title: Melanocortin-4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis.
abstract: Melanocortin-4 receptor (MC4R) mutations cause dysregulation of energy balance and hyperinsulinemia. We have used mouse models to study the physiological roles of extrahypothalamic MC4Rs. Re-expression of MC4Rs in cholinergic neurons (ChAT-Cre, loxTB MC4R mice) modestly reduced body weight gain without altering food intake and was sufficient to normalize energy expenditure and attenuate hyperglycemia and hyperinsulinemia. In contrast, restoration of MC4R expression in brainstem neurons including those in the dorsal motor nucleus of the vagus (Phox2b-Cre, loxTB MC4R mice) was sufficient to attenuate hyperinsulinemia, while the hyperglycemia and energy balance were not normalized. Additionally, hepatic insulin action and insulin-mediated suppression of hepatic glucose production were improved in ChAT-Cre, loxTB MC4R mice. These findings suggest that MC4Rs expressed by cholinergic neurons regulate energy expenditure and hepatic glucose production. Our results also provide further evidence of the dissociation in pathways mediating the effects of melanocortins on energy balance and glucose homeostasis.
authors.affiliation: Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Jari
authors.initials: J
authors.lastname: Rossi
authors.forename: Nina
authors.initials: N
authors.lastname: Balthasar
authors.forename: David
authors.initials: D
authors.lastname: Olson
authors.forename: Michael
authors.initials: M
authors.lastname: Scott
authors.forename: Eric
authors.initials: E
authors.lastname: Berglund
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Lee
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Choi
authors.forename: Danielle
authors.initials: D
authors.lastname: Lauzon
authors.forename: Bradford B
authors.initials: BB
authors.lastname: Lowell
authors.forename: Joel K
authors.initials: JK
authors.lastname: Elmquist
mesh_terms: D000818:Animals; D002795:Choline O-Acetyltransferase / Q000235:genetics; D004435:Eating; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D006943:Hyperglycemia / Q000378:metabolism; D006946:Hyperinsulinism / Q000378:metabolism; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D044105:Receptor, Melanocortin, Type 4; D002795:Choline O-Acetyltransferase; C045073:Cre recombinase; D019426:Integrases; D005947:Glucose