Plin2-deficiency reduces lipophagy and results in increased lipid accumulation in the heart.

Myocardial dysfunction is commonly associated with accumulation of cardiac lipid droplets (LDs). Perilipin 2 (Plin2) is a LD protein that is involved in LD formation, stability and trafficking events within the cell. Even though Plin2 is highly expressed in the heart, little is known about its role in myocardial lipid storage. A recent report shows that cardiac overexpression of Plin2 result in massive myocardial steatosis suggesting that Plin2 stabilizes LDs. In this study, we hypothesized that deficiency in Plin2 would result in reduced myocardial lipid storage. In contrast to our hypothesis, we found increased accumulation of triglycerides in hearts, and specifically in cardiomyocytes, from Plin2-/- mice. Although Plin2-/- mice had markedly enhanced lipid levels in the heart, they had normal heart function under baseline conditions and under mild stress. However, after an induced myocardial infarction, stroke volume and cardiac output were reduced in Plin2-/- mice compared with Plin2+/+ mice. We further demonstrated that the increased triglyceride accumulation in Plin2-deficient hearts was caused by altered lipophagy. Together, our data show that Plin2 is important for proper hydrolysis of LDs.

Perilipin-2 deletion promotes carbohydrate-mediated browning of white adipose tissue at ambient temperature.

Mice lacking perilipin-2 (Plin2-null) are resistant to obesity, insulin resistance, and fatty liver induced by Western or high-fat diets. In the current study, we found that, compared with WT mice on Western diet, Plin2-null adipose tissue was more insulin sensitive and inguinal subcutaneous white adipose tissue (iWAT) exhibited profound browning and robust induction of thermogenic and carbohydrate-responsive genetic programs at room temperature. Surprisingly, these Plin2-null responses correlated with the content of simple carbohydrates, rather than fat, in the diet, and were independent of adipose Plin2 expression. To define Plin2 and sugar effects on adipose browning, WT and Plin2-null mice were placed on chow diets containing 20% sucrose in their drinking water for 6 weeks. Compared with WT mice, iWAT of Plin2-null mice exhibited pronounced browning and striking increases in the expression of thermogenic and insulin-responsive genes on this diet. Significantly, Plin2-null iWAT browning was associated with reduced sucrose intake and elevated serum fibroblast growth factor (FGF)21 levels, which correlated with greatly enhanced hepatic FGF21 production. These data identify Plin2 actions as novel mediators of sugar-induced adipose browning through indirect effects of hepatic FGF21 expression, and suggest that adipose browning mechanisms may contribute to Plin2-null resistance to obesity.

Perilipin-2 modulates dietary fat-induced microbial global gene expression profiles in the mouse intestine.

BACKGROUND: Intestinal microbiota are critical determinants of obesity and metabolic disease risk. In previous work, we showed that deletion of the cytoplasmic lipid droplet (CLD) protein perilipin-2 (Plin2) modulates gut microbial community structure and abrogates long-term deleterious effects of a high-fat (HF) diet in mice. However, the impact of Plin2 on microbiome function is unknown. RESULTS: Here, we used metatranscriptomics to identify differences in microbiome transcript expression in WT and Plin2-null mice following acute exposure to high-fat/low-carbohydrate (HF) or low-fat/high-carbohydrate (LF) diets. Consistent with previous studies, dietary changes resulted in significant taxonomic shifts. Unexpectedly, when fed a HF diet, the microbiota of Plin2-null and WT mice exhibited dramatic shifts in transcript expression despite no discernible shift in community structure. For Plin2-null mice, these changes included the coordinated upregulation of metabolic enzymes directing flux towards the production of growth metabolites such as fatty acids, nucleotides, and amino acids. In contrast, the LF diet did not appear to induce the same dramatic changes in transcript or pathway expression between the two genotypes. CONCLUSIONS: Our data shows that a host genotype can modulate microbiome function without impacting community structure and identify Plin2 as a specific host determinant of diet effects on microbial function. Along with uncovering potential mechanisms for integrating how diet modulates host and microbial metabolism, our findings demonstrate the limits of 16S rRNA surveys to inform on community functional activities and the need to prioritize metatranscriptomic studies to gain more meaningful insights into microbiome function.

Loss of perilipin 2 in cultured myotubes enhances lipolysis and redirects the metabolic energy balance from glucose oxidation towards fatty acid oxidation.

Lipid droplet (LD) coating proteins are essential for the formation and stability of intracellular LDs. Plin2 is an abundant LD coating protein in skeletal muscle, but its importance for muscle function is unclear. We show that myotubes established from Plin2-/- mice contain reduced content of LDs and accumulate less oleic acid (OA) in triacylglycerol (TAG) due to elevated LD hydrolysis in comparison with Plin2+/+ myotubes. The reduced ability to store TAG in LDs in Plin2-/- myotubes is accompanied by a shift in energy metabolism. Plin2-/- myotubes are characterized by increased oxidation of OA, lower glycogen synthesis, and reduced glucose oxidation in comparison with Plin2+/+ myotubes, perhaps reflecting competition between FAs and glucose as part of the Randle cycle. In accord with these metabolic changes, Plin2-/- myotubes have elevated expression of Ppara and Ppargc1a, transcription factors that stimulate expression of genes important for FA oxidation, whereas genes involved in glucose uptake and oxidation are suppressed. Loss of Plin2 had no impact on insulin-stimulated Akt phosphorylation. Our results suggest that Plin2 is essential for protecting the pool of skeletal muscle LDs to avoid an uncontrolled hydrolysis of stored TAG and to balance skeletal muscle energy metabolism.