What does this research mean for the field?

Adipose-specific ROCK2 plays a pivotal role in maintaining insulin sensitivity and limiting adiposity during overnutrition, acting in part by directly binding to and phosphorylating the insulin receptor. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This study aims to understand the role of adipose-specific ROCK2 deletion on insulin signaling and obesity.

June 7, 2026

1145-OR: Adipose-Specific Deletion of ROCK2 Exacerbates Diet-Induced Obesity and Impairs Insulin Signaling

Key Points

This study aims to understand the role of adipose-specific ROCK2 deletion on insulin signaling and obesity.
Used adiponectin-Cre; ROCK2loxP/loxP mice to investigate effects under normal and high-fat diets.
Examined changes in body weight, glucose homeostasis, and insulin sensitivity in A-ROCK2-/- mice.
Conducted in vitro assays to observe ROCK2 binding and phosphorylation of the insulin receptor.
A-ROCK2-/- mice showed increased weight gain and hyperinsulinemia on a high-fat diet.
Reduced insulin-stimulated phosphorylation of the insulin receptor and downstream signaling proteins in adipose tissue.
No significant changes in energy expenditure or locomotor activity were observed.

Abstract

Introduction and Objective: Rho-kinase (ROCK) isoforms, ROCK1 and ROCK2, have been implicated in regulating glucose metabolism, insulin signaling, and energy balance. However, the isoform-specific role of ROCK2 in adipose tissue remains elusive. This study investigated the effects of adipose-specific ROCK2 deletion on insulin signaling, energy metabolism, and obesity development using adiponectin-Cre; ROCK2loxP/loxP mice (A-ROCK2-/-). Methods: Under a normal chow diet, A-ROCK2-/- mice maintained normal body weight, glucose homeostasis, and thermogenic responses. However, when challenged with a high-fat diet, A-ROCK2-/- mice showed increased weight gain and adiposity, accompanied by hyperinsulinemia, hyperleptinemia, and impaired insulin sensitivity. Results: These effects occurred without changes in energy expenditure or locomotor activity. Thermogenic gene expression in brown fat was not changed, but was significantly reduced in inguinal white fat. Furthermore, hypothalamic expression of orexigenic neuropeptides and TGF-β was modestly elevated. Importantly, adipose-specific ROCK2 deletion markedly reduced insulin-stimulated phosphorylation of insulin receptor, Akt, and AS160 in adipose tissue but not the liver or muscle. In vitro studies showed that ROCK2 physically binds to the insulin receptor and directly phosphorylates it at residues T1058, S1064, and T1172, identifying the insulin receptor as a new substrate for ROCK2. The function of these specific phosphorylation sites on insulin signaling is currently under investigation. These adipose-specific effects contrast with the results from systemic ROCK2 deletion, which has been shown to enhance energy expenditure and insulin sensitivity, highlighting the importance of tissue context. Conclusion: Our findings demonstrate that adipose ROCK2 plays a pivotal role in regulating insulin sensitivity and adiposity, particularly under conditions of overnutrition. Disclosure K. Rodrigues: None. M. Kang: None. W. Yang: None. D. Lim: None. M. Shibata: None. M. Lee: None. J. Young: None. S. Kim: None. C.S. Ryu: None. S. Han: None. A.A. Uner: None. Y. Kim: None. Funding American Diabetes Association (1-25-PDF-49), National Institutes of Health (R01 DK129946)

Ask AI

Mark Helpful

Bookmark

Relay