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Leptin action through hypothalamic nitric oxide synthase-1–expressing neurons controls energy balance

Abstract

Few effective measures exist to combat the worldwide obesity epidemic1, and the identification of potential therapeutic targets requires a deeper understanding of the mechanisms that control energy balance. Leptin, an adipocyte-derived hormone that signals the long-term status of bodily energy stores, acts through multiple types of leptin receptor long isoform (LepRb)-expressing neurons (called here LepRb neurons) in the brain to control feeding, energy expenditure and endocrine function2,3,4. The modest contributions to energy balance that are attributable to leptin action in many LepRb populations5,6,7,8,9 suggest that other previously unidentified hypothalamic LepRb neurons have key roles in energy balance. Here we examine the role of LepRb in neuronal nitric oxide synthase (NOS1)-expressing LebRb (LepRbNOS1) neurons that comprise approximately 20% of the total hypothalamic LepRb neurons. Nos1cre-mediated genetic ablation of LepRb (LeprNos1KO) in mice produces hyperphagic obesity, decreased energy expenditure and hyperglycemia approaching that seen in whole-body LepRb-null mice. In contrast, the endocrine functions in LeprNos1KO mice are only modestly affected by the genetic ablation of LepRb in these neurons. Thus, hypothalamic LepRbNOS1 neurons are a key site of action of the leptin-mediated control of systemic energy balance.

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Figure 1: Generation of Nos1cre and the lack of Nos1 in ARC Pomc and Agrp neurons.
Figure 2: LepRbNOS1 neurons regulate energy balance and glucose homeostasis.
Figure 3: LepRbNOS1 neurons contribute modestly to endocrine functions.
Figure 4: Gene expression in the ARCs of LeprNos1KO mice.

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Acknowledgements

We thank Amylin Pharmaceuticals for the generous gift of leptin; S. Chua (Albert Einstein College of Medicine), B. Lowell (Beth Israel-Deaconess Medical Center) and G. Barsh (Stanford University) for the gift of Leprflox/flox, Agrpcre and Pomccre mice, respectively; and members of the Myers lab for helpful discussions and technical support. Core support (animal phenotyping, Cell and Molecular Biology (CMB); clinical, Microscopy and Image Analysis Core (MIAC)) was provided by the Michigan Diabetes Research and Training Center and Nutrition and Obesity Research Center. This work was supported by the Marilyn H. Vincent Foundation and grants from the American Diabetes Association (M.G.M.), the American Heart Association (M.G.M. and R.L.L.) and the US National Institutes of Health (NIH) (DK057768 to M.G.M.). M.G.-Y. is supported by NIH grant T32GM008322; C.M.P. was supported by NIH grant T32HL007853.

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R.L.L., M.G.-Y., C.M.P. and I.E.G. carried out the experiments (with staff of the Core facilities and other technical assistance). R.L.L., M.G.-Y. and C.M.P. analyzed and prepared data for publication. M.G.M. guided the overall approach, in collaboration with R.L.L. and M.G.-Y. M.G.M., R.L.L. and M.G.-Y. cowrote the manuscript.

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Correspondence to Martin G Myers Jr.

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Leshan, R., Greenwald-Yarnell, M., Patterson, C. et al. Leptin action through hypothalamic nitric oxide synthase-1–expressing neurons controls energy balance. Nat Med 18, 820–823 (2012). https://doi.org/10.1038/nm.2724

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