title: Glucagon is essential for adaptive thermogenesis in brown adipose tissue.
abstract: Glucagon, a counterregulatory hormone to insulin, serves as a regulator of glucose homeostasis and acts in response to hypoglycemia. Earlier studies have shown that glucagon administration induces thermogenesis in experimental animal models. However, it is not known whether endogenous glucagon is involved in the regulation of brown adipose tissue (BAT) function. Here we investigated the role of glucagon in cold-induced thermogenesis in male mice deficient in proglucagon-derived peptides (GCGKO mice). Upon exposure to cold, GCGKO mice exhibited a greater decrease in rectal temperature than control mice. The cold exposure-induced increase in oxygen consumption in GCGKO mice was less than that seen in control mice. Moreover, the increase in oxygen consumption after administration of a β3-adrenergic receptor agonist, CL-316,243, was also lesser in GCGKO than in control mice. Expression of thermogenic genes, including the gene encoding uncoupling protein 1 (Ucp1), was reduced in the BAT of GCGKO mice under ambient as well as cold conditions. Administration of glucagon restored the expression of Ucp1 mRNA in the BAT as well as the expression of the fibroblast growth factor 21 gene (Fgf21) in the liver. Supplementation with glucagon for 2 weeks resulted in higher plasma Fgf21 levels and improved responses to CL-316,243 in GCGKO mice. These results indicated that endogenous glucagon is essential for adaptive thermogenesis and that it regulates BAT function, most likely by increasing hepatic Fgf21 production.
authors.affiliation: Research Center of Health, Physical Fitness and Sports (K.K., N.O., Y.T., Y.O.), and Department of Genetics (K.K., Y.T., Y.M., Y.H.), Division of Stress Adaptation and Recognition, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Kinoshita
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Ozaki
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takagi
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Murata
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Oshida
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hayashi
mesh_terms: D000222:Adaptation, Physiological; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D003080:Cold Temperature; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D005934:Glucagon / Q000378:metabolism*; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D022722:Thermogenesis; D000071256:Uncoupling Protein 1
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D005934:Glucagon; D010100:Oxygen