Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice

Eric D. Berglund, Claudia R. Vianna, Jose Donato, Mi Hwa Kim, Jen Chieh Chuang, Charlotte E. Lee, Danielle A. Lauzon, Peagan Lin, Laura J. Brule, Michael M. Scott, Roberto Coppari, Joel K. Elmquist

Research output: Contribution to journalArticle

190 Scopus citations

Abstract

Leptin action on its receptor (LEPR) stimulates energy expenditure and reduces food intake, thereby lowering body weight. One leptin-sensitive target cell mediating these effects on energy balance is the proopiomelanocortin (POMC) neuron. Recent evidence suggests that the action of leptin on POMC neurons regulates glucose homeostasis independently of its effects on energy balance. Here, we have dissected the physiological impact of direct leptin action on POMC neurons using a mouse model in which endogenous LEPR expression was prevented by a LoxP-flanked transcription blocker (loxTB), but could be reactivated by Cre recombinase. Mice homozygous for the Lepr loxTB allele were obese and exhibited defects characteristic of LEPR deficiency. Reexpression of LEPR only in POMC neurons in the arcuate nucleus of the hypothalamus did not reduce food intake, but partially normalized energy expenditure and modestly reduced body weight. Despite the moderate effects on energy balance and independent of changes in body weight, restoring LEPR in POMC neurons normalized blood glucose and ameliorated hepatic insulin resistance, hyperglucagonemia, and dyslipidemia. Collectively, these results demonstrate that direct leptin action on POMC neurons does not reduce food intake, but is sufficient to normalize glucose and glucagon levels in mice otherwise lacking LEPR.

Original languageEnglish (US)
Pages (from-to)1000-1009
Number of pages10
JournalJournal of Clinical Investigation
Volume122
Issue number3
DOIs
StatePublished - Mar 1 2012

ASJC Scopus subject areas

  • Medicine(all)

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    Berglund, E. D., Vianna, C. R., Donato, J., Kim, M. H., Chuang, J. C., Lee, C. E., Lauzon, D. A., Lin, P., Brule, L. J., Scott, M. M., Coppari, R., & Elmquist, J. K. (2012). Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice. Journal of Clinical Investigation, 122(3), 1000-1009. https://doi.org/10.1172/JCI59816