 Belgrade, Serbia; Department of Biology and Center for Obesity Reversal (N.L.N., E.Z., T.J.B.), Georgia State University, Atlanta, Georgia 30302-4010; and Diabetes Research (A.C.A., A.K.), Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285-0001.
Melissa J
MJ
Chee
Division of Endocrinology (N.D., D.M.S., f.M.F., T.I.C., M.J.C., J.S.F., E.M.-F.), Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215-5491; Institute of Medical Physiology (D.M.S.), School of Medicine, University of Belgrade, 11000 Belgrade, Serbia; Department of Biology and Center for Obesity Reversal (N.L.N., E.Z., T.J.B.), Georgia State University, Atlanta, Georgia 30302-4010; and Diabetes Research (A.C.A., A.K.), Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285-0001.
Ngoc L
NL
Nguyen
Division of Endocrinology (N.D., D.M.S., f.M.F., T.I.C., M.J.C., J.S.F., E.M.-F.), Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215-5491; Institute of Medical Physiology (D.M.S.), School of Medicine, University of Belgrade, 11000 Belgrade, Serbia; Department of Biology and Center for Obesity Reversal (N.L.N., E.Z., T.J.B.), Georgia State University, Atlanta, Georgia 30302-4010; and Diabetes Research (A.C.A., A.K.), Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285-0001.
Eleen
E
Zarebidaki
Division of Endocrinology (N.D., D.M.S., f.M.F., T.I.C., M.J.C., J.S.F., E.M.-F.), Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215-5491; Institute of Medical Physiology (D.M.S.), School of Medicine, University of Belgrade, 11000 Belgrade, Serbia; Department of Biology and Center for Obesity Reversal (N.L.N., E.Z., T.J.B.), Georgia State University, Atlanta, Georgia 30302-4010; and Diabetes Research (A.C.A., A.K.), Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285-0001.
Andrew C
AC
Adams
Division of Endocrinology (N.D., D.M.S., f.M.F., T.I.C., M.J.C., J.S.F., E.M.-F.), Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215-5491; Institute of Medical Physiology (D.M.S.), School of Medicine, University of Belgrade, 11000 Belgrade, Serbia; Department of Biology and Center for Obesity Reversal (N.L.N., E.Z., T.J.B.), Georgia State University, Atlanta, Georgia 30302-4010; and Diabetes Research (A.C.A., A.K.), Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285-0001.
Alexei
A
Kharitonenkov
Division of Endocrinology (N.D., D.M.S., f.M.F., T.I.C., M.J.C., J.S.F., E.M.-F.), Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215-5491; Institute of Medical Physiology (D.M.S.), School of Medicine, University of Belgrade, 11000 Belgrade, Serbia; Department of Biology and Center for Obesity Reversal (N.L.N., E.Z., T.J.B.), Georgia State University, Atlanta, Georgia 30302-4010; and Diabetes Research (A.C.A., A.K.), Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285-0001.
Jeffrey S
JS
Flier
Division of Endocrinology (N.D., D.M.S., f.M.F., T.I.C., M.J.C., J.S.F., E.M.-F.), Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215-5491; Institute of Medical Physiology (D.M.S.), School of Medicine, University of Belgrade, 11000 Belgrade, Serbia; Department of Biology and Center for Obesity Reversal (N.L.N., E.Z., T.J.B.), Georgia State University, Atlanta, Georgia 30302-4010; and Diabetes Research (A.C.A., A.K.), Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285-0001.
Timothy J
TJ
Bartness
Division of Endocrinology (N.D., D.M.S., f.M.F., T.I.C., M.J.C., J.S.F., E.M.-F.), Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215-5491; Institute of Medical Physiology (D.M.S.), School of Medicine, University of Belgrade, 11000 Belgrade, Serbia; Department of Biology and Center for Obesity Reversal (N.L.N., E.Z., T.J.B.), Georgia State University, Atlanta, Georgia 30302-4010; and Diabetes Research (A.C.A., A.K.), Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285-0001.
Eleftheria
E
Maratos-Flier
D052437:Adipocytes, Brown / Q000378:metabolism; D052438:Adipocytes, White / Q000187:drug effects* / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000187:drug effects* / Q000378:metabolism; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D057967:Infusions, Intraventricular; D007473:Ion Channels / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000187:drug effects* / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000235:genetics*; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics; D022702:Receptors, Adrenergic, beta-3 / Q000235:genetics; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000378:metabolism; D022722:Thermogenesis; D000071256:Uncoupling Protein 1
D000319:Adrenergic beta-Antagonists; D007473:Ion Channels; D024101:Mitochondrial Proteins; D011943:Receptors, Adrenergic, beta; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D022702:Receptors, Adrenergic, beta-3; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors