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


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.


  1. Bray, G.A. & Ryan, D.H. Drug treatment of obesity. Psychiatr. Clin. North Am. 34, 871–880 (2011).

    Article  Google Scholar 

  2. Ahima, R.S., Saper, C.B., Flier, J.S. & Elmquist, J.K. Leptin regulation of neuroendocrine systems. Front. Neuroendocrinol. 21, 263–307 (2000).

    Article  CAS  Google Scholar 

  3. Friedman, J.M. & Halaas, J.L. Leptin and the regulation of body weight in mammals. Nature 395, 763–770 (1998).

    Article  CAS  Google Scholar 

  4. Farooqi, I.S. & O'Rahilly, S. Leptin: a pivotal regulator of human energy homeostasis. Am. J. Clin. Nutr. 89, 980S–984S (2009).

    Article  CAS  Google Scholar 

  5. Balthasar, N. et al. Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron 42, 983–991 (2004).

    Article  CAS  Google Scholar 

  6. Dhillon, H. et al. Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis. Neuron 49, 191–203 (2006).

    Article  CAS  Google Scholar 

  7. van de Wall, E. et al. Collective and individual functions of leptin receptor modulated neurons controlling metabolism and ingestion. Endocrinology 149, 1773–1785 (2008).

    Article  CAS  Google Scholar 

  8. Hayes, M.R. et al. Endogenous leptin signaling in the caudal nucleus tractus solitarius and area postrema is required for energy balance regulation. Cell Metab. 11, 77–83 (2010).

    Article  CAS  Google Scholar 

  9. Scott, M.M., Williams, K.W., Rossi, J., Lee, C.E. & Elmquist, J.K. Leptin receptor expression in hindbrain Glp-1 neurons regulates food intake and energy balance in mice. J. Clin. Invest. 121, 2413–2421 (2011).

    Article  CAS  Google Scholar 

  10. Scott, M.M. et al. Leptin targets in the mouse brain. J. Comp. Neurol. 514, 518–532 (2009).

    Article  CAS  Google Scholar 

  11. Myers, M.G. Jr., Münzberg, H., Leinninger, G.M. & Leshan, R.L. The geometry of leptin action in the brain: more complicated than a simple ARC. Cell Metab. 9, 117–123 (2009).

    Article  CAS  Google Scholar 

  12. Patterson, C.M., Leshan, R.L., Jones, J.C. & Myers, M.G. Jr. Molecular mapping of mouse brain regions innervated by leptin receptor-expressing cells. Brain Res. 1378, 18–28 (2011).

    Article  CAS  Google Scholar 

  13. Grill, H.J. Distributed neural control of energy balance: contributions from hindbrain and hypothalamus. Obesity (Silver Spring) 14 (suppl. 5), 216S–221S (2006).

    Article  Google Scholar 

  14. Fulton, S. et al. Leptin regulation of the mesoaccumbens dopamine pathway. Neuron 51, 811–822 (2006).

    Article  CAS  Google Scholar 

  15. Hommel, J.D. et al. Leptin receptor signaling in midbrain dopamine neurons regulates feeding. Neuron 51, 801–810 (2006).

    Article  CAS  Google Scholar 

  16. Liu, J., Perez, S.M., Zhang, W., Lodge, D.J. & Lu, X.Y. Selective deletion of the leptin receptor in dopamine neurons produces anxiogenic-like behavior and increases dopaminergic activity in amygdala. Mol. Psychiatry 16, 1024–1038 (2011).

    Article  CAS  Google Scholar 

  17. Leshan, R.L. et al. Ventral tegmental area leptin receptor neurons specifically project to and regulate cocaine- and amphetamine-regulated transcript neurons of the extended central amygdala. J. Neurosci. 30, 5713–5723 (2010).

    Article  CAS  Google Scholar 

  18. Lam, D.D. et al. Leptin does not directly affect CNS serotonin neurons to influence appetite. Cell Metab. 13, 584–591 (2011).

    Article  CAS  Google Scholar 

  19. Yadav, V.K. et al. A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure. Cell 138, 976–989 (2009).

    Article  CAS  Google Scholar 

  20. Ring, L.E. & Zeltser, L.M. Disruption of hypothalamic leptin signaling in mice leads to early-onset obesity, but physiological adaptations in mature animals stabilize adiposity levels. J. Clin. Invest. 120, 2931–2941 (2010).

