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Rho-kinase regulates energy balance by targeting hypothalamic leptin receptor signaling

Nature Neuroscience volume 15, pages 1391–1398 (2012)Cite this article

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Abstract

Leptin regulates energy balance. However, knowledge of the critical intracellular transducers of leptin signaling remains incomplete. We found that Rho-kinase 1 (ROCK1) regulates leptin action on body weight homeostasis by activating JAK2, an initial trigger of leptin receptor signaling. Leptin promoted the physical interaction of JAK2 and ROCK1, thereby increasing phosphorylation of JAK2 and downstream activation of Stat3 and FOXO1. Mice lacking ROCK1 in either pro-opiomelanocortin (POMC) or agouti-related protein neurons, mediators of leptin action, displayed obesity and impaired leptin sensitivity. In addition, deletion of ROCK1 in the arcuate nucleus markedly enhanced food intake, resulting in severe obesity. Notably, ROCK1 was a specific mediator of leptin, but not insulin, regulation of POMC neuronal activity. Our data identify ROCK1 as a key regulator of leptin action on energy homeostasis.

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Figure 1: ROCK1 interacts with and phosphorylates JAK2 in hypothalamic GT1-7 cells and hypothalamus.
Figure 2: ROCK1 stimulates Stat3 phosphorylation and FOXO1 nuclear export.
Figure 3: Leptin increases ROCK1 activity in the hypothalamus.
Figure 4: ROCK1 deficiency in POMC neurons leads to obesity.
Figure 5: ROCK1 deficiency in POMC neurons impairs leptin-stimulated Stat3 phosphorylation and food intake.
Figure 6: Leptin-induced POMC neuronal activity is dependent on ROCK1.
Figure 7: Loss of ROCK1 in AgRP neurons leads to obesity.
Figure 8: Hypothalamic ROCK1 signaling regulates food intake and adiposity.

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Acknowledgements

We would like to thank B. Kahn and T. Flier for valuable suggestions; L. Huo, S.D. Ha, S. Baver, S. Yee, T. Liu, S.-M. Hong, N. Wang, D. Kim, B. Enkhjargal for technical assistance, and L. Wei for DN-Rock1 cDNA. This work was supported by grants from the US National Institutes of Health (1R01DK083567 to Y.-B.K., 5R01CA127247 to S.W.L. and P30DK057521 to D.K.) and the American Diabetes Association (1-09-RA-87 to Y.-B.K.).

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Authors and Affiliations

  1. Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA

    Hu Huang, Dong Kong, Chianping Ye, Shuichi Koda, Dae Ho Lee, Janice M Zabolotny, Christian Bjørbæk, Bradford B Lowell & Young-Bum Kim

  2. Gachon University of Medicine and Science, Graduate Schools of Medicine, Lee Gil Ya Cancer and Diabetes Institute, Incheon, Korea

    Kyung Hee Byun, Byung-Chul Oh, Bonghee Lee & Young-Bum Kim

  3. Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA

    Sam W Lee

  4. Department of Internal Medicine, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Korea

    Min Seon Kim

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  1. Hu Huang
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Contributions

Y.-B.K., H.H. and B.B.L. designed the study. J.M.Z. and C.B. provided conceptual advice. H.H. performed most of the mice experiments and some of the in vitro studies. D.K. generated several lines of model mice. K.H.B. and B.L. performed most of the in vitro studies, including PLA and FCCS experiments. C.Y. was responsible for the electrophysiology studies. S.K. carried out AAV injection experiments. D.H.L. bred and maintained Rock1loxP/loxP mice. S.W.L. generated adenovirus encoding ROCK1. B.-C.O. performed immunoblotting analyses. M.S.K. performed food intake studies with adenovirus. C.B. carried out immunohistochemistry experiments. All of the authors analyzed and interpreted experimental data. J.M.Z., C.B., B.B.L. and Y.-B.K. wrote the manuscript.

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Correspondence to Young-Bum Kim.

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Huang, H., Kong, D., Byun, K. et al. Rho-kinase regulates energy balance by targeting hypothalamic leptin receptor signaling. Nat Neurosci 15, 1391–1398 (2012). https://doi.org/10.1038/nn.3207

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