Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice
Eric D. Berglund, … , Roberto Coppari, Joel K. Elmquist
Eric D. Berglund, … , Roberto Coppari, Joel K. Elmquist
Published February 13, 2012
Citation Information: J Clin Invest. 2012;122(3):1000-1009. https://doi.org/10.1172/JCI59816.
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Research Article Neuroscience

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

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 LeprloxTB 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.

Authors

Eric D. Berglund, Claudia R. Vianna, Jose Donato Jr., 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

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Figure 1

LEPRs are only reactivated in the ARH in LeprloxTB × POMC-cre mice.

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LEPRs are only reactivated in the ARH in LeprloxTB × POMC-cre mice. ...
Representative images of leptin-stimulated (5 mg/kg body weight; i.p.) increases in phosphorylation of Stat3 (p-Stat3) immunoreactivity in 18-hour–fasted, 8-week-old, male WT, LEPR-null mice generated by inserting floxed transcription blocking sequences in the LEPR gene (LeprloxTB) and mice in which LEPRs are selectively reactivated in POMC neurons (LeprloxTB × POMC-cre). Hypothalamus is shown in A–C. Double immunohistochemistry for p-Stat3 (black) and β-endorphin (brown) is shown in D–F. Insets in D–F show increased magnification of cells, if any, which overlap. Hindbrain is shown in G–I. 3v, third ventricle; VMH, ventromedial hypothalamus; AP, area postrema. n = 8–10 for p-Stat3; n = 3 for β-endorphin. Scale bars: 400 μm (C); 200 μm (F); 10 μm (F, inset).