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

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-oxideand branched chain amino acidlevels, 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 cohousedwi...