Attenuation of obesity-induced insulin resistance in mice with heterozygous deletion of ROCK2

Soliman, H. S.; Varela, Julia Nogueira; Nyamandi, Vongai; Garcia-Patino, Marysol; Lin, Guorong; Bankar, Girish; Jia, Zheng; MacLeod, Kathleen M.

doi:10.1038/ijo.2016.89

Cited by 12 publications

(25 citation statements)

References 31 publications

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“…The former involves the ROCK2mediated actin cytoskeleton dynamics as discussed above ( Figure 8A) and the latter relies on the direct phosphorylation of IRS1 by ROCK2 ( Figure 8B). 7,11,12,20,21,24,[55][56][57] It is widely believed that serine phosphorylation of IRS1 by ROCK activity in WAT and vascular cells 11,20,21,24,55 leads to reduced IRS1-mediated PI3K activation, resulting in decreased insulin sensitivity ( Figure 8B). 7,11,12,20,21,24,[55][56][57] It is widely believed that serine phosphorylation of IRS1 by ROCK activity in WAT and vascular cells 11,20,21,24,55 leads to reduced IRS1-mediated PI3K activation, resulting in decreased insulin sensitivity ( Figure 8B).…”

Section: Discussionmentioning

confidence: 99%

“…The relationship between ROCK activity and IRS1 phosphorylation has been documented in various cell types and organs including fat tissues. 7,11,12,20,21,24,[55][56][57] It is widely believed that serine phosphorylation of IRS1 by ROCK activity in WAT and vascular cells 11,20,21,24,55 leads to reduced IRS1-mediated PI3K activation, resulting in decreased insulin sensitivity ( Figure 8B). However, ROCK-mediated IRS1 phosphorylation can also positively impact on insulin signaling such as in skeletal muscle and in cultured adipocytes and muscle cells.…”

Section: Discussionmentioning

confidence: 99%

“…8,[18][19][20][21][22][23] To investigate the direct roles of ROCKs in adipose tissues, ROCK1 was specifically deleted from adipocytes in mice, which showed modest amelioration of insulin sensitivity and insulin signaling, but no significant effects were detected on adipocyte hypertrophy and inflammation under a high-fat diet (HFD), 8 suggesting that the ROCK2 isoform in adipose tissue may play a dominant role in controlling insulin sensitivity and adiposity. 8,[18][19][20][21][22][23] To investigate the direct roles of ROCKs in adipose tissues, ROCK1 was specifically deleted from adipocytes in mice, which showed modest amelioration of insulin sensitivity and insulin signaling, but no significant effects were detected on adipocyte hypertrophy and inflammation under a high-fat diet (HFD), 8 suggesting that the ROCK2 isoform in adipose tissue may play a dominant role in controlling insulin sensitivity and adiposity.…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, a partial deletion of ROCK2 in mice on a CD-1 background results in reduced adipocyte hypertrophy associated with reduced production of inflammatory cytokines and insulin resistance. [25][26][27] However, increased adipogenesis has not been reported in partial ROCK2-deficient mice 21 and in transgenic mice expressing adipocyte-specific dominant-negative RhoA mutant. Nevertheless, the role of ROCK2 in adipogenesis and adiposity in vivo remains unexplored.…”

Section: Introductionmentioning

confidence: 99%

“…ROCK2-deficient mouse embryonic fibroblasts (MEF) show enhanced adipogenesis in vitro, 24 consistent with other reports indicating that suppression of RhoA/ROCK activity enhances adipocyte differentiation. [25][26][27] However, increased adipogenesis has not been reported in partial ROCK2-deficient mice 21 and in transgenic mice expressing adipocyte-specific dominant-negative RhoA mutant. 7 A well-defined role and the underlying mechanism of ROCK2 in adipogenesis need to be elucidated in greater detail.…”

