Selective enhancement of insulin sensitivity in the mature adipocyte is sufficient for systemic metabolic improvements

Morley, Thomas S.; Xia, Jonathan Y.; Scherer, Philipp E.

doi:10.1038/ncomms8906

Cited by 94 publications

(79 citation statements)

References 24 publications

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“…A tight regulation of insulin action in adipose tissue is required for the proper modulation of nutrient storage and mobilization throughout the daily cycles of fasting and feeding [7], [51], [52]. Our in vitro and in vivo results combined suggest that removal of GPS2-mediated regulation is sufficient to promote aberrant activation of the insulin signaling pathway through constitutive phosphorylation and activation of AKT.…”

Section: Resultsmentioning

confidence: 66%

Systemic insulin sensitivity is regulated by GPS2 inhibition of AKT ubiquitination and activation in adipose tissue

Cederquist

Lentucci

Martinez-Calejman

et al. 2017

Molecular Metabolism

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ObjectiveInsulin signaling plays a unique role in the regulation of energy homeostasis and the impairment of insulin action is associated with altered lipid metabolism, obesity, and Type 2 Diabetes. The main aim of this study was to provide further insight into the regulatory mechanisms governing the insulin signaling pathway by investigating the role of non-proteolytic ubiquitination in insulin-mediated activation of AKT.MethodsThe molecular mechanism of AKT regulation through ubiquitination is first dissected in vitro in 3T3-L1 preadipocytes and then validated in vivo using mice with adipo-specific deletion of GPS2, an endogenous inhibitor of Ubc13 activity (GPS2-AKO mice).ResultsOur results indicate that K63 ubiquitination is a critical component of AKT activation in the insulin signaling pathway and that counter-regulation of this step is provided by GPS2 preventing AKT ubiquitination through inhibition of Ubc13 enzymatic activity. Removal of this negative checkpoint, through GPS2 downregulation or genetic deletion, results in sustained activation of insulin signaling both in vitro and in vivo. As a result, the balance between lipid accumulation and utilization is shifted toward storage in the adipose tissue and GPS2-AKO mice become obese under normal laboratory chow diet. However, the adipose tissue of GPS2-AKO mice is not inflamed, the levels of circulating adiponectin are elevated, and systemic insulin sensitivity is overall improved.ConclusionsOur findings characterize a novel layer of regulation of the insulin signaling pathway based on non-proteolytic ubiquitination of AKT and define GPS2 as a previously unrecognized component of the insulin signaling cascade. In accordance with this role, we have shown that GPS2 presence in adipocytes modulates systemic metabolism by restricting the activation of insulin signaling during the fasted state, whereas in absence of GPS2, the adipose tissue is more efficient at lipid storage, and obesity becomes uncoupled from inflammation and insulin resistance.

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Section: Resultsmentioning

confidence: 66%

Systemic insulin sensitivity is regulated by GPS2 inhibition of AKT ubiquitination and activation in adipose tissue

Cederquist

Lentucci

Martinez-Calejman

et al. 2017

Molecular Metabolism

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“…Among them, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) antagonizes PI3K actions to negatively regulate the phosphorylation of AKT. Numerous studies revealed that overexpression of PTEN could suppress insulin-induced PtdIns (3,4) P2/PtdIns (3,4,5) P3 PIP3 production, thereby inhibiting AKT activation, GLUT4 translocation and glucose uptake121314.…”

mentioning

confidence: 99%

Hepatic MiR-291b-3p Mediated Glucose Metabolism by Directly Targeting p65 to Upregulate PTEN Expression

Guo

Dou

Meng

et al. 2017

Sci Rep

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Several studies have suggested an important role of miR-291b-3p in the development of embryonic stem cells. In previous study, we found that the expression of miR-291b-3p was significantly upregulated in the liver of db/db mice. However, the role of miR-291b-3p in glucose metabolism and its underlying mechanisms remain unknown. In the present study, we demonstrated that miR-291b-3p was abundantly expressed in the liver. Of note, hepatic miR-291b-3p expression was upregulated in HFD-fed mice and induced by fasting in C57BL/6 J normal mice. Importantly, hepatic inhibition miR-291b-3p expression ameliorated hyperglycemia and insulin resistance in HFD-fed mice, whereas hepatic overexpression of miR-291b-3p led to hyperglycemia and insulin resistance in C57BL/6 J normal mice. Further study revealed that miR-291b-3p suppressed insulin-stimulated AKT/GSK signaling and increased the expression of gluconeogenic genes in hepatocytes. Moreover, we identified that p65, a subunit of nuclear factor-κB (NF-κB), is a target of miR-291b-3p by bioinformatics analysis and luciferase reporter assay. Silencing of p65 significantly augmented the expression of PTEN and impaired AKT activation. In conclusion, we found novel evidence suggesting that hepatic miR-291b-3p mediated glycogen synthesis and gluconeogenesis through targeting p65 to regulate PTEN expression. Our findings indicate the therapeutic potential of miR-291b-3p inhibitor in hyperglycemia and insulin resistance.

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“…The importance of coordinated adipose tissue expansion in the maintenance of whole body metabolic homeostasis is well-established (Acosta et al 2016, Henninger et al 2014, Morley et al 2015 and increasing evidence provides a link between the FGF-1 axis and obesity-related adipose tissue remodeling (Jonker et al 2012, Ohta andItoh 2014). Hence, we sought to extend our in vitro observations by exploring the relationship between expression of CPA4 in shAT with indices of adipose tissue and hepatic and muscle insulin sensitivity in a cohort of obese males who had been subject to comprehensive metabolic characterization (Chen et al 2015).…”

mentioning

confidence: 99%

Fibroblast growth factor-1 (FGF-1) promotes adipogenesis by downregulation of carboxypeptidase A4 (CPA4) – a negative regulator of adipogenesis implicated in the modulation of local and systemic insulin sensitivity

Chen

Samocha-Bonet

et al. 2016

Growth Factors

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Selective enhancement of insulin sensitivity in the mature adipocyte is sufficient for systemic metabolic improvements

Cited by 94 publications

References 24 publications

Systemic insulin sensitivity is regulated by GPS2 inhibition of AKT ubiquitination and activation in adipose tissue

Systemic insulin sensitivity is regulated by GPS2 inhibition of AKT ubiquitination and activation in adipose tissue

Hepatic MiR-291b-3p Mediated Glucose Metabolism by Directly Targeting p65 to Upregulate PTEN Expression

Fibroblast growth factor-1 (FGF-1) promotes adipogenesis by downregulation of carboxypeptidase A4 (CPA4) – a negative regulator of adipogenesis implicated in the modulation of local and systemic insulin sensitivity

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