Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance

David S. Ludwig, Nicholas A. Tritos, Jason W. Mastaitis, Rohit Kulkarni, Efi Kokkotou, Joel Elmquist, Bradford Lowell, Jeffrey S. Flier, Eleftheria Maratos-Flier

Research output: Contribution to journalArticle

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Abstract

Several lines of investigation suggest that the hypothalamic neuropeptide melanin-concentrating hormone (MCH) regulates body weight in mammals. Obese mice lacking functional leptin overexpress the MCH message in the fed or fasted state. Acute intracerebroventricular injection of MCH increases energy intake in rats. Mice lacking the MCH gene are lean. To test the hypothesis that chronic overexpression of MCH in mice causes obesity, we produced transgenic mice that overexpress MCH (MCH-OE) in the lateral hypothalamus at approximately twofold higher levels than normal mice. On the FVB genetic background, homozygous transgenic animals fed a high-fat diet ate 10% more and were 12% heavier at 13 weeks of age than wild-type animals, and they had higher systemic leptin levels. Blood glucose levels were higher both preprandially and after an intraperitoneal glucose injection. MCH-OE animals were insulin-resistant, as demonstrated by markedly higher plasma insulin levels and a blunted response to insulin; MCH-OE animals had only a 5% decrease in blood glucose after insulin administration, compared with a 31% decrease in wild-type animals. MCH-OE animals also exhibited a twofold increase in islet size. To evaluate the contribution of genetic background to the predisposition to obesity seen in MCH-OE mice, the transgene was bred onto the C57BL/6J background. Heterozygote C57BL/6J mice expressing the transgene showed increased body weight on a standard diet, confirming that MCH overexpression can lead to obesity.

Original languageEnglish (US)
Pages (from-to)379-386
Number of pages8
JournalJournal of Clinical Investigation
Volume107
Issue number3
StatePublished - 2001

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Transgenic Mice
Insulin Resistance
Obesity
Insulin
Wild Animals
Leptin
Transgenes
Blood Glucose
melanin-concentrating hormone
Body Weight
Lateral Hypothalamic Area
Obese Mice
Genetically Modified Animals
High Fat Diet
Heterozygote
Energy Intake
Intraperitoneal Injections
Neuropeptides
Inbred C57BL Mouse
Mammals

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ludwig, D. S., Tritos, N. A., Mastaitis, J. W., Kulkarni, R., Kokkotou, E., Elmquist, J., ... Maratos-Flier, E. (2001). Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance. Journal of Clinical Investigation, 107(3), 379-386.

Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance. / Ludwig, David S.; Tritos, Nicholas A.; Mastaitis, Jason W.; Kulkarni, Rohit; Kokkotou, Efi; Elmquist, Joel; Lowell, Bradford; Flier, Jeffrey S.; Maratos-Flier, Eleftheria.

In: Journal of Clinical Investigation, Vol. 107, No. 3, 2001, p. 379-386.

Research output: Contribution to journalArticle

Ludwig, DS, Tritos, NA, Mastaitis, JW, Kulkarni, R, Kokkotou, E, Elmquist, J, Lowell, B, Flier, JS & Maratos-Flier, E 2001, 'Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance', Journal of Clinical Investigation, vol. 107, no. 3, pp. 379-386.
Ludwig, David S. ; Tritos, Nicholas A. ; Mastaitis, Jason W. ; Kulkarni, Rohit ; Kokkotou, Efi ; Elmquist, Joel ; Lowell, Bradford ; Flier, Jeffrey S. ; Maratos-Flier, Eleftheria. / Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance. In: Journal of Clinical Investigation. 2001 ; Vol. 107, No. 3. pp. 379-386.
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