title: A role for the melatonin-related receptor GPR50 in leptin signaling, adaptive thermogenesis, and torpor.
abstract: The ability of mammals to maintain a constant body temperature has proven to be a profound evolutionary advantage, allowing members of this class to thrive in most environments on earth. Intriguingly, some mammals employ bouts of deep hypothermia (torpor) to cope with reduced food supply and harsh climates [1, 2]. During torpor, physiological processes such as respiration, cardiac function, and metabolic rate are severely depressed, yet the neural mechanisms that regulate torpor remain unclear [3]. Hypothalamic responses to energy signals, such as leptin, influence the expression of torpor [4-7]. We show that the orphan receptor GPR50 plays an important role in adaptive thermogenesis and torpor. Unlike wild-type mice, Gpr50(-/-) mice readily enter torpor in response to fasting and 2-deoxyglucose administration. Decreased thermogenesis in Gpr50(-/-) mice is not due to a deficit in brown adipose tissue, the principal site of nonshivering thermogenesis in mice [8]. GPR50 is highly expressed in the hypothalamus of several species, including man [9, 10]. In line with this, altered thermoregulation in Gpr50(-/-) mice is associated with attenuated responses to leptin and a suppression of thyrotropin-releasing hormone. Thus, our findings identify hypothalamic circuits involved in torpor and reveal GPR50 to be a novel component of adaptive thermogenesis in mammals.
authors.affiliation: University of Manchester, Manchester M13 9PT, UK. david.bechtold@manchester.ac.uk
authors.forename: David A
authors.initials: DA
authors.lastname: Bechtold
authors.forename: Anissa
authors.initials: A
authors.lastname: Sidibe
authors.forename: Ben R C
authors.initials: BR
authors.lastname: Saer
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Laura E
authors.initials: LE
authors.lastname: Hand
authors.forename: Elena A
authors.initials: EA
authors.lastname: Ivanova
authors.forename: Veerle M
authors.initials: VM
authors.lastname: Darras
authors.forename: Julie
authors.initials: J
authors.lastname: Dam
authors.forename: Ralf
authors.initials: R
authors.lastname: Jockers
authors.forename: Simon M
authors.initials: SM
authors.lastname: Luckman
authors.forename: Andrew S I
authors.initials: AS
authors.lastname: Loudon
mesh_terms: D000818:Animals; D001833:Body Temperature Regulation / Q000502:physiology*; D005215:Fasting; D007031:Hypothalamus / Q000378:metabolism; D020738:Leptin / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D015398:Signal Transduction; D022722:Thermogenesis; D013973:Thyrotropin-Releasing Hormone / Q000378:metabolism
chemical_list: C509755:Gpr50 receptor, mouse; D020738:Leptin; D009419:Nerve Tissue Proteins; D043562:Receptors, G-Protein-Coupled; D013973:Thyrotropin-Releasing Hormone