Impaired (‘diabetic’) insulin signaling and action occur in fat cells long before glucose intolerance—is insulin resistance initiated in the adipose tissue?

Smith, Ulf

doi:10.1038/sj.ijo.0802028

Cited by 177 publications

(129 citation statements)

References 64 publications

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“…Thus, while white adipose tissue, diaphragm, and soleus muscle present a clear decrease in glucose metabolic index under hyperinsulinemic conditions, other skeletal muscles like quadriceps remain insulin sensitive with ageing (Escrivá et al 1997). In agreement with the resistance observed in adipose tissue, isolated adipocytes from aged rats show a decreased insulin response (Carrascosa et al 1989, Molero et al 1998, 2002, Villar et al 2006.…”

Section: Introductionsupporting

confidence: 56%

“…These data agree with the decreased insulin effect on lipogenesis observed in isolated adipocytes and indicates that this insulin-resistant state develops early after sexual maturation. Impaired insulin action in adipose tissue could represent an early step leading to the overall insulin resistance characteristic of aged and/or obese rats (Smith 2002). Moreover, recent in vitro studies have demonstrated that adipocyte-conditioned medium impairs insulin signaling in skeletal muscle cells (Dietze et al 2004) and hepatocytes (Wang et al 2006a).…”

Section: Discussionmentioning

confidence: 99%

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Effect of age and moderate food restriction on insulin sensitivity in Wistar rats: role of adiposity

Escrivá

Gavete

Fermín

et al. 2007

Journal of Endocrinology

116

117

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Insulin resistance develops with ageing in humans and rodents. Here, we have studied the evolution of insulin sensitivity with ageing trying to discriminate the role of adiposity from that of ageing in this process. We performed oral glucose tolerance tests and determined overall and tissue-specific glucose utilization under euglycemic-hyperinsulinemic conditions in 3-, 8-, and 24-month-old rats fed ad libitum, and in 8-and 24-month-old rats after 3 months of calorie restriction. Body composition and adipocytederived cytokines such as leptin, resistin, and adiponectin were analyzed. Overall insulin sensitivity decreases with ageing. Calorie restriction improves global insulin sensitivity in 8-but not in 24-month-old rats. Insulin-stimulated glucose utilization in adipose tissues decreases in 8 months, while in oxidative muscles it reaches significance only in older rats. Calorie restriction restores adipose tissue insulin sensitivity only in 8-month-old rats and no changes are observed in muscles of 24-month-old rats. Resistin and leptin increase with ageing. Food restriction lowers resistin and increases adiponectin in 8-month-old rats and decreases leptin in both ages. Visceral and total fat increase with ageing and decrease after calorie restriction. We conclude that accretion of visceral fat plays a key role in the development of insulin resistance after sexual maturity, which is reversible by calorie restriction. With aging, accumulation of retroperitoneal and total body fat leads to impaired muscle glucose uptake and to a state of insulin resistance that is difficult to reverse.

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Section: Introductionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Effect of age and moderate food restriction on insulin sensitivity in Wistar rats: role of adiposity

Escrivá

Gavete

Fermín

et al. 2007

Journal of Endocrinology

116

117

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“…Serine phosphorylation of IRS-1 eventually leads to protein degradation (23), accounting in part for decreased IRS content in fat cells from type II diabetic patients (24). To further investigate p66shc effects on nutrient-elicited insulin desensitization, vascular stromal cells (which include vascular cells, macrophages, preadipocytes, and stem cells) were isolated from adipose tissue of p66 +/+ and p66KO mice and exposed in vitro to FFA and high (25 mM) glucose for 16 h, before stimulation with insulin.…”

Section: Resultsmentioning

confidence: 99%

Mammalian life-span determinant p66 ^shcA mediates obesity-induced insulin resistance

