Mice Carrying a Dominant-Negative Human PI3K Mutation Are Protected From Obesity and Hepatic Steatosis but Not Diabetes

Abstract

Phosphatidylinositol 3-kinase (PI3K) plays a central role in insulin signaling, glucose metabolism, cell growth, cell development, and apoptosis. A heterozygous missense mutation (R649W) in the p85α regulatory subunit gene of PI3K () has been identified in patients with SHORT (Short stature, Hyperextensibility/Hernia, Ocular depression, Rieger anomaly, and Teething delay) syndrome, a disorder characterized by postnatal growth retardation, insulin resistance, and partial lipodystrophy. Knock-in mice with the same heterozygous mutation mirror the human phenotype. In this study, we show that R649W knock-in mice fed a high-fat diet (HFD) have reduced weight gain and adipose accumulation. This is accompanied by reduced expression of several genes involved in lipid metabolism. Interestingly, despite the lower level of adiposity, the HFD knock-in mice are more hyperglycemic and more insulin-resistant than HFD-fed control mice. Likewise, when crossed with genetically obese/ mice, the / mice carrying the heterozygous R649W mutation were protected from obesity and hepatic steatosis but developed a severe diabetic state. Together, our data demonstrate a central role of PI3K in development of obesity and fatty liver disease, separating these effects from the role of PI3K in insulin resistance and the resultant hyperglycemia.

Truncation of Pik3r1 causes severe insulin resistance uncoupled from obesity and dyslipidaemia by increased energy expenditure

“…Pik3r1 R649W/WT mice have been shown to have less subcutaneous adipose tissue [ 31 ] and reduced adipose expansion in obesogenic conditions [ 40 ], as in the current report, which was interpreted as evidence of lipodystrophy. However, constrained adipose expansion produces inflammation of overloaded, hypertrophic adipose tissue during chronic positive energy balance [ 1 ], and the normal adipocyte appearance, lack of adipose inflammation, and normal differentiation of preadipocytes ex vivo in both studies argue against this [ 31 ].…”

“…Reduced adipose mass can reflect altered energy balance rather than lipodystrophy. Reduction of PI3K pathway activity by overexpression of the lipid phosphatase Pten in mice was previously reported to enhance energy expenditure via brown adipose tissue activation [ 41 ], albeit without IR, while pharmacological or genetic inhibition of the p110α catalytic subunit of PI3K has also been associated with increased energy expenditure [ [40] , [41] , [42] , [43] ]. Moreover, a similar energetic phenotype on brown adipose-specific knockout of Pik3r1 has recently been described [ 44 ].…”

“…Reduced thermal insulation in smaller animals is an unlikely explanation [ 43 ]; hence, we conclude that increased energy expenditure explains reduced adipose accretion. Increased brown adipose tissue activity is the most likely explanation, as in models with p110α inhibition [ [40] , [41] , [42] , [43] ], but this requires further study.…”

Arrestin domain-containing 3 (Arrdc3) modulates insulin action and glucose metabolism in liver

“…Consistent with this differential regulation by insulin, Arrdc3 expression has been shown to increase by two-to fivefold in response to fasting in adipose tissue and muscle, while it tends to decrease in liver during a fast (9). Arrdc3 is also induced in livers of hyperinsulinemic HFDinduced or genetically obese (ob/ob) mice, despite the presence of hepatic insulin resistance and hepatic steatosis (25).…”

Novel Insights into Adipogenesis from the Perspective of Transcriptional and RNA N6‐Methyladenosine‐Mediated Post‐Transcriptional Regulation

“…[67,68] It is widely acknowledged that these intracellular effectors in insulin signaling are inevitably associated with nutritional physiology and metabolism, and elimination of them blocks adipogenesis. [69][70][71][72][73][74][75][76][77] Thus, insulin is an essential component of adipogenic differentiation medium in vitro and promotes adipogenesis in highly adipogenic progenitor cells by FACS. [40] Even though glucocorticoid signaling has been reported to sensitize preadipocytes to insulin signaling and consequently enhance adipogenic action of the insulin pathway, [78] it still needs to be clarified how other signals facilitate or suppress insulin signaling.…”