title: Regulation of glucose tolerance and sympathetic activity by MC4R signaling in the lateral hypothalamus.
abstract: Melanocortin 4 receptor (MC4R) signaling mediates diverse physiological functions, including energy balance, glucose homeostasis, and autonomic activity. Although the lateral hypothalamic area (LHA) is known to express MC4Rs and to receive input from leptin-responsive arcuate proopiomelanocortin neurons, the physiological functions of MC4Rs in the LHA are incompletely understood. We report that MC4R(LHA) signaling regulates glucose tolerance and sympathetic nerve activity. Restoring expression of MC4Rs specifically in the LHA improves glucose intolerance in obese MC4R-null mice without affecting body weight or circulating insulin levels. Fluorodeoxyglucose-mediated tracing of whole-body glucose uptake identifies the interscapular brown adipose tissue (iBAT) as a primary source where glucose uptake is increased in MC4R(LHA) mice. Direct multifiber sympathetic nerve recording further reveals that sympathetic traffic to iBAT is significantly increased in MC4R(LHA) mice, which accompanies a significant elevation of Glut4 expression in iBAT. Finally, bilateral iBAT denervation prevents the glucoregulatory effect of MC4R(LHA) signaling. These results identify a novel role for MC4R(LHA) signaling in the control of sympathetic nerve activity and glucose tolerance independent of energy balance.
authors.affiliation: Department of Pharmacology, University of Iowa, Carver College of Medicine, Iowa City, IA.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Morgan
authors.affiliation: Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, IA.
authors.forename: Latisha N
authors.initials: LN
authors.lastname: McDaniel
authors.affiliation: Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, IA.
authors.forename: Terry
authors.initials: T
authors.lastname: Yin
authors.affiliation: Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, IA.
authors.forename: Michael
authors.initials: M
authors.lastname: Khan
authors.affiliation: Department of Pharmacology, University of Iowa, Carver College of Medicine, Iowa City, IA.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Small Animal Imaging Core, University of Iowa, Carver College of Medicine, Iowa City, IA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Acevedo
authors.affiliation: Small Animal Imaging Core, University of Iowa, Carver College of Medicine, Iowa City, IA.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Walsh
authors.affiliation: Department of Radiology, University of Iowa, Carver College of Medicine, Iowa City, IA Department of Pediatrics, University of Iowa, Carver College of Medicine, Iowa City, IA.
authors.forename: Laura L Boles
authors.initials: LL
authors.lastname: Ponto
authors.affiliation: Department of Pediatrics, University of Iowa, Carver College of Medicine, Iowa City, IA.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Norris
authors.affiliation: Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, IA Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Carver College of Medicine, Iowa City, IA Obesity Research and Education Initiative, University of Iowa, Carver College of Medicine, Iowa City, IA.
authors.forename: Michael
authors.initials: M
authors.lastname: Lutter
authors.affiliation: Department of Pharmacology, University of Iowa, Carver College of Medicine, Iowa City, IA Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Carver College of Medicine, Iowa City, IA Obesity Research and Education Initiative, University of Iowa, Carver College of Medicine, Iowa City, IA.
authors.forename: Kamal
authors.initials: K
authors.lastname: Rahmouni
authors.affiliation: Department of Pharmacology, University of Iowa, Carver College of Medicine, Iowa City, IA Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, IA Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Carver College of Medicine, Iowa City, IA huxing-cui@uiowa.edu.
authors.forename: Huxing
authors.initials: H
authors.lastname: Cui
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology; D004435:Eating / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D007026:Hypothalamic Area, Lateral / Q000378:metabolism*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000502:physiology*; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: C574273:MC4R protein, mouse; D044105:Receptor, Melanocortin, Type 4; D005947:Glucose