Resistance to age-related, normal body weight gain in RGS2 deficient mice

Nunn, Caroline; Zhao, Peishen; Zou, Min; Summers, Kelly M; Guglielmo, Christopher G.; Chidiac, Peter

doi:10.1016/j.cellsig.2011.03.020

Cited by 24 publications

(39 citation statements)

References 56 publications

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“…Although we can not determine the exact reasons for the discrepancies between Cho's study and ours, the phenotype of obesity in RGS5 KO mice are evident in our experiment and KO mice exhibited an increased body weight through increasing calorie intake, promoting adipocyte differentiation and hypertrophy in the adipose tissue and accelerating ectopic fat deposition in the liver. Our observation may be confirmed indirectly by Caroline's research for RGS2 [9]. RGS2 is unique among RGS proteins and limits signals mediated via Gαs- or Gαq- but not Gαi-coupled GPCRs.…”

Section: Discussionsupporting

confidence: 68%

“…Few studies were reported to explore the exact mechanism of RGS proteins on insulin signaling except for some researches described the phenotype of body weight and insulin sensitivity and explained the potential reasons through GPCRs and G proteins [8], [9]. Gαi2 and Gaq/11 are positive regulator of insulin action, including insulin-stimulated tyrosine phosphorylation of insulin-receptor (IR) and IR substrate 1(IRS1) and subsequent glucose uptake [6], [48], [49], [50].…”

Section: Discussionmentioning

confidence: 99%

“…The effect of downregulating total RGS proteins in obesity has been studied, demonstrating a block in weight gain and insulin resistance in homozygous Gαi2G184S knock-in male mice, which express RGS-insensitive Gαi2 with a G184S mutation that blocks RGS protein binding and GTPase acceleration, fed an HF [8]. Mice without RGS2, which is known to limit signals mediated via Gαs- and Gαq-coupled GPCRs, exhibited greatly reduced fat deposits, decreased serum lipids, low leptin levels, improved glucose clearance and insulin sensitivity [9]. Functional diversity may exist among RGS proteins and RGS5 is an important member of the RGS protein superfamily that has recently been reported to regulate cardiac hypertrophy, atherosclerosis and angiogenesis through the inhibition of several Gαi- and Gαq-mediated signaling pathways [10], [11], [12], [13].…”

Section: Introductionmentioning

confidence: 99%

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Loss of Regulator of G Protein Signaling 5 Exacerbates Obesity, Hepatic Steatosis, Inflammation and Insulin Resistance

et al. 2012

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BackgroundThe effect of regulator of G protein signaling 5 (RGS5) on cardiac hypertrophy, atherosclerosis and angiogenesis has been well demonstrated, but the role in the development of obesity and insulin resistance remains completely unknown. We determined the effect of RGS5 deficiency on obesity, hepatic steatosis, inflammation and insulin resistance in mice fed either a normal-chow diet (NC) or a high-fat diet (HF).Methodology/Principal FindingsMale, 8-week-old RGS5 knockout (KO) and littermate control mice were fed an NC or an HF for 24 weeks and were phenotyped accordingly. RGS5 KO mice exhibited increased obesity, fat mass and ectopic lipid deposition in the liver compared with littermate control mice, regardless of diet. When fed an HF, RGS5 KO mice had a markedly exacerbated metabolic dysfunction and inflammatory state in the blood serum. Meanwhile, macrophage recruitment and inflammation were increased and these increases were associated with the significant activation of JNK, IκBα and NF-κBp65 in the adipose tissue, liver and skeletal muscle of RGS5 KO mice fed an HF relative to control mice. These exacerbated metabolic dysfunction and inflammation are accompanied with decreased systemic insulin sensitivity in the adipose tissue, liver and skeletal muscle of RGS5 KO mice, reflected by weakened Akt/GSK3β phosphorylation.Conclusions/SignificanceOur data suggest that loss of RGS5 exacerbates HF-induced obesity, hepatic steatosis, inflammation and insulin resistance.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Loss of Regulator of G Protein Signaling 5 Exacerbates Obesity, Hepatic Steatosis, Inflammation and Insulin Resistance

et al. 2012

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“…Human and mouse studies have also implicated RGS2, 4 and 5, in the regulation of body weight and obesity [48], [49], [50], [51]. However these RGS proteins and RGS9 likely regulate body weight through different mechanisms: RGS2, 4 and 5 are members of a different R4 subfamily of RGS proteins, have a different molecular architecture and strikingly different cellular and tissue expression patterns compared to RGS9 [18], [37], [52].…”

