p66Shc deletion or deficiency protects from obesity but not metabolic dysfunction in mice and humans

Ciciliot, Stefano; Albiero, Mattia; Menegazzo, Lisa; Poncina, Nicol; Scattolini, Valentina; Danesi, Andrea; Pagnin, Elisa; Marabita, Manuela; Blaauw, Bert; Giorgio, Marco; Trinei, Mirella; Foletto, Mirto; Prevedello, Luca; Nitti, Donato; Avogaro, Angelo; Fadini, Gian Paolo

doi:10.1007/s00125-015-3667-8

Cited by 29 publications

(33 citation statements)

References 22 publications

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“…It has been demonstrated that p66shc −/− mice are protected from HFD-induced obesity 14, 15 . Similarly, protection by p66shc deletion was observed in lep Ob/Ob mice 20 , although the beneficial effects on glucose intolerance and insulin resistance have been questioned 21 . Muscle atrophy and weakness have been linked to obesity 31, 32 .…”

Section: Resultsmentioning

confidence: 99%

“…Comparison with a “pure” p66shc −/− mouse strain suggested that, while p66shc deletion accounts for the increased insulin sensitivity and glucose tolerance, resistance to diet-induced obesity may be due to p46shc overexpression in adipose tissue 15 . Protection from obesity was reported also in p66shc −/− lep Ob/Ob mice, a genetic model of obesity 20 , even though adipose tissue analysis and metabolic parameters demonstrated that p66shc deletion does not protect lep Ob/Ob mice from glucose intolerance and insulin resistance 21 , suggesting a different role of p66shc in different obesity models.…”

Section: Introductionmentioning

confidence: 95%

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Role of p66shc in skeletal muscle function

Granatiero

Gherardi

Vianello

et al. 2017

Sci Rep

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p66shc is a growth factor adaptor protein that contributes to mitochondrial ROS production. p66shc is involved in insulin signaling and its deletion exerts a protective effect against diet-induced obesity. In light of the role of skeletal muscle activity in the control of systemic metabolism and obesity, we investigated which is the contribution of p66shc in regulating muscle structure and function. Here, we show that p66shc−/− muscles are undistinguishable from controls in terms of size, resistance to denervation-induced atrophy, and force. However, p66shc−/− mice perform slightly better than wild type animals during repetitive downhill running. Analysis of the effects after placing mice on a high fat diet (HFD) regimen demonstrated that running distance is greatly reduced in obese wild type animals, but not in overweight-resistant p66shc−/− mice. In addition, muscle force measured after exercise decreases upon HFD in wild type mice while p66shc−/− animals are protected. Our data indicate that p66shc affect the response to damage of adult muscle in chow diet, and it determines the maintenance of muscle force and exercise performance upon a HFD regimen.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Role of p66shc in skeletal muscle function

Granatiero

Gherardi

Vianello

et al. 2017

Sci Rep

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“…However, a role for p66Shc in MetS is still debated. Ciciliot et al (178) have recently shown that p66Shc-KO mice, following an HFD regimen, were leaner than their wild-type counterparts but equally glucose intolerant and insulin resistant. In addition, patients with reduced p66Shc levels were less obese, but were not protected from other features of MetS features-diabetes, dyslipidemia, and hypertension (178).…”

Section: P66shc: a Healthspan Gene Involved In Oxidative Stress Fat mentioning

confidence: 99%

Molecular mechanisms underlying metabolic syndrome: the expanding role of the adipocyte

et al. 2017

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The metabolic syndrome (MetS) is defined as a cluster of 3 or more metabolic and cardiovascular risk factors and represents a serious problem for public health. Altered function of adipose tissue has a significant impact on whole-body metabolism and represents a key driver for the development of these metabolic derangements, collectively referred as to MetS. In particular, increased visceral and ectopic fat deposition play a major role in the development of insulin resistance and MetS. A large body of evidence demonstrates that aging and MetS share several metabolic alterations. Of importance, molecular pathways that regulate lifespan affect key processes of adipose tissue physiology, and transgenic mouse models with adipose-specific alterations in these pathways show derangements of adipose tissue and other metabolic features of MetS, which highlights a causal link between dysfunctional adipose tissue and deleterious effects on whole-body homeostasis. This review analyzes adipose tissue-specific dysfunctions, including metabolic alterations that are related to aging, that have a significant impact on the development of MetS.-Armani, A., Berry, A., Cirulli, F., Caprio, M. Molecular mechanisms underlying metabolic syndrome: the expanding role of the adipocyte.

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“…Interestingly, deletion of p66Shc by suppressing H 2 O 2 production inhibited insulin-dependent adipogenesis (12). As a result, p66Shc 2/2 mice were leaner than wild-type (WT) mice fed a standard diet (SD), fed a high-fat diet (HFD), or under leptin deficiency (Lep Ob/Ob ) (12)(13)(14)(15). While lower body weight of p66Shc 2/2 mice has been confirmed in several laboratories, the metabolic consequences of such a leaner phenotype are debated.…”

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confidence: 99%

Interplay between gut microbiota and p66Shc affects obesity‐associated insulin resistance

et al. 2018

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The 66 kDa isoform of the mammalian Shc gene promotes adipogenesis, and p66Shc mice accumulate less body weight than wild-type (WT) mice. As the metabolic consequences of the leaner phenotype of p66Shc mice is debated, we hypothesized that gut microbiota may be involved. We confirmed that p66Shc mice gained less weight than WT mice when on a high-fat diet (HFD), but they were not protected from insulin resistance and glucose intolerance. p66Shc deletion significantly modified the composition of gut microbiota and their modification after an HFD. This was associated with changes in gene expression of Il-1b and regenerating islet-derived protein 3 γ ( Reg3g) in the gut and in systemic trimethylamine N-oxide and branched chain amino acid levels, despite there being no difference in intestinal structure and permeability. Depleting gut microbiota at the end of HFD rendered both strains more glucose tolerant but improved insulin sensitivity only in p66Shc mice. Microbiota-depleted WT mice cohoused with microbiota-competent p66Shc mice became significantly more insulin resistant than WT mice cohoused with WT mice, despite no difference in weight gain. These findings reconcile previous inconsistent observations on the metabolic phenotype of p66Shc mice and illustrate the complex microbiome-host-genotype interplay under metabolic stress.-Ciciliot, S., Albiero, M., Campanaro, S., Poncina, N., Tedesco, S., Scattolini, V., Dalla Costa, F., Cignarella, A., Vettore, M., Di Gangi, I. M., Bogialli, S., Avogaro, A., Fadini, G. P. Interplay between gut microbiota and p66Shc affects obesity-associated insulin resistance.

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p66Shc deletion or deficiency protects from obesity but not metabolic dysfunction in mice and humans

Abstract: In mice and humans, reduced p66Shc levels protect from obesity, but not from ectopic fat accumulation, glucose intolerance and insulin resistance.

Cited by 29 publications

References 22 publications

Role of p66shc in skeletal muscle function

Role of p66shc in skeletal muscle function

Molecular mechanisms underlying metabolic syndrome: the expanding role of the adipocyte

Interplay between gut microbiota and p66Shc affects obesity‐associated insulin resistance

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