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

Abstract

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.

Modulation of Obesity and Insulin Resistance by the Redox Enzyme and Adaptor Protein p66Shc

“…However, our data depicted a different scenario in mice on a pure C57Bl/6J background: worsened glucose tolerance in 18-week-old and more insulin resistance in 30-week-old p66 Shc−/− lean compared with WT lean animals, while obese p66 Shc−/− were more insulin resistant and equally glucose intolerant [39]. We further confirmed that obese p66 Shc−/− are not protected from insulin resistance and glucose intolerance [43]. These data on mice were supported by data on human samples, in which a decreased expression of p66 Shc in the visceral adipose tissue was associated with a lower BMI, but without any improvement in diabetes, dyslipidemia, or hypertension [39].…”

“…We and others found that the muscles of obese p66 Shc−/− mice have increased ectopic fat accumulation, which in part can explain these results [32,39,44]. Moreover, we also demonstrated that the microbiota hosted by p66 Shc−/− mice is different from that of WT controls, and that this might explain the differences between studies [43]. Finally, a recent paper studied the metabolic effect on the offspring of WT and p66 Shc−/− where dams were given a HFD before and during pregnancy.…”

“…Even if there is a general consensus about the fact that p66 Shc deletion confers protection against obesity, some conflicting data were found. It was shown by many authors that p66 Shc−/− mice are obesity-resistant, whether obesity is genetically- [39,42] or diet-induced [38,39,43]. However, in another study, a new p66 Shc−/− mouse model was generated, named ShcL [44], and some contrasting data were shown.…”

Beef, Casein, and Soy Proteins Differentially Affect Lipid Metabolism, Triglycerides Accumulation and Gut Microbiota of High-Fat Diet-Fed C57BL/6J Mice

“…A study indicates that colonization of zebrafish gut with Firmicutes enhances epithelial absorption and energy balance of the host ( Semova et al, 2012 ). Gut microbes can modulate the host metabolism and affect hypercholesterolemia, dyslipidemia, obesity, and diabetes ( Tremaroli and Bäckhed, 2012 ; Karlsson et al, 2013 ; Ciciliot et al, 2018 ). It has been suggested that Akkermansia, Christensenellaceae , and Tenericutes have the ability to interact with lipid metabolism, body mass, and triglycerides accumulation in mice ( Everard et al, 2011 ; Kitano et al, 2012 ).…”

The Role of p66Shc in Diabetes: A Comprehensive Review from Bench to Bedside

“…There are some controversial data in the literatures about p66Shc effect on obesity and body weight. Some studies have shown that ablation of p66Shc has protective effects against obesity and causes better insulin sensitivity; some reported that p66Shc-negative mice are leaner, but they are insulin resistant like wild-type mice [18,[69][70][71]. In some other studies, the body weight of knockout mice was reported equal to the wild type.…”