Section: Discussionmentioning

confidence: 99%

Association between Regulator of G Protein Signaling 9–2 and Body Weight

et al. 2011

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Regulator of G protein signaling 9–2 (RGS9–2) is a protein that is highly enriched in the striatum, a brain region that mediates motivation, movement and reward responses. We identified a naturally occurring 5 nucleotide deletion polymorphism in the human RGS9 gene and found that the mean body mass index (BMI) of individuals with the deletion was significantly higher than those without. A splicing reporter minigene assay demonstrated that the deletion had the potential to significantly decrease the levels of correctly spliced RGS9 gene product. We measured the weights of rats after virally transduced overexpression of RGS9–2 or the structurally related RGS proteins, RGS7, or RGS11, in the nucleus accumbens (NAc) and observed a reduction in body weight after overexpression of RGS9–2 but not RGS7 or 11. Conversely, we found that the RGS9 knockout mice were heavier than their wild-type littermates and had significantly higher percentages of abdominal fat. The constituent adipocytes were found to have a mean cross-sectional area that was more than double that of corresponding cells from wild-type mice. However, food intake and locomotion were not significantly different between the two strains. These studies with humans, rats and mice implicate RGS9–2 as a factor in regulating body weight.

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“…At the lower part of the table in Figure 1B two RGS (regulator of G-protein signalling) encoding genes, RGS1 and RGS2 are down-regulated in ALD but up-regulated in NAFLD. Nunn et al[30] reported reduced fat deposits, decreased serum lipids, and low Leptin levels in RGS2 deficient mice.…”

Section: Resultsmentioning

confidence: 99%

Meta-analysis reveals up-regulation of cholesterol processes in non-alcoholic and down-regulation in alcoholic fatty liver disease

Wruck

Adjaye

2017

WJH

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AIMTo compare transcriptomes of non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) in a meta-analysis of liver biopsies.METHODSEmploying transcriptome data from patient liver biopsies retrieved from several public repositories we performed a meta-analysis comparing ALD and NAFLD.RESULTSWe observed predominating commonalities at the transcriptome level between ALD and NAFLD, most prominently numerous down-regulated metabolic pathways and cytochrome-related pathways and a few up-regulated pathways which include ECM-receptor interaction, phagosome and lysosome. However some pathways were regulated in opposite directions in ALD and NAFLD, for example, glycolysis was down-regulated in ALD and up-regulated in NAFLD. Interestingly, we found rate-limiting genes such as HMGCR, SQLE and CYP7A1 which are associated with cholesterol processes adversely regulated between ALD (down-regulated) and NAFLD (up-regulated). We propose that similar phenotypes in both diseases may be due to a lower level of the enzyme CYP7A1 compared to the cholesterol synthesis enzymes HMGCR and SQLE. Additionally, we provide a compendium of comparative KEGG pathways regulation in ALD and NAFLD.CONCLUSIONOur finding of adversely regulated cholesterol processes in ALD and NAFLD draws the focus to regulation of cholesterol secretion into bile. Thus, it will be interesting to further investigate CYP7A1-mediated cholesterol secretion into bile - also as possible drug targets. The list of potential novel biomarkers may assist differential diagnosis of ALD and NAFLD.

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Resistance to age-related, normal body weight gain in RGS2 deficient mice

Cited by 24 publications

References 56 publications

Loss of Regulator of G Protein Signaling 5 Exacerbates Obesity, Hepatic Steatosis, Inflammation and Insulin Resistance

Loss of Regulator of G Protein Signaling 5 Exacerbates Obesity, Hepatic Steatosis, Inflammation and Insulin Resistance

Association between Regulator of G Protein Signaling 9–2 and Body Weight

Meta-analysis reveals up-regulation of cholesterol processes in non-alcoholic and down-regulation in alcoholic fatty liver disease

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