Gene

Serine

Biology

Endocrinology

Metabolism

Receptor

Polymorphism (computer science)

Insulin

Phosphorylation

Genetics

In vivo

Peroxisome proliferator-activated receptor

Genotype

Insulin resistance

Glycemic

Internal medicine

Activator (genetics)

Medicine

Allele

Adipose tissue

Carbohydrate metabolism

Canadian Journal of Diabetes

Peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1alpha) is a transcriptional coregulator, which plays a major role in the control of metabolism. Our laboratory recently demonstrated that a diabetes-linked polymorphism of human PGC-1alpha (Gly482Ser) results in a reduction in protein stability. To study the physiological and molecular consequences of this polymorphism in vivo, we generated whole-body homozygous glycine (G/G), serine (S/S) and heterozygous (S/G) mice using CRISPR/Cas9 technology. Male and female mice of all genotypes received a standard chow diet or a diet rich in fat and fructose (HFHF), and various metabolic parameters were analyzed after 14 and 24 weeks. Our results show that males on a HFHF diet and bearing a glycine allele (G/G or S/G) are more resistant to insulin and secrete more insulin to maintain euglycemia during an oral glucose tolerance test (OGTT). Consistent with insulin resistance, hyperinsulinemic/euglycemic clamps (HIEC) revealed decreased glucose uptake in the muscle and adipose tissue of glycine allele carrying mice. Over time, these males developed glucose intolerance due to insulin insufficiency. Females of all genotypes had no differences on all metabolic parameters throughout the course of the study. Overall, our results suggest that the PGC-1alpha Gly482Ser polymorphism likely modulates whole body insulin sensitivity, leading to murine glycine allele carriers having worsened glycemic control when challenged with an obesogenic diet. These data demonstrate important diet and sex-dependent physiological outcomes for the polymorphism, identifying it as a potential factor in genetic screening tools aimed at identifying individuals at risk for metabolic disease.

Impact of the PGC-1α Gly482Ser Polymorphism on Mouse Metabolism