Ablation of neurons expressing melanin-concentrating hormone (MCH) in adult mice improves glucose tolerance independent of MCH signaling.
Melanin-concentrating hormone (MCH)-expressing neurons have been ascribed many roles based on studies of MCH-deficient mice. However, MCH neurons express other neurotransmitters, including GABA, nesfatin, and cocaine-amphetamine-regulated transcript. The importance of these other signaling molecules made by MCH neurons remains incompletely characterized. To determine the roles of MCH neurons in vivo, we targeted expression of the human diphtheria toxin receptor (DTR) to the gene for MCH (Pmch). Within 2 weeks of diphtheria toxin injection, heterozygous Pmch(DTR/+) mice lost 98% of their MCH neurons. These mice became lean but ate normally and were hyperactive, especially during a fast. They also responded abnormally to psychostimulants. For these phenotypes, ablation of MCH neurons recapitulated knock-out of MCH, so MCH appears to be the critical neuromodulator released by these neurons. In contrast, MCH-neuron-ablated mice showed improved glucose tolerance when compared with MCH-deficient mutant mice and wild-type mice. We conclude that MCH neurons regulate glucose tolerance through signaling molecules other than MCH.
Howard Hughes Medical Institute and Departments of Biochemistry and Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
Benjamin B
BB
Whiddon
Richard D
RD
Palmiter
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D003042:Cocaine / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004435:Eating / Q000187:drug effects / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D007028:Hypothalamic Hormones / Q000235:genetics / Q000378:metabolism*; D008543:Melanins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D010907:Pituitary Hormones / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D018765:Dopamine Uptake Inhibitors; D007028:Hypothalamic Hormones; D008543:Melanins; D010879:Piperazines; D010907:Pituitary Hormones; C019463:melanin-concentrating hormone; C043425:vanoxerine; D003042:Cocaine; D005947:Glucose