Ranieri

Fusco

Panieri

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

125

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Obesity and metabolic syndrome result from excess calorie intake and genetic predisposition and are mechanistically linked to type II diabetes and accelerated body aging; abnormal nutrient and insulin signaling participate in this pathologic process, yet the underlying molecular mechanisms are incompletely understood. Mice lacking the p66 kDa isoform of the Shc adaptor molecule live longer and are leaner than wild-type animals, suggesting that this molecule may have a role in metabolic derangement and premature senescence by overnutrition. We found that p66 deficiency exerts a modest but significant protective effect on fat accumulation and premature death in lep Ob/Ob mice, an established genetic model of obesity and insulin resistance; strikingly, however, p66 inactivation improved glucose tolerance in these animals, without affecting (hyper)insulinaemia and independent of body weight. Protection from insulin resistance was cell autonomous, because isolated p66KO preadipocytes were relatively resistant to insulin desensitization by free fatty acids in vitro. Biochemical studies revealed that p66shc promotes the signal-inhibitory phosphorylation of the major insulin transducer IRS-1, by bridging IRS-1 and the mTOR effector p70S6 kinase, a molecule previously linked to obesity-induced insulin resistance. Importantly, IRS-1 was strongly up-regulated in the adipose tissue of p66KO lep Ob/Ob mice, confirming that effects of p66 on tissue responsiveness to insulin are largely mediated by this molecule. Taken together, these findings identify p66shc as a major mediator of insulin resistance by excess nutrients, and by extension, as a potential molecular target against the spreading epidemic of obesity and type II diabetes.O besity and metabolic syndrome represent ramping public health issues in the Western world, due to overnutrition and reduced physical activity, coupled with genetic susceptibility (1). Although a correct lifestyle remains the mainstream solution to this problem, pharmacological strategies are also being actively seeked; to this end, a better knowledge of the molecular players and biochemical mechanisms linking excess body fat to glucose intolerance and an increased cardiovascular risk is critically needed.Genetic and diet-induced disturbances in insulin and nutrient signaling have been compellingly linked to diabetes, obesity, and accelerated aging (2-4). In particular, deregulated activity of the nutrient-sensitive kinase mTOR (mammalian target of rapamycin) and of its downstream effector S6 kinase (S6K) by high-fat diet or leptin deficiency promotes fat accumulation, induces insulin resistance, and shortens mouse lifespan (5, 6). On the other hand, calorie restriction and hypomorphic mutations or pharmacological blockade within the insulin and mTOR/S6 kinase signaling cascades increase longevity both in lower model organisms and in mammals (7-11), and adipose-specific deletion of the insulin receptor (IR) extends lifespan of FIRKO mice (12).Mice lacking the 66-kDa isoform of the adaptor Shc (Src ...

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“…Several studies have suggested that insulin resistance is initiated in the adipose tissue and that this may induce insulin resistance in skeletal muscle and liver before the development of obesity and type 2 diabetes [14,15]. Excess energy intake has unfavourable effects on whole-body insulin sensitivity independent of changes in body weight in both healthy lean [1,16] and obese diabetic individuals [17].…”

Section: Introductionmentioning

confidence: 99%

Adipose tissue transcriptomics and epigenomics in low birthweight men and controls: role of high-fat overfeeding

et al. 2016

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Aims/hypothesis Individuals who had a low birthweight (LBW) are at an increased risk of insulin resistance and type 2 diabetes when exposed to high-fat overfeeding (HFO). We studied genome-wide mRNA expression and DNA methylation in subcutaneous adipose tissue (SAT) after 5 days of HFO and after a control diet in 40 young men, of whom 16 had LBW. Methods mRNA expression was analysed using Affymetrix Human Gene 1.0 ST arrays and DNA methylation using Illumina 450K BeadChip arrays. Results We found differential DNA methylation at 53 sites in SAT from LBW vs normal birthweight (NBW) men (false discovery rate <5%), including sites in the FADS2 and CPLX1 genes previously associated with type 2 diabetes. When we used reference-free cell mixture adjustments to potentially adjust for cell composition, 4,323 sites had differential methylation in LBW vs NBW men. However, no differences in SAT gene expression levels were identified between LBW and NBW men. In the combined group of all 40 participants, 3,276 genes (16.5%) were differentially expressed in SAT after HFO (false discovery rate <5%) and there was no difference between LBW men and controls. The most strongly upregulated genes were ELOVL6, FADS2 and NNAT; in contrast, INSR, IRS2 and the SLC27A2 fatty acid transporter showed decreased expression after HFO. Interestingly, SLC27A2 expression correlated negatively with diabetes-and obesity-related traits in a replication cohort of 142 individuals. DNA methylation at 652 CpG sites (including in CDK5, IGFBP5 and SLC2A4) was altered in SAT after overfeeding in this and in another cohort. Conclusions/interpretation Young men who had a LBW exhibit epigenetic alterations in their adipose tissue that potentially influence insulin resistance and risk of type 2 diabetes. Short-term overfeeding influences gene transcription and, to some extent, DNA methylation in adipose tissue; there was no major difference in this response between LBW and control participants.

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Impaired (‘diabetic’) insulin signaling and action occur in fat cells long before glucose intolerance—is insulin resistance initiated in the adipose tissue?

Cited by 177 publications

References 64 publications

Effect of age and moderate food restriction on insulin sensitivity in Wistar rats: role of adiposity

Effect of age and moderate food restriction on insulin sensitivity in Wistar rats: role of adiposity

Mammalian life-span determinant p66 ^shcA mediates obesity-induced insulin resistance

Adipose tissue transcriptomics and epigenomics in low birthweight men and controls: role of high-fat overfeeding

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Impaired (‘diabetic’) insulin signaling and action occur in fat cells long before glucose intolerance—is insulin resistance initiated in the adipose tissue?

Cited by 177 publications

References 64 publications

Effect of age and moderate food restriction on insulin sensitivity in Wistar rats: role of adiposity

Effect of age and moderate food restriction on insulin sensitivity in Wistar rats: role of adiposity

Mammalian life-span determinant p66 shcA mediates obesity-induced insulin resistance

Adipose tissue transcriptomics and epigenomics in low birthweight men and controls: role of high-fat overfeeding

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Mammalian life-span determinant p66 ^shcA mediates obesity-induced insulin resistance