title: Direct control of brown adipose tissue thermogenesis by central nervous system glucagon-like peptide-1 receptor signaling.
abstract: We studied interscapular brown adipose tissue (iBAT) activity in wild-type (WT) and glucagon-like peptide 1 receptor (GLP-1R)-deficient mice after the administration of the proglucagon-derived peptides (PGDPs) glucagon-like peptide (GLP-1), glucagon (GCG), and oxyntomodulin (OXM) directly into the brain. Intracerebroventricular injection of PGDPs reduces body weight and increases iBAT thermogenesis. This was independent of changes in feeding and insulin responsiveness but correlated with increased activity of sympathetic fibers innervating brown adipose tissue (BAT). Despite being a GCG receptor agonist, OXM requires GLP-1R activation to induce iBAT thermogenesis. The increase in thermogenesis in WT mice correlates with increased expression of genes upregulated by adrenergic signaling and required for iBAT thermogenesis, including PGC1a and UCP-1. In spite of the increase in iBAT thermogenesis induced by GLP-1R activation in WT mice, Glp1r(-/-) mice exhibit a normal response to cold exposure, demonstrating that endogenous GLP-1R signaling is not essential for appropriate thermogenic response after cold exposure. Our data suggest that the increase in BAT thermogenesis may be an additional mechanism whereby pharmacological GLP-1R activation controls energy balance.
authors.affiliation: Department of Internal Medicine, Metabolic Disease Institute, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Lockie
authors.forename: Kristy M
authors.initials: KM
authors.lastname: Heppner
authors.forename: Nilika
authors.initials: N
authors.lastname: Chaudhary
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Chabenne
authors.forename: Donald A
authors.initials: DA
authors.lastname: Morgan
authors.forename: Christelle
authors.initials: C
authors.lastname: Veyrat-Durebex
authors.forename: Gayathri
authors.initials: G
authors.lastname: Ananthakrishnan
authors.forename: Françoise
authors.initials: F
authors.lastname: Rohner-Jeanrenaud
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
authors.forename: Richard
authors.initials: R
authors.lastname: DiMarchi
authors.forename: Kamal
authors.initials: K
authors.lastname: Rahmouni
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Oldfield
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
authors.forename: Diego
authors.initials: D
authors.lastname: Perez-Tilve
mesh_terms: D002001:Adipose Tissue, Brown / Q000294:innervation / Q000378:metabolism*; D000818:Animals; D002490:Central Nervous System / Q000378:metabolism*; D005934:Glucagon / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000819:agonists / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor; D007333:Insulin Resistance; 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; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D053772:Oxyntomodulin / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D018027:Receptors, Glucagon / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D012540:Scapula; D015398:Signal Transduction; D013564:Sympathetic Nervous System / Q000378:metabolism; D022722:Thermogenesis; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D000071256:Uncoupling Protein 1; D015854:Up-Regulation
chemical_list: C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007473:Ion Channels; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D053772:Oxyntomodulin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D018027:Receptors, Glucagon; D015534:Trans-Activators; D014157:Transcription Factors; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D052216:Glucagon-Like Peptide 1; D005934:Glucagon