ROCKing the JAKs

The endocrine cytokine leptin is mainly secreted by white adipose tissue and plasma leptin levels positively correlate with body fat mass. Via its action on neurons in the hypothalamic arcuate nucleus (ARC), leptin regulates body weight by stimulating energy expenditure and inhibiting food intake. The main signaling pathway of the leptin receptor is the JAK2-STAT3 pathway. A recent publication of Huang et al. in Nature Neuroscience shows that leptin's hypothalamic signaling via JAK2 requires the kinase ROCK1 (Rho-associated coiled-coil-containing protein kinase 1). ROCK1 directly phosphorylates JAK2, and this phosphorylation is required for the JAK2-STAT3 pathway of the leptin receptor. Gene deletion of ROCK1 in ARC neurons targeted by leptin makes these neurons less sensitive to leptin. This is reflected by a pronounced weight gain with hyperphagia, reduced locomotor activity, and increased fat accumulation. In this article we comment on the article of Huang et al. While the mechanism of ROCK1 activation in the neurons remains uncharacterized for the moment, a literature survey suggests that the interplay between ROCK1 and a JAK kinase may be a common theme for receptors that function via a JAK2 and even for other members of the JAK kinase family.