TY - JOUR
T1 - The brown adipose tissue glucagon receptor is functional but not essential for control of energy homeostasis in mice
AU - Beaudry, Jacqueline L.
AU - Kaur, Kiran Deep
AU - Varin, Elodie M.
AU - Baggio, Laurie L.
AU - Cao, Xiemin
AU - Mulvihill, Erin E.
AU - Stern, Jennifer H.
AU - Campbell, Jonathan E.
AU - Scherer, Phillip E.
AU - Drucker, Daniel J.
N1 - Funding Information:
J.L.B. and E.M.V. have received fellowship funding from Diabetes Canada. E.E.M. has received fellowship funding from the Canadian Diabetes Association and the Canadian Institutes of Health Research. J.E.C. has received fellowships from the Banting and Best Diabetes Centre, University of Toronto, and the Canadian Institutes of Health Research. J.H.S. was supported by the US National Institutes of Health (NIH) grant R00AG055649. P.E.S. was supported by US National Institutes of Health (NIH) grants R01-DK55758, P01-DK088761, R01-DK099110, P01-AG051459 and by an unrestricted grant from the Novo Nordisk Research Foundation.D.J.D. has served as a speaker for Eli Lilly and as an advisor or consultant to Forkhead Therapeutics, Intarcia, Kallyope, Merck Research Laboratories, Pfizer, Novo Nordisk, and Zafgen. Mt. Sinai receives investigator-initiated funding from Merck, Novo Nordisk, and Shire for preclinical studies of peptide biology in the Drucker laboratory. E.E.M. has received speaker's honoraria from Merck Canada, and the Ottawa Heart Institute receives funding from Merck for preclinical studies in the Mulvihill laboratory. J.E.C. has received speaker honoraria from Merck, and Duke Molecular Physiology Institute receives funding from Eli Lilly for preclinical studies in the Campbell laboratory. The other authors have no other conflicts of interest relevant to this article to disclose.
Funding Information:
J.L.B. and E.M.V. have received fellowship funding from Diabetes Canada. E.E.M. has received fellowship funding from the Canadian Diabetes Association and the Canadian Institutes of Health Research . J.E.C. has received fellowships from the Banting and Best Diabetes Centre , University of Toronto , and the Canadian Institutes of Health Research. J.H.S. was supported by the US National Institutes of Health (NIH) grant R00AG055649 . P.E.S. was supported by US National Institutes of Health (NIH) grants R01-DK55758 , P01-DK088761 , R01-DK099110 , P01-AG051459 and by an unrestricted grant from the Novo Nordisk Research Foundation .
Funding Information:
D.J.D. has served as a speaker for Eli Lilly and as an advisor or consultant to Forkhead Therapeutics, Intarcia, Kallyope, Merck Research Laboratories, Pfizer, Novo Nordisk, and Zafgen. Mt. Sinai receives investigator-initiated funding from Merck , Novo Nordisk , and Shire for preclinical studies of peptide biology in the Drucker laboratory. E.E.M. has received speaker's honoraria from Merck Canada, and the Ottawa Heart Institute receives funding from Merck for preclinical studies in the Mulvihill laboratory. J.E.C. has received speaker honoraria from Merck, and Duke Molecular Physiology Institute receives funding from Eli Lilly for preclinical studies in the Campbell laboratory. The other authors have no other conflicts of interest relevant to this article to disclose.
Funding Information:
D.J.D. is supported by Banting and Best Diabetes Centre-Novo Nordisk Chair in Incretin Biology, by Canadian Institutes of Health Research grant 154321 and by operating grant support from Novo Nordisk Inc..
Funding Information:
J.L.B. and E.M.V. have received fellowship funding from Diabetes Canada. E.E.M. has received fellowship funding from the Canadian Diabetes Association and the Canadian Institutes of Health Research. J.E.C. has received fellowships from the Banting and Best Diabetes Centre, University of Toronto, and the Canadian Institutes of Health Research. J.H.S. was supported by the US National Institutes of Health (NIH) grant R00AG055649. P.E.S. was supported by US National Institutes of Health (NIH) grants R01-DK55758, P01-DK088761, R01-DK099110, P01-AG051459 and by an unrestricted grant from the Novo Nordisk Research Foundation. D.J.D. is supported by Banting and Best Diabetes Centre-Novo Nordisk Chair in Incretin Biology, by Canadian Institutes of Health Research grant 154321 and by operating grant support from Novo Nordisk Inc..D.J.D. has served as a speaker for Eli Lilly and as an advisor or consultant to Forkhead Therapeutics, Intarcia, Kallyope, Merck Research Laboratories, Pfizer, Novo Nordisk, and Zafgen. Mt. Sinai receives investigator-initiated funding from Merck, Novo Nordisk, and Shire for preclinical studies of peptide biology in the Drucker laboratory. E.E.M. has received speaker's honoraria from Merck Canada, and the Ottawa Heart Institute receives funding from Merck for preclinical studies in the Mulvihill laboratory. J.E.C. has received speaker honoraria from Merck, and Duke Molecular Physiology Institute receives funding from Eli Lilly for preclinical studies in the Campbell laboratory. The other authors have no other conflicts of interest relevant to this article to disclose.
