Perilipin 5 fine-tunes lipid oxidation to metabolic demand and protects against lipotoxicity in skeletal muscle.

Lipid droplets (LD) play a central role in lipid homeostasis by controlling transient fatty acid (FA) storage and release from triacylglycerols stores, while preventing high levels of cellular toxic lipids. This crucial function in oxidative tissues is altered in obesity and type 2 diabetes. Perilipin 5 (PLIN5) is a LD protein whose mechanistic and causal link with lipotoxicity and insulin resistance has raised controversies. We investigated here the physiological role of PLIN5 in skeletal muscle upon various metabolic challenges. We show that PLIN5 protein is elevated in endurance-trained (ET) subjects and correlates with muscle oxidative capacity and whole-body insulin sensitivity. When overexpressed in human skeletal muscle cells to recapitulate the ET phenotype, PLIN5 diminishes lipolysis and FA oxidation under basal condition, but paradoxically enhances FA oxidation during forskolin- and contraction- mediated lipolysis. Moreover, PLIN5 partly protects muscle cells against lipid-induced lipotoxicity. In addition, we demonstrate that down-regulation of PLIN5 in skeletal muscle inhibits insulin-mediated glucose uptake under normal chow feeding condition, while paradoxically improving insulin sensitivity upon high-fat feeding. These data highlight a key role of PLIN5 in LD function, first by finely adjusting LD FA supply to mitochondrial oxidation, and second acting as a protective factor against lipotoxicity in skeletal muscle.

Interaction between HNF4A polymorphisms and physical activity in relation to type 2 diabetes-related traits: results from the Quebec Family Study.

AIMS: To test for associations between type 2 diabetes mellitus (T2DM)-related traits and polymorphisms (SNPs) in the hepatocyte nuclear factor 4-alpha gene (HNF4A) in the Quebec Family Study cohort, and determine whether these associations are modulated by physical activity (PA). METHODS: Two HNF4A SNPs (rs1885088 G>A; rs745975 C>T), previously reported to be associated with T2DM, were studied in 528 non-diabetic subjects who underwent a 75g oral glucose tolerance test (OGTT). Glucose, insulin and C-peptide plasma levels, measured in the fasting state and during the OGTT, were used in the analysis. The amount (hours per week) of PA was assessed by questionnaire. RESULTS: The HNF4A rs1885088 SNP was not independently associated with T2DM-related traits, whereas the rs745975 was associated with fasting insulin, HOMA-IR and 2-h glucose levels (p<0.05 for all). Genotype by PA interactions were found for glucose homeostasis (p<0.0001) and insulin secretion (p2h/week) was associated with smaller glucose area under the curve (AUC) and 2-h glucose levels in rs1885088 A/A homozygotes and with lower fasting C-peptide and insulin AUC in rs745975 T/T homozygotes. CONCLUSION: These results indicate that the associations of HNF4A rs1885088 with glucose tolerance and rs745975 with insulin secretion are modulated by PA. Our finding therefore suggests that the effect of HNF4A polymorphisms on the risk of T2DM is influenced by PA.