title: Contribution of regional brain melanocortin receptor subtypes to elevated activity energy expenditure in lean, active rats.
abstract: Physical activity and non-exercise activity thermogenesis (NEAT) are crucial factors accounting for individual differences in body weight, interacting with genetic predisposition. In the brain, a number of neuroendocrine intermediates regulate food intake and energy expenditure (EE); this includes the brain melanocortin (MC) system, consisting of MC peptides as well as their receptors (MCR). MC3R and MC4R have emerged as critical modulators of EE and food intake. To determine how variance in MC signaling may underlie individual differences in physical activity levels, we examined behavioral response to MC receptor agonists and antagonists in rats that show high and low levels of physical activity and NEAT, that is, high- and low-capacity runners (HCR, LCR), developed by artificial selection for differential intrinsic aerobic running capacity. Focusing on the hypothalamus, we identified brain region-specific elevations in expression of MCR 3, 4, and also MC5R, in the highly active, lean HCR relative to the less active and obesity-prone LCR. Further, the differences in activity and associated EE as a result of MCR activation or suppression using specific agonists and antagonists were similarly region-specific and directly corresponded to the differential MCR expression patterns. The agonists and antagonists investigated here did not significantly impact food intake at the doses used, suggesting that the differential pattern of receptor expression may by more meaningful to physical activity than to other aspects of energy balance regulation. Thus, MCR-mediated physical activity may be a key neural mechanism in distinguishing the lean phenotype and a target for enhancing physical activity and NEAT.
authors.affiliation: Department of Biological Sciences, Kent State University, Kent, OH, United States; Harvard Medical School - VA Boston Healthcare System, Boston, MA, United States. Electronic address: charu_shukla@hms.harvard.edu.
authors.forename: C
authors.initials: C
authors.lastname: Shukla
authors.affiliation: Department of Anesthesiology, University of Michigan, Ann Arbor, MI, United States; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, United States.
authors.forename: L G
authors.initials: LG
authors.lastname: Koch
authors.affiliation: Department of Anesthesiology, University of Michigan, Ann Arbor, MI, United States; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, United States.
authors.forename: S L
authors.initials: SL
authors.lastname: Britton
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ, United States.
authors.forename: M
authors.initials: M
authors.lastname: Cai
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ, United States.
authors.forename: V J
authors.initials: VJ
authors.lastname: Hruby
authors.affiliation: MedImmune Limited, Cambridge, United Kingdom.
authors.forename: M
authors.initials: M
authors.lastname: Bednarek
authors.affiliation: Department of Biological Sciences, Kent State University, Kent, OH, United States.
authors.forename: C M
authors.initials: CM
authors.lastname: Novak
mesh_terms: D000818:Animals; D001835:Body Weight; D004435:Eating; D004734:Energy Metabolism; D005260:Female; D007031:Hypothalamus / Q000378:metabolism*; D008297:Male; D009043:Motor Activity; D012333:RNA, Messenger; D051381:Rats; D044101:Receptors, Melanocortin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D044101:Receptors, Melanocortin
keywords: HCR/LCR; non-exercise activity thermogenesis (NEAT); obesity; spontaneous physical activity