Identifying ROCK1 as a novel regulator of insulin signaling, glucose homeostasis, and lipogenesis: My works suggested that Rho-kinase positively regulates insulin-stimulated glucose transport and signaling via either IRS-1 serine phosphorylation or active polymerization, establishing a new mechanism for the regulation of glucose transport. My works also demonstrated that inhibition of Rho-kinase causes insulin resistance in vivo. Our studies also revealed that adipose ROCK1 isoform plays an inhibitory role for the regulation of insulin sensitivity in diet-induced obesity in vivo. Recent our work established a ROCK1-AMPK signaling axis that regulates de novo lipogenesis, providing a unique target for treating obesity-related metabolic disorders such as NAFLD. Identification of ROCK1 as a key player of glucose and lipid metabolism has a major impact on the understanding of the pathogenesis of diabetes and has significantly advanced the diabetes field.

Discovery of Rho-kinase as a key regulator of leptin action: Our recent works also have established the critical roles of the serine threonine kinase ROCK1 on regulation of leptin signaling and action in hypothalamus in vivo, using transgenic mouse models. Our study establishes a new hypothesis that ROCK1 regulates energy balance by targeting leptin receptor signaling, suggesting ROCK1 as a key regulator of leptin action. In fact, genetic disruption of ROCK1 in either POMC or AgRP neurons increases body weight and adiposity. Mice lacking ROCK1 in POMC neurons show hyperphagia and hypoactivity. However, AgRP neuron-specific ROCK1-deficient mice display lower oxygen consumption and locomotor activity. The molecular mechanism for this is involved in ROCK1-mediated JAK2 phosphorylation, which promotes downstream signaling pathways of leptin, including STAT3 and PI3K signaling, ultimately leading to the control of energy balance. This model provides a new mechanism that advances our understanding of central leptin action and energy homeostasis.

ApoJ is a new metabolic signal controlling energy homeostasis and glucose metabolism: Identification of a new molecule that cures potentially eating disorder has been a key subject of obesity field. Our recent work discovered ApoJ as a novel anorexigenic molecule that regulates appetite and energy balance. Like leptin, ApoJ treatment caused anorexia, weight loss, and hypothalamic Stat3 activation. These effects were most likely mediated by a cellular mechanism that was dependent on a physical interaction between functional leptin receptors and LRP (low-density lipoprotein receptor-related protein). However, peripheral actions of ApoJ in the context of glucose metabolism are unknown. Our studies demonstrated that ApoJ functions as a hepatokine targeting insulin signaling and glucose metabolism in skeletal muscle, which is mediated via the LRP signaling cascade. Taken together, our works identify the ApoJ ® LRP signaling axis as a novel metabolic signaling pathway that is central for the maintenance of normal glucose homeostasis and energy balance.