KM. Partial deletion of ROCK2 protects mice from high-fat diet-induced cardiac insulin resistance and contractile dysfunction. Am J Physiol Heart Circ Physiol 309: H70 -H81, 2015. First published April 24, 2015 doi:10.1152/ajpheart.00664.2014.-Obesity is associated with cardiac insulin resistance and contractile dysfunction, which contribute to the development of heart failure. The RhoA-Rho kinase (ROCK) pathway has been reported to modulate insulin resistance, but whether it is implicated in obesity-induced cardiac dysfunction is not known. To test this, wild-type (WT) and ROCK2 ϩ/Ϫ mice were fed normal chow or a high-fat diet (HFD) for 17 wk. Whole body insulin resistance, determined by an insulin tolerance test, was observed in HFD-WT, but not HFD-ROCK2 ϩ/Ϫ , mice. The echocardiographically determined myocardial performance index, a measure of global systolic and diastolic function, was significantly increased in HFD-WT mice, indicating a deterioration of cardiac function. However, no change in myocardial performance index was found in hearts from HFD-ROCK2 ϩ/Ϫ mice. Speckle-tracking-based strain echocardiography also revealed regional impairment in left ventricular wall motion in hearts from HFD-WT, but not HFD-ROCK2 ϩ/Ϫ , mice. Activity of ROCK1 and ROCK2 was significantly increased in hearts from HFD-WT mice, and GLUT4 expression was significantly reduced. Insulin-induced phosphorylation of insulin receptor substrate (IRS) Tyr 612 , Akt, and AS160 was also impaired in these hearts, while Ser 307 phosphorylation of IRS was increased. In contrast, the increase in ROCK2, but not ROCK1, activity was prevented in hearts from HFD-ROCK2 ϩ/Ϫ mice, and cardiac levels of TNF␣ were reduced. This was associated with normalization of IRS phosphorylation, downstream insulin signaling, and GLUT4 expression. These data suggest that increased activation of ROCK2 contributes to obesityinduced cardiac dysfunction and insulin resistance and that inhibition of ROCK2 may constitute a novel approach to treat this condition. ROCK2; insulin signaling; heart; insulin receptor substrate phosphorylation

These data suggest that activation of ROCK2 in adipose tissue contributes to obesity-induced insulin resistance. This may result in part from suppression of PPARγ expression, leading to adipocyte hypertrophy and an increase in inflammatory cytokine production. ROCK2 may be a suitable target to improve insulin sensitivity in obesity.

Obesity is a chronic condition involving the excessive accumulation of adipose tissue that adversely affects all systems in the body. The aim of the present study was to employ an unbiased, genome-wide assessment of transcript abundance in order to identify common gene expression pathways within insulin-sensitive tissues in response to dietary-induced diabetes. Following 20 weeks of chow or high-fat feeding (60% kcal), age-matched mice underwent a euglycemic-hyperinsulinemic clamp to assess insulin sensitivity. High-fat-fed animals were obese and highly insulin resistant, disposing of ∼75% less glucose compared with their chow-fed counterparts. Tissues were collected, and gene expression was examined by microarray in 4 tissues known to exhibit obesity-related metabolic disturbances: white adipose tissue, skeletal muscle, liver, and heart. A total of 463 genes were differentially expressed between diets. Analysis of individual tissues showed skeletal muscle to exhibit the largest number of differentially expressed genes (191) in response to high-fat feeding, followed by adipose tissue (169), liver (115), and heart (65). Analyses revealed that the response of individual genes to obesity is distinct and largely tissue specific, with less than 10% of transcripts being shared among tissues. Although transcripts are largely tissue specific, a systems approach shows numerous commonly activated pathways, including those involved in signal transduction, inflammation, oxidative stress, substrate transport, and metabolism. This suggests a coordinated attempt by tissues to limit metabolic perturbations occurring in early-stage obesity. Many identified genes were associated with a variety of disorders, thereby serving as potential links between obesity and its related health risks.

Objective: The impact of dietary-induced obesity (DIO) on stem cell engraftment and the respective therapeutic potential of stem cell engraftment in DIO have not been reported. The objectives of this study were to examine the impact of DIO on the survival and efficacy of intravenous bone marrow-derived mesenchymal stem cell (MSC) administration in the conscious C57BL/6 mouse. Methods: Male mice consumed either a chow (CH) or high fat (HF, 60% kcal) diet for 18 weeks and were subsequently treated with MSC over a 6-day period. Key measurements included tissue-specific cell engraftment, glucose and insulin sensitivity, inflammation, and oxidative stress. Results: MSC administration had no effect on inflammatory markers, glucose, or insulin sensitivity. DIO mice showed increases in MSC engraftment in multiple tissues compared with their CH counterparts. Engraftment was increased in the HF liver where MSC administration attenuated DIO-induced oxidative stress. These liver-specific alterations in HF-MSC were associated with increases in stanniocalcin-1 (STC1) and uncoupling protein 2 (UCP2), which contribute to cell survival and modulate mitochondrial bioenergetics. Conclusion: Results suggest that MSC administration in DIO promotes engraftment and mitigates hepatic oxidative stress. These data invite further exploration into the therapeutic potential of stem cells for the treatment of DIO oxidative stress in the liver.

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Mesenchymal stem cells (MSCs) are thought to exert their effects in part by limiting oxidative stress. Of therapeutic interest are the effects of MSCs in insulin resistance, a cause of elevated reactive oxygen species (ROS). In this study, we analyzed the antioxidant activity of MSCs in the dietary‐induced insulin resistant C57BL6 model. Male mice were placed on either a chow (CH) or high fat (HFF, 60% kcal) diet for 18wk. Over a 6d period, mice received two serial injections of either murine serum or MSC enriched serum (2 million cells/injection, separated by 2d) via the tail vein. Analyses included cell survival, glucose tolerance, insulin resistance, respirometry and levels of hepatic mitochondrial ROS production. HFF mice were obese (31±2g vs. 46±3g) and hyperglycemic. Results demonstrated no difference in glucose tolerance or insulin resistance with MSCs. Interestingly, MSCs did not alter the rate of ROS production in CH (H2O2 production: 0.68±0.14 pmol.min−1μg−1 in CH‐MSC vs. 0.63±0.11 pmol.min−1μg−1 in CH‐Serum) but significantly reduced mitochondrial ROS production in HFF (4.85±0.39 vs. 0.72±0.17 pmol.min−1μg−1). In conclusion, short‐term MSC treatment does not impact hyperglycemia but significantly reduces rates of hepatic mitochondrial ROS production. Results invite further exploration into the specific mechanisms by which MSCs reduce ROS in insulin resistant states.Support: HSF, CDA, AIHS

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