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Mol Metab. 2017 Jan 12;6(3):306-312. doi: 10.1016/j.molmet.2017.01.001. eCollection 2017 Mar.

Cholinergic neurons in the dorsomedial hypothalamus regulate food intake.

Author information

1
Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, NY, USA.
2
Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, NY, USA; Department of Physiology, College of Medicine, Gyeongsang National University, Jinju, South Korea.
3
Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, NY, USA; Department of Molecular Pharmacology, Albert Einstein College of Medicine, NY, USA. Electronic address: young-hwan.jo@einstein.yu.edu.

Abstract

OBJECTIVE:

Central cholinergic neural circuits play a role in the regulation of feeding behavior. The dorsomedial hypothalamus (DMH) is considered the appetite-stimulating center and contains cholinergic neurons. Here, we study the role of DMH cholinergic neurons in the control of food intake.

METHODS:

To selectively stimulate DMH cholinergic neurons, we expressed stimulatory designer receptors exclusively activated by designer drugs (DREADDs) and channelrhodopsins in DMH cholinergic neurons by injection of adeno-associated virus (AAV) vectors into the DMH of choline acetyltransferase (ChAT)-IRES-Cre mice. We also generated transgenic mice expressing channelrhodopsins in cholinergic neurons with the Cre-LoxP technique. To delete the Chat gene exclusively in the DMH, we injected an AAV carrying a Cre recombinase transgene into the DMH of floxed ChAT mice. Food intake was measured with and without selective stimulation of DMH cholinergic neurons.

RESULTS:

Mice lacking the Chat gene in the DMH show reduced body weight as compared to control. Chemogenetic activation of DMH cholinergic neurons promotes food intake. This orexigenic effect is further supported by experiments of optogenetic stimulation of DMH cholinergic neurons. DMH cholinergic neurons innervate pro-opiomelanocortin neurons in the arcuate nucleus of the hypothalamus (ARC). Treatment with acetylcholine (ACh) enhances GABAergic inhibitory transmission to ARC POMC neurons that is blocked by the muscarinic receptor antagonist. Direct activation of cholinergic fibers in the ARC readily stimulates food intake that is also abolished by the muscarinic receptor antagonist.

CONCLUSION:

ACh released from DMH cholinergic neurons regulates food intake and body weight. This effect is mediated in part through regulation of ARC POMC neurons. Activation of muscarinic receptors on GABAergic axon terminals enhances inhibitory tone to ARC POMC neurons. Hence, this novel DMHACh → ARCPOMC pathway plays an important role in the control of food intake and body weight.

KEYWORDS:

Acetylcholine; Hypothalamus; Muscarinic; Nicotinic; Obesity; POMC

PMID:
28271037
PMCID:
PMC5323886
DOI:
10.1016/j.molmet.2017.01.001
[Indexed for MEDLINE]
Free PMC Article

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