Inactivation of Ppp1r15a minimises weight gain and insulin resistance during caloric excess in female mice

Area of Science:

• Metabolism and Endocrinology
• Molecular Biology
• Neuroscience

Background:

• Phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α) in the hypothalamus suppresses appetite.
• The function of eIF2α phosphatases in body weight regulation remains unclear.
• PPP1R15A is a stress-inducible eIF2α phosphatase.

Purpose of the Study:

• To investigate the role of the eIF2α phosphatase PPP1R15A in regulating body weight and diet-induced obesity.
• To determine the effects of Ppp1r15a deficiency on food intake, body weight, and metabolic health in mice.

Main Methods:

• Utilized Ppp1r15a mutant mice lacking the C-terminal PP1-binding domain.
• Administered high-fat and standard diets to wild-type and mutant mice.
• Monitored body weight, food intake, hepatic steatosis, and insulin sensitivity.

Main Results:

• Female Ppp1r15a mutant mice gained less weight than wild-type littermates when fed a high-fat diet, due to reduced food intake.
• Mutant mice exhibited reduced hepatic steatosis and improved insulin sensitivity.
• No significant weight differences were observed between genotypes on a standard diet.
• A potential modest defect in insulin secretion was noted in mutant mice.

Conclusions:

• Female mice deficient in PPP1R15A exhibit reduced dietary intake and resist diet-induced obesity.
• Loss of PPP1R15A function leads to healthier metabolic profiles, including preserved glucose tolerance and reduced hepatic steatosis.
• PPP1R15A plays a critical role in modulating energy balance and protecting against obesity in response to high-fat diets.