title: The thermogenic effect of leptin is dependent on a distinct population of prolactin-releasing peptide neurons in the dorsomedial hypothalamus.
abstract: Leptin is a critical regulator of metabolism, which acts on brain receptors (Lepr) to reduce energy intake and increase energy expenditure. Some of the cellular pathways mediating leptin's anorectic actions are identified, but those mediating the thermogenic effects have proven more difficult to decipher. We define a population of neurons in the dorsomedial hypothalamic nucleus (DMH) containing the RFamide PrRP, which is activated by leptin. Disruption of Lepr selectively in these cells blocks thermogenic responses to leptin and causes obesity. A separate population of leptin-insensitive PrRP neurons in the brainstem is required, instead, for the satiating actions of the gut-derived hormone cholecystokinin (CCK). Global deletion of PrRP (in a loxSTOPlox-PrRP mouse) results in obesity and attenuated responses to leptin and CCK. Cre-recombinase-mediated reactivation of PrRP in brainstem rescues the anorectic actions of CCK, but reactivation in the hypothalamus is required to re-establish the thermogenic effect of leptin.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Garron T
authors.initials: GT
authors.lastname: Dodd
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Amy A
authors.initials: AA
authors.lastname: Worth
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Nunn
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Aaron K
authors.initials: AK
authors.lastname: Korpal
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Bechtold
authors.affiliation: Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Ann Arbor, Michigan 48105, USA.
authors.forename: Margaret B
authors.initials: MB
authors.lastname: Allison
authors.affiliation: Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Ann Arbor, Michigan 48105, USA.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Myers
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Statnick
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK. Electronic address: simon.luckman@manchester.ac.uk.
authors.forename: Simon M
authors.initials: SM
authors.lastname: Luckman
mesh_terms: D000483:Alleles; D000818:Animals; D002766:Cholecystokinin / Q000378:metabolism; D004302:Dorsomedial Hypothalamic Nucleus / Q000378:metabolism*; D004734:Energy Metabolism; D020738:Leptin / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000209:etiology; D056690:Prolactin-Releasing Hormone / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054411:Receptors, Leptin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D022722:Thermogenesis
chemical_list: D020738:Leptin; D056690:Prolactin-Releasing Hormone; D054411:Receptors, Leptin; D002766:Cholecystokinin