Publisher Copyright:
© 2019 The Authors
PY - 2019/4
Y1 - 2019/4
N2 - Objective: Administration of glucagon (GCG) or GCG-containing co-agonists reduces body weight and increases energy expenditure. These actions appear to be transduced by multiple direct and indirect GCG receptor (GCGR)-dependent mechanisms. Although the canonical GCGR is expressed in brown adipose tissue (BAT) the importance of BAT GCGR activity for the physiological control of body weight, or the response to GCG agonism, has not been defined. Methods: We studied the mechanisms linking GCG action to acute increases in oxygen consumption using wildtype (WT), Ucp1 −/− and Fgf21 −/− mice. The importance of basal GCGR expression within the Myf5 + domain for control of body weight, adiposity, glucose and lipid metabolism, food intake, and energy expenditure was examined in Gcgr BAT−/− mice housed at room temperature or 4 °C, fed a regular chow diet (RCD) or after a prolonged exposure to high fat diet (HFD). Results: Acute GCG administration induced lipolysis and increased the expression of thermogenic genes in BAT cells, whereas knockdown of Gcgr reduced expression of genes related to thermogenesis. GCG increased energy expenditure (measured by oxygen consumption) both in vivo in WT mice and ex vivo in BAT and liver explants. GCG also increased acute energy expenditure in Ucp1 −/− mice, but these actions were partially blunted in Ffg21 −/− mice. However, acute GCG administration also robustly increased oxygen consumption in Gcgr BAT−/− mice. Moreover, body weight, glycemia, lipid metabolism, body temperature, food intake, activity, energy expenditure and adipose tissue gene expression profiles were normal in Gcgr BAT−/− mice, either on RCD or HFD, whether studied at room temperature, or chronically housed at 4 °C. Conclusions: Exogenous GCG increases oxygen consumption in mice, also evident both in liver and BAT explants ex vivo, through UCP1-independent, FGF21-dependent pathways. Nevertheless, GCGR signaling within BAT is not physiologically essential for control of body weight, whole body energy expenditure, glucose homeostasis, or the adaptive metabolic response to cold or prolonged exposure to an energy dense diet.
AB - Objective: Administration of glucagon (GCG) or GCG-containing co-agonists reduces body weight and increases energy expenditure. These actions appear to be transduced by multiple direct and indirect GCG receptor (GCGR)-dependent mechanisms. Although the canonical GCGR is expressed in brown adipose tissue (BAT) the importance of BAT GCGR activity for the physiological control of body weight, or the response to GCG agonism, has not been defined. Methods: We studied the mechanisms linking GCG action to acute increases in oxygen consumption using wildtype (WT), Ucp1 −/− and Fgf21 −/− mice. The importance of basal GCGR expression within the Myf5 + domain for control of body weight, adiposity, glucose and lipid metabolism, food intake, and energy expenditure was examined in Gcgr BAT−/− mice housed at room temperature or 4 °C, fed a regular chow diet (RCD) or after a prolonged exposure to high fat diet (HFD). Results: Acute GCG administration induced lipolysis and increased the expression of thermogenic genes in BAT cells, whereas knockdown of Gcgr reduced expression of genes related to thermogenesis. GCG increased energy expenditure (measured by oxygen consumption) both in vivo in WT mice and ex vivo in BAT and liver explants. GCG also increased acute energy expenditure in Ucp1 −/− mice, but these actions were partially blunted in Ffg21 −/− mice. However, acute GCG administration also robustly increased oxygen consumption in Gcgr BAT−/− mice. Moreover, body weight, glycemia, lipid metabolism, body temperature, food intake, activity, energy expenditure and adipose tissue gene expression profiles were normal in Gcgr BAT−/− mice, either on RCD or HFD, whether studied at room temperature, or chronically housed at 4 °C. Conclusions: Exogenous GCG increases oxygen consumption in mice, also evident both in liver and BAT explants ex vivo, through UCP1-independent, FGF21-dependent pathways. Nevertheless, GCGR signaling within BAT is not physiologically essential for control of body weight, whole body energy expenditure, glucose homeostasis, or the adaptive metabolic response to cold or prolonged exposure to an energy dense diet.
KW - Adiposity
KW - Energy expenditure
KW - Glucagon
KW - Lipolysis
KW - Thermogenesis
KW - brown adipose tissue
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U2 - 10.1016/j.molmet.2019.01.011
DO - 10.1016/j.molmet.2019.01.011
M3 - Article
C2 - 30772257
AN - SCOPUS:85061403358
SN - 2212-8778
VL - 22
SP - 37
EP - 48
JO - Molecular Metabolism
JF - Molecular Metabolism
ER -