ROCK Mediates Leptin Signaling

Science Signaling  02 Oct 2012:
Vol. 5, Issue 244, pp. ec254
DOI: 10.1126/scisignal.2003656

The adipose-derived hormone leptin suppresses appetite by regulating distinct sets of neurons, pro-opiomelanocortin (POMC) neurons and AgRP/neuropeptide Y (NPY)–producing neurons, in the arcuate nucleus of the hypothalamus. Defects in leptin or its receptor result in uncontrolled eating (hyperphagia) and obesity. Rho-associated kinase (ROCK) isoforms mediate insulin signaling in peripheral tissues. Huang et al. reported that ROCK1 was also involved in leptin signaling. Treatment of the rat hypothalamic GT1-7 cell line with leptin activated Janus kinase 2 (JAK2), which was blocked when ROCK1 was inhibited. In response to leptin, ROCK1 associated with and phosphorylated JAK2, which resulted in activation of JAK2 and its target, the transcription factor signal transducer and activator of transcription 3 (STAT3). Compared with control mice, mice deficient in ROCK1, specifically in POMC neurons or in AgRP neurons, had increased body weights and adipose tissue. Immunohistochemical analysis of brain sections showed that leptin-induced STAT3 phosphorylation was inhibited in mice deficient in ROCK1 in POMC neurons. Administration of leptin to control mice reduced their food intake but had no effect on mice with POMC-specific deficiency in ROCK1. Electrophysiological studies showed that leptin induced neuronal activity in POMC neurons from control mice but not in those from mice with ROCK1-deficient POMC neurons. Loss of ROCK1 in POMC neurons had no effect on insulin-induced neuronal activity. Wild-type mice injected in the hypothalamus with adenovirus expressing ROCK1 showed decreased food intake and body weight compared with those of control mice. Together, these data suggest that ROCK1 mediates leptin signaling in the hypothalamus to inhibit food intake and suppress weight gain.

H. Huang, D. Kong, K. H. Byun, C. Ye, S. Koda, D. H. Lee, B.-C. Oh, S. W. Lee, B. Lee, J. M. Zabolotny, M. S. Kim, C. Bjørbæk, B. B. Lowell, Y.-B. Kim, Rho-kinase regulates energy balance by targeting hypothalamic leptin receptor signaling. Nat. Neurosci. 15, 1391–1398 (2012). [PubMed]