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Melanocortin-4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis.

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.

Pubmed ID: 21284986

Authors

  • Rossi J
  • Balthasar N
  • Olson D
  • Scott M
  • Berglund E
  • Lee CE
  • Choi MJ
  • Lauzon D
  • Lowell BB
  • Elmquist JK

Journal

Cell metabolism

Publication Data

February 2, 2011

Associated Grants

  • Agency: NIDDK NIH HHS, Id: 5TL1DK081181
  • Agency: NIDDK NIH HHS, Id: DK071320
  • Agency: British Heart Foundation, Id: FS/06/057
  • Agency: NIDDK NIH HHS, Id: K08 DK071561
  • Agency: NIDDK NIH HHS, Id: K08 DK071561-03
  • Agency: NIDDK NIH HHS, Id: K08 DK071561-04
  • Agency: NIDDK NIH HHS, Id: K08 DK071561-05
  • Agency: NIDDK NIH HHS, Id: K08DK071561
  • Agency: NIDA NIH HHS, Id: K99 DA024719-02
  • Agency: NIDDK NIH HHS, Id: K99DK024719-02
  • Agency: NIDDK NIH HHS, Id: P30 DK046200
  • Agency: NIDDK NIH HHS, Id: P30 DK046200-15
  • Agency: NIDDK NIH HHS, Id: P30 DK046200-16
  • Agency: NIDDK NIH HHS, Id: P30 DK057521
  • Agency: NIDDK NIH HHS, Id: P30 DK057521-10
  • Agency: NIDDK NIH HHS, Id: P30DK046200
  • Agency: NIDDK NIH HHS, Id: PL1 DK081182
  • Agency: NIDDK NIH HHS, Id: PL1 DK081182-03
  • Agency: NIDDK NIH HHS, Id: PL1 DK081182-04
  • Agency: NIDDK NIH HHS, Id: R01 DK056690
  • Agency: NIDDK NIH HHS, Id: R01 DK071320
  • Agency: NIDDK NIH HHS, Id: R01 DK071320-06
  • Agency: NIDDK NIH HHS, Id: R01 DK071320-07
  • Agency: NIDDK NIH HHS, Id: R01 DK075632
  • Agency: NIDDK NIH HHS, Id: R01 DK075632-03
  • Agency: NIDDK NIH HHS, Id: R01 DK075632-04
  • Agency: NIDDK NIH HHS, Id: R01 DK075632-05
  • Agency: NIDDK NIH HHS, Id: R01DK075632
  • Agency: NIDDK NIH HHS, Id: R01DK53301
  • Agency: NIDDK NIH HHS, Id: R37 DK053301
  • Agency: NIDDK NIH HHS, Id: R37 DK053301-11
  • Agency: NIDDK NIH HHS, Id: R37 DK053301-12
  • Agency: NIDDK NIH HHS, Id: R37 DK053301-13
  • Agency: NIDDK NIH HHS, Id: R37 DK053301-13S1
  • Agency: NIDDK NIH HHS, Id: R37 DK053301-13S2
  • Agency: NIDDK NIH HHS, Id: RL1 DK081185
  • Agency: NIDDK NIH HHS, Id: RL1 DK081185-03
  • Agency: NIDDK NIH HHS, Id: RL1 DK081185-04
  • Agency: NIDDK NIH HHS, Id: RL1 DK081185-05
  • Agency: NIDDK NIH HHS, Id: RL1DK081185
  • Agency: NIDDK NIH HHS, Id: TL1 DK081181
  • Agency: NIDDK NIH HHS, Id: TL1 DK081181-03
  • Agency: NIDDK NIH HHS, Id: TL1 DK081181-04
  • Agency: NIDCR NIH HHS, Id: UL1 DE019584
  • Agency: NIDCR NIH HHS, Id: UL1 DE019584-03
  • Agency: NIDCR NIH HHS, Id: UL1 DE019584-04

Mesh Terms

  • Animals
  • Choline O-Acetyltransferase
  • Eating
  • Energy Metabolism
  • Glucose
  • Homeostasis
  • Hyperglycemia
  • Hyperinsulinism
  • Integrases
  • Mice
  • Mice, Transgenic
  • Neurons
  • Receptor, Melanocortin, Type 4