The Shc locus regulates insulin signaling and adiposity in mammals

Abstract

Summary Longevity of a p66Shc knockout strain (ShcP) was previously attributed to increased stress resistance and altered mitochondria. Microarrays of ShcP tissues indicated alterations in insulin signaling. Consistent with this observation, ShcP mice were more insulin sensitive and glucose tolerant at organismal and tissue levels, as was a novel p66Shc knockout (ShcL). Increasing and decreasing Shc expression in cell lines decreased and increased insulin sensitivity, respectively – consistent with p66Shc's function as a repressor of insulin signaling. However, differences between the two p66Shc knockout strains were also observed. ShcL mice were fatter and susceptible to fatty diets, and their fat was more insulin sensitive than controls. On the other hand, ShcP mice were leaner and resisted fatty diets, and their adipose was less insulin sensitive than controls. ShcL and ShcP strains are both highly inbred on the C57Bl/6 background, so we investigated gene expression at the Shc locus, which encodes three isoforms, p66, p52, and p46. Isoform p66 is absent in both strains; thus, the remaining difference to which to attribute the ‘lean’ phenotype is expression of the other two isoforms. ShcL mice have a precise deletion of p66Shc and normal expression of p52 and p46Shc isoforms in all tissues; thus, a simple deletion of p66Shc results in a ‘fat’ phenotype. However, ShcP mice in addition to p66Shc deletion have a fourfold increase in p46Shc expression in white fat. Thus, p46Shc overexpression in fat, rather than p66Shc deletion, is the likely cause of decreased adiposity and reduced insulin sensitivity in the fat of ShcP mice, which has implications for the longevity of the strain.

P66SHC deletion improves fertility and progeric phenotype of late-generation TERC-deficient mice but not their short lifespan

“…P66SHC null mice (p66SHC −/− ) develop normally and resulted to be protected from aging‐associated diseases, such as atherosclerosis (Martin‐Padura et al ., 2008), diabetes compliances (Menini et al ., 2007), onset (Tomilov et al ., 2011), cognitive decline (Berry et al ., 2007), and neurodegeneration (Savino et al ., 2013). Moreover, p66SHC null cells were shown to be resistant to apoptosis induced by a variety of different signals, including hydrogen peroxide, UV, staurosporine, taxol, growth factor deprivation, calcium ionophore, osmotic shock, and CD3–CD4 cross‐linking (as reviewed in Migliaccio et al ., 2006).…”

p46Shc Inhibits Thiolase and Lipid Oxidation in Mitochondria

“…Shc proteins have three isoforms: p46, p52, and p66, and have major effects on metabolism (1)(2)(3)(4). p52Shc contacts the insulin receptor and regulates the signaling between the IRS1 and Ras pathway (5).…”

“…There are two mouse models of Shc depletion produced to date: ShcL, also known as p66ShcKO developed by the Tom Prolla group (ShcProlla, Ref. 4), and Shc mice developed by the Pelicci group (ShcP or ShcPelicci, also known as p66Shc(Ϫ/Ϫ, Refs. 3,4,8,9).…”

“…4), and Shc mice developed by the Pelicci group (ShcP or ShcPelicci, also known as p66Shc(Ϫ/Ϫ, Refs. 3,4,8,9). Names in literature for these two models can be described by these definitions: ShcL, ShcProlla; ShcKO, ShcP ϭ ShcPelicci ϭ p66Shc(Ϫ/Ϫ).…”

“…Briefly, ShcL or ShcProlla mice have a deletion of only the minor p66Shc isoform and have no health benefits: ShcL mice are not lean, do not resist weight gain on high fat diets (HFD), 2 and are not longer-lived on HFD, and do not have improved insulin sensitivity (4). Thus p66Shc deletion by itself does not result in health benefits.…”