Section: Introductionmentioning

confidence: 99%

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ROCK2 inhibition enhances the thermogenic program in white and brown fat tissue in mice

et al. 2019

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The RhoA/ROCK‐mediated actin cytoskeleton dynamics have been implicated in adipogenesis. The two ROCK isoforms, ROCK1 and ROCK2, are highly homologous. The contribution of ROCK2 to adipogenesis in vivo has not been elucidated. The present study aimed at the in vivo and in vitro roles of ROCK2 in the regulation of adipogenesis and the development of obesity. We performed molecular, histological, and metabolic analyses in ROCK2+/− and ROCK2+/KD mouse models, the latter harboring an allele with a kinase‐dead (KD) mutation. Both ROCK2+/− and ROCK2+/KD mouse models showed a lean body mass phenotype during aging, associated with increased amounts of beige cells in subcutaneous white adipose tissue (sWAT) and increased thermogenic gene expression in all fat depots. ROCK2+/− mice on a high‐fat diet showed increased energy expenditure accompanying by reduced obesity, and improved insulin sensitivity. In vitro differentiated ROCK2+/− stromal‐vascular (SV) cells revealed increased beige adipogenesis associated with increased thermogenic gene expressions. Treatment with a selective ROCK2 inhibitor, KD025, to inhibit ROCK2 activity in differentiated SV cells reproduced the pro‐beige phenotype of ROCK2+/− SV cells. In conclusion, ROCK2 activity‐mediated actin cytoskeleton dynamics contribute to the inhibition of beige adipogenesis in WAT, and also promotes age‐related and diet‐induced fat mass gain and insulin resistance.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ROCK2 inhibition enhances the thermogenic program in white and brown fat tissue in mice

et al. 2019

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Unraveling the rationale and conducting a comprehensive assessment of KD025 (Belumosudil) as a candidate drug for inhibiting adipogenic differentiation—a systematic review

Barbalho,

de Alvares Goulart,

Minniti

et al. 2023

Naunyn-Schmiedeberg's Arch Pharmacol

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Regulation of hepatic Na+/K+-ATPase in obese female and male rats: involvement of ERK1/2, AMPK, and Rho/ROCK

et al. 2017

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In this study, we assessed whether the disturbed regulation of sodium/potassium-adenosine-triphosphatase (Na/K-ATPase) occurs as a consequence of obesity-induced IR in sex-specific manner. We also assessed whether alterations of IRS/PI3K/Akt, ERK1/2, AMPKα, and RhoA/ROCK signaling cascades have an important role in this pathology. Female and male Wistar rats (150-200 g, 8 weeks old) were fed a standard laboratory diet or a high-fat (HF) diet (42% fat) for 10 weeks. The activity of hepatic Na/K-ATPase and Rho, and the association of IRS-1/p85 were assessed in liver. Furthermore, the protein level of α Na/K-ATPase in plasma membrane fractions, and protein levels of IRS-1, PI3K-p85, -p110, RhoA, ROCK1, ROCK2, ERK1/2, AMPKα, ERα, and ERβ in liver lysates were assessed. The expression of hepatic α Na/K-ATPase mRNA was also analyzed by qRT-PCR. The results show that HF-fed female rats exhibited an increase in hepatic ERK1/2 (p < 0.05) and AMPKα (p < 0.05) phosphorylation levels, unchanged level of Na/K-ATPase α mRNA, decreased level of Na/K-ATPase activity (p < 0.05), and decreased α Na/K-ATPase protein expression (p < 0.01). In liver of HF-fed male rats, results show decreased levels of Na/K-ATPase activity (p < 0.01), both protein and mRNA of α subunit (p < 0.05), but significant increase in Rho activity (p < 0.05). Our results indicate significant sex differences in α Na/K-ATPase mRNA expression and activation of ERK1/2, AMPKα, and Rho in the liver. Exploring the sex-specific factors and pathways that promote obesity-related diseases may lead to a better understanding of pathogenesis and discovering new therapeutic targets.

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Attenuation of obesity-induced insulin resistance in mice with heterozygous deletion of ROCK2

Cited by 12 publications

References 31 publications

ROCK2 inhibition enhances the thermogenic program in white and brown fat tissue in mice

ROCK2 inhibition enhances the thermogenic program in white and brown fat tissue in mice

Unraveling the rationale and conducting a comprehensive assessment of KD025 (Belumosudil) as a candidate drug for inhibiting adipogenic differentiation—a systematic review

Regulation of hepatic Na+/K+-ATPase in obese female and male rats: involvement of ERK1/2, AMPK, and Rho/ROCK

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