Increased insulin sensitivity in mice lacking p85β subunit of phosphoinositide 3-kinase

Abstract

On the basis of ex vivo studies using insulin-responsive cells, activation of a Class IA phosphoinositide 3-kinase (PI3K) seems to be required for a wide variety of cellular responses downstream of insulin. The Class IA PI3K enzymes are heterodimers of catalytic and regulatory subunits. In mammals, insulin-responsive tissues express both the p85␣ and p85␤ isoforms of the regulatory subunit. Surprisingly, recent studies have revealed that disruption of the p85␣ gene in the mouse (p85␣ ؊/؊ mice) results in hypoglycemia with decreased plasma insulin, and the p85␣ ؉/؊ mice exhibit significantly increased insulin sensitivity. These results suggest either that p85␣ negatively regulates insulin signaling, or that p85␤, which mediates the major fraction of Class IA PI3K signaling in the absence of p85␣, is more efficient than p85␣ in mediating insulin responses. To address this question, we have generated mice in which the p85␤ gene is deleted (p85␤ ؊/؊ mice). As with the p85␣ ؊/؊ mice, the p85␤ ؊/؊ mice showed hypoinsulinemia, hypoglycemia, and improved insulin sensitivity. At the molecular level, PI3K activity associated with phosphotyrosine complexes was preserved despite a 20 -30% reduction in the total protein level of the regulatory subunits. Moreover, insulin-induced activation of AKT was significantly up-regulated in muscle from the p85␤ ؊/؊ mice. In addition, insulin-dependent tyrosine phosphorylation of insulin receptor substrate-2 was enhanced in the p85␤ ؊/؊ mice, a phenotype not observed in the p85␣ ؊/؊ mice. These results indicate that in addition to their roles in recruiting the catalytic subunit of PI3K to the insulin receptor substrate proteins, both p85␣ and p85␤ play negative roles in insulin signaling.

PI3Kα inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction

“…Examples of this are mouse models with deletion of p85α or p85β regulatory subunits. Although PI3K is crucial for insulin action in glucose homeostasis, the genetic dis- ruption of p85 subunits increases insulin sensitivity and causes hypoglycemia (57)(58)(59)(60). Our findings in LR Δα mice indicate a similar effect with increased leptin sensitivity for metabolic regulation suggested by the decrease in body weight and increase in leptin-induced pSTAT3 in the hypothalamus.…”

The p110α and p110β isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis

“…Similar genetic behavior has previously been noted for the gene encoding the p85 adapter protein (Mauvais-Jarvis et al 2002;Ueki et al 2002Ueki et al , 2003Taniguchi et al 2006); p85 has a dual role as a negative regulator of the ground-state activity of p110 catalytic kinase subunits while also functioning to dock the kinases to activating receptors. In the case of p110b, its negative effect lies at least in part in its role as a weak kinase competing with the more potent p110a isoform for binding sites on RTKs.…”

Class IA phosphatidylinositol 3-kinase regulates osteoclastic bone resorption through protein kinase B–mediated vesicle transport

“…Because homozygous deletion of Pik3r1, which encodes p85a, p55a, and p50a, results in perinatal lethality, (34) we crossed Pik3r1 F/À mice (25) with Ctsk Cre/þ mice (27) to obtain osteoclast-specific Pik3r1 knockout (Pik3r1 DOc/À ) mice. We mated Pik3r1 DOc/À mice with Pik3r2 À/À mice (26) to generate mice deficient in both p85a and b (Pik3r1 DOc/À Pik3r2 À/À mice). The expression level of p85 in osteoclasts was slightly decreased in Pik3r1 DOc/À and Pik3r2 À/À mice, and greatly decreased in Pik3r1 DOc/À Pik3r2 À/À mice ( Fig.…”

“…Mice and the in vivo analysis of bone tissues Pik3r1 F/F , (25) Pik3r2 À/À , (26) CtsKCre transgenic, (27) and Akt pleckstrin homology domain-green fluorescent protein (AktPH-GFP) transgenic mice (28) were previously generated and are described elsewhere. Because a small population of osteoclasts from CtsKCrePik3r1 F/F mice still expressed p85a, CtsKCrePik3r1 F/F we mated mice to Pik3r1 þ/À mice to generate CtsKCrePik3r1 F/À (Pik3r1 Doc/À ) mice.…”