Perilipin 5 (PLIN5) is a lipid-droplet associated protein that is highly expressed in oxidative tissues, such as skeletal muscle and heart, and is proposed to play a major role in regulating lipid metabolism. The in vivo role of perilipin 5 (PLIN5) remains uncertain.

Accordingly, we generated Plin5^-/- mice to determine PLIN5 involvement in lipid metabolism and insulin action. Plin5^-/- mice developed normally with lean and fat masses the same as wild-type mice following low fat (5% energy from fat) and high fat diet (59% energy from fat). Indirect calorimetry revealed an increase in the respiratory exchange ratio in Plin5^-/- mice fed a low fat and high fat diet, demonstrating a decrease in whole-body fatty acid oxidation and a reciprocal increase in carbohydrate oxidation.  Studies in myotubes isolated from the skeletal muscle of Plin5^-/- mice showed that PLIN5 deletion increases the oxidation of fatty acids derived from triglyceride under basal and β-adrenergic stimulated conditions. These changes occurred independently of alterations in mitochondrial function or oxidative capacity and support the notion that PLIN5 suppresses triglyceride breakdown. These changes in lipid metabolism prompted us to investigate the effect PLIN5 on insulin action. Plin5^-/- mice have improved glucose tolerance (2 mg/kg glucose i.p) on LF and HF diet, but Plin5^-/- mice on LFD (assessed with euglycemic-hyperinsulmaemic) had impaired whole-body insulin action. This was not associated with any changes in ceramide or diacylglycerol content.

These results suggest that PLIN5 exerts mild effects on lipid metabolism in skeletal muscle and that PLIN5 deletion results in tissue-specific effects on insulin action. Further studies using tissue-specific Plin5^-/- will help to determine the biology underpinning these differences.