Exploring the roles of neurons that express melanin-concentrating hormone (MCH)
Whiddon, Benjamin Barnett
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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 (CART). 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 (<italic>Pmch</italic>). Within two weeks of diphtheria toxin (DT) injection, heterozygous <italic>Pmch<super>DTR/+</super></italic> 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. In leptin-deficient obese mice (<italic>Lep<super>ob/ob</super></italic>), ablation of MCH neurons lowered body weight only slightly, leaving leptin-deficient mice grossly overweight, similar to the effect of knocking out MCH. For these phenotypes, ablation of MCH neurons recapitulated knockout of MCH, so MCH appears to be the critical neuromodulator. In contrast, MCH-neuron-ablated mice showed improved glucose tolerance when compared to MCH-deficient mutant mice or wild-type mice. I conclude that the important roles of neurons expressing MCH are predominantly achieved by the release of MCH itself. Congenital absence of MCH is neither ameliorated nor exacerbated by development. The roles of non-MCH neurotransmitters released by MCH neurons are likely minor but include modulation of blood glucose homeostasis.
- Genetics