Oral Presentation The Annual Scientific Meeting of the Australian Diabetes Society and the Australian Diabetes Educators Association 2013

Perilipin 5 deficiency in mice alters fatty acid metabolism and causes skeletal muscle insulin resistance (#73)

Rachael Mason 1 , Ruzaidi Mokhtar 1 , Maria Matzaris 1 , Aharthy Selathurai 1 , Clinton Bruce 1 , Matthew Watt 1
  1. Monash University, Clayton, VIC, Australia

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. Indirect calorimetry revealed an increase in the respiratory exchange ratio, 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), but impaired whole-body insulin action as assessed during euglycemic-hyperinsulmaemic clamps. The glucose disposal rate during insulin stimulation was reduced by 22% in Plin5-/- mice and 2-deoxyglucose uptake into mixed skeletal muscle was similarly reduced (34%, P=0.08). This was associated with reduced ROS production and no changes in ceramide and diacylglycerol contents, or JNK and NF-ΚB activation. In contrast, hepatic glucose production was 41% lower (P=0.08) in Plin5-/- vs. wild-type mice during the clamp with no changes in ROS production or lipid storage.    

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.