Central Melanin-Concentrating Hormone Influences Liver and Adipose Metabolism via Specific Hypothalamic Nuclei and Efferent autonomic/JNK1 Pathways

Gastroenterology. 2013 Mar;144(3):636-649.e6. doi: 10.1053/j.gastro.2012.10.051. Epub 2012 Nov 6.

Abstract

Background & aims: Specific neuronal circuits modulate autonomic outflow to liver and white adipose tissue. Melanin-concentrating hormone (MCH)-deficient mice are hypophagic, lean, and do not develop hepatosteatosis when fed a high-fat diet. Herein, we sought to investigate the role of MCH, an orexigenic neuropeptide specifically expressed in the lateral hypothalamic area, on hepatic and adipocyte metabolism.

Methods: Chronic central administration of MCH and adenoviral vectors increasing MCH signaling were performed in rats and mice. Vagal denervation was performed to assess its effect on liver metabolism. The peripheral effects on lipid metabolism were assessed by real-time polymerase chain reaction and Western blot.

Results: We showed that the activation of MCH receptors promotes nonalcoholic fatty liver disease through the parasympathetic nervous system, whereas it increases fat deposition in white adipose tissue via the suppression of sympathetic traffic. These metabolic actions are independent of parallel changes in food intake and energy expenditure. In the liver, MCH triggers lipid accumulation and lipid uptake, with c-Jun N-terminal kinase being an essential player, whereas in adipocytes MCH induces metabolic pathways that promote lipid storage and decreases lipid mobilization. Genetic activation of MCH receptors or infusion of MCH specifically in the lateral hypothalamic area modulated hepatic lipid metabolism, whereas the specific activation of this receptor in the arcuate nucleus affected adipocyte metabolism.

Conclusions: Our findings show that central MCH directly controls hepatic and adipocyte metabolism through different pathways.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / drug effects
  • Adipocytes / metabolism*
  • Adipose Tissue / drug effects
  • Adipose Tissue / metabolism*
  • Adiposity / physiology*
  • Animals
  • Eating
  • Fatty Acids / metabolism
  • Fatty Liver / metabolism
  • Fatty Liver / physiopathology
  • Hypothalamic Area, Lateral / drug effects
  • Hypothalamic Area, Lateral / physiology*
  • Hypothalamic Hormones / administration & dosage
  • Hypothalamic Hormones / physiology*
  • Lipid Metabolism / drug effects
  • Lipid Metabolism / physiology
  • Lipogenesis / drug effects
  • Lipogenesis / physiology
  • Liver / drug effects
  • Liver / metabolism*
  • Male
  • Melanins / administration & dosage
  • Melanins / physiology*
  • Mice
  • Mitogen-Activated Protein Kinase 8 / metabolism*
  • Non-alcoholic Fatty Liver Disease
  • Pituitary Hormones / administration & dosage
  • Pituitary Hormones / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Pituitary Hormone / agonists
  • Receptors, Pituitary Hormone / physiology
  • Vagus Nerve / drug effects
  • Vagus Nerve / physiology
  • Vagus Nerve / physiopathology

Substances

  • Fatty Acids
  • Hypothalamic Hormones
  • Melanins
  • Pituitary Hormones
  • Receptors, Pituitary Hormone
  • melanin-concentrating hormone receptor
  • melanin-concentrating hormone
  • Mitogen-Activated Protein Kinase 8