ROCK1 isoform-specific deletion reveals a role for diet-induced insulin resistance

Seung Hwan Lee, Hu Huang, Kangduk Choi, Dae Ho Lee, Jianjian Shi, Tiemin Liu, Kwang Hoon Chun, Ji A. Seo, Ines S. Lima, Janice M. Zabolotny, Lei Wei, Young Bum Kim

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29 Citations (Scopus)

Abstract

Rho kinase (ROCK) isoforms regulate insulin signaling and glucose metabolism negatively or positively in cultured cell lines and skeletal muscle. However, the in vivo function of the ROCK1 isoform in adipose tissue has not been addressed. To determine the specific role of the adipose ROCK1 isoform in the development of insulin resistance and obesity, mice lacking ROCK1 in adipose tissue globally or selectively were studied. Here, we show that insulin's ability to activate IRS-1/PI3K/Akt signaling was greatly enhanced in adipose tissue of ROCK1-/- mice compared with wild-type mice. These effects resulted from the inhibitory effect of ROCK1 on insulin receptor action, as evidenced by the fact that IR tyrosine phosphorylation was abolished in ROCK1-/- MEF cells when ROCK1 was reexpressed. Consistently, adipose-specific disruption of ROCK1 increased IR tyrosine phosphorylation in adipose tissue and modestly improved sensitivity to insulin in obese mice induced by high-fat feeding. This effect is independent of any changes in adiposity, number or size of adipocytes, and metabolic parameters, including glucose, insulin, leptin, and triglyceride levels, demonstrating a minimal effect of adipose ROCK1 on whole body metabolism. Enzymatic activity of ROCK1 in adipose tissue remained ~50%, which likely originated from the fraction of stromal vascular cells, suggesting involvement of these cells for adipose metabolic regulation. Moreover, ROCK isoform activities were increased in adipose tissue of diet-induced or genetically obese mice. These data suggest that adipose ROCK1 isoform plays an inhibtory role for the regulation of insulin sensitivity in diet-induced obesity in vivo.

Original languageEnglish
Pages (from-to)E332-E343
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume306
Issue number3
DOIs
Publication statusPublished - 2014 Feb 1

Keywords

  • Adipocyte
  • Insulin sensitivity
  • Insulin signaling
  • ROCK1
  • Rho kinase

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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    Lee, S. H., Huang, H., Choi, K., Lee, D. H., Shi, J., Liu, T., Chun, K. H., Seo, J. A., Lima, I. S., Zabolotny, J. M., Wei, L., & Kim, Y. B. (2014). ROCK1 isoform-specific deletion reveals a role for diet-induced insulin resistance. American Journal of Physiology - Endocrinology and Metabolism, 306(3), E332-E343. https://doi.org/10.1152/ajpendo.00619.2013