Abstract
Phosphorylation of the translation initiation factor eIF2α within the mediobasal hypothalamus is known to suppress food intake, but the role of the eIF2α phosphatases in regulating body weight is poorly understood. Mice deficient in active PPP1R15A, a stress-inducible eIF2α phosphatase, are healthy and more resistant to endoplasmic reticulum stress than wild type controls. We report that when female Ppp1r15a mutant mice are fed a high fat diet they gain less weight than wild type littermates owing to reduced food intake. This results in healthy leaner Ppp1r15a mutant animals with reduced hepatic steatosis and improved insulin sensitivity, albeit with a possible modest defect in insulin secretion. By contrast, no weight differences are observed between wild type and Ppp1r15a deficient mice fed a standard diet. We conclude that female mice lacking the C-terminal PP1-binding domain of PPP1R15A show reduced dietary intake and preserved glucose tolerance. Our data indicate that this results in reduced weight gain and protection from diet-induced obesity.
Highlights
Phosphorylation of the translation initiation factor eIF2α within the mediobasal hypothalamus is known to suppress food intake, but the role of the eIF2α phosphatases in regulating body weight is poorly understood
As expected, when mouse embryonic fibroblasts (MEFs) generated from wild type embryos were treated with the endoplasmic reticulum (ER) stressor thapsigargin, full length PPP1R15A protein was induced progressively over an 8-hour period (Fig. 1a,b)
This confirmed that Ppp1r15aΔC/ΔC cells are impaired in the dephosphorylation of P-eIF2α during ER stress
Summary
Vruti Patel[1,2], Guillaume Bidault[3], Joseph E. We report that when female Ppp1r15a mutant mice are fed a high fat diet they gain less weight than wild type littermates owing to reduced food intake. This results in healthy leaner Ppp1r15a mutant animals with reduced hepatic steatosis and improved insulin sensitivity, albeit with a possible modest defect in insulin secretion. While increased levels of eIF2α phosphorylation within the hypothalamus have been shown to reduce food intake[16], a recent report suggested that PPP1R15A deficient mice, which are impaired in P-eIF2α dephosphorylation, spontaneously become obese[17]. Despite having a likely subtle defect in insulin secretion, Ppp1r15aΔC/ΔC mice were resistant to diet induced obesity, remaining leaner and less insulin resistant than their wild type littermates fed on a high-fat diet
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