    Article  CAS  Google Scholar 

  21. Leinninger, G.M. et al. Leptin action via neurotensin neurons controls orexin, the mesolimbic dopamine system and energy balance. Cell Metab. 14, 313–323 (2011).

    Article  CAS  Google Scholar 

  22. Louis, G.W., Leinninger, G.M., Rhodes, C.J. & Myers, M.G. Jr. Direct innervation and modulation of orexin neurons by lateral hypothalamic LepRb neurons. J. Neurosci. 30, 11278–11287 (2010).

    Article  CAS  Google Scholar 

  23. Leinninger, G.M. et al. Leptin acts via leptin receptor-expressing lateral hypothalamic neurons to modulate the mesolimbic dopamine system and suppress feeding. Cell Metab. 10, 89–98 (2009).

    Article  CAS  Google Scholar 

  24. Donato, J. Jr., Frazao, R., Fukuda, M., Vianna, C.R. & Elias, C.F. Leptin induces phosphorylation of neuronal nitric oxide synthase in defined hypothalamic neurons. Endocrinology 151, 5415–5427 (2010).

    Article  CAS  Google Scholar 

  25. Leshan, R.L. et al. Direct innervation of GnRH neurons by metabolic- and sexual odorant–sensing leptin receptor neurons in the hypothalamic ventral premammillary nucleus. J. Neurosci. 29, 3138–3147 (2009).

    Article  CAS  Google Scholar 

  26. Elmquist, J.K., Elias, C.F. & Saper, C.B. From lesions to leptin: hypothalamic control of food intake and body weight. Neuron 22, 221–232 (1999).

    Article  CAS  Google Scholar 

  27. Münzberg, H., Huo, L., Nillni, E.A., Hollenberg, A.N. & Bjørbaek, C. Role of signal transducer and activator of transcription 3 in regulation of hypothalamic proopiomelanocortin gene expression by leptin. Endocrinology 144, 2121–2131 (2003).

    Article  Google Scholar 

  28. McMinn, J.E. et al. An allelic series for the leptin receptor gene generated by CRE and FLP recombinase. Mamm. Genome 15, 677–685 (2004).

    Article  CAS  Google Scholar 

  29. Bjørbaek, C., Elmquist, J.K., Frantz, J.D., Shoelson, S.E. & Flier, J.S. Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol. Cell 1, 619–625 (1998).

    Article  Google Scholar 

  30. Vong, L. et al. Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron 71, 142–154 (2011).

    Article  CAS  Google Scholar 

  31. Feil, R. & Kleppisch, T. NO/cGMP-dependent modulation of synaptic transmission. Handb. Exp. Pharmacol. 184, 529–560 (2008).

    Article  CAS  Google Scholar 

  32. Huang, P.L. Mouse models of nitric oxide synthase deficiency. J. Am. Soc. Nephrol. 11, (suppl. 16), S120–S123 (2000).

    CAS  Google Scholar 

  33. Williams, K.W. et al. The acute effects of leptin require PI3K signaling in the hypothalamic ventral premammillary nucleus. J. Neurosci. 31, 13147–13156 (2011).

    Article  CAS  Google Scholar 

  34. Donato, J. Jr. et al. Leptin's effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons. J. Clin. Invest. 121, 355–368 (2011).

    Article  Google Scholar 

  35. Yokosuka, M., Prins, G.S. & Hayashi, S. Co-localization of androgen receptor and nitric oxide synthase in the ventral premammillary nucleus of the newborn rat: an immunohistochemical study. Brain Res. Dev. Brain Res. 99, 226–233 (1997).

    Article  CAS  Google Scholar 

  36. Soliman, G.A. et al. A simple qPCR-based method to detect correct insertion of homologous targeting vectors in murine ES cells. Transgenic Res. 16, 665–670 (2007).

    Article  CAS  Google Scholar 

  37. Münzberg, H. et al. Appropriate inhibition of orexigenic hypothalamic arcuate nucleus neurons independently of leptin receptor/STAT3 signaling. J. Neurosci. 27, 69–74 (2007).

    Article  Google Scholar 

  38. Bates, S.H. et al. STAT3 signaling is required for leptin regulation of energy balance but not reproduction. Nature 421, 856–859 (2003).

    Article  CAS  Google Scholar 

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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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The authors declare no competing financial interests.

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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).

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