Perilipin Overexpression in White Adipose Tissue Induces a Brown Fat-Like Phenotype

Abstract

BackgroundPerilipin A (PeriA) exclusively locates on adipocyte lipid droplets and is essential for lipid storage and lipolysis. Previously, we reported that adipocyte specific overexpression of PeriA caused resistance to diet-induced obesity and resulted in improved insulin sensitivity. In order to better understand the biological basis for this observed phenotype, we performed additional studies in this transgenic mouse model.Methodology and Principal FindingsWhen compared to control animals, whole body energy expenditure was increased in the transgenic mice. Subsequently, we performed DNA microarray analysis and real-time PCR on white adipose tissue. Consistent with the metabolic chamber data, we observed increased expression of genes associated with fatty acid β-oxidation and heat production, and a decrease in the genes associated with lipid synthesis. Gene expression of Pgc1a, a regulator of fatty acid oxidation and Ucp1, a brown adipocyte specific protein, was increased in the white adipose tissue of the transgenic mice. This observation was subsequently verified by both Western blotting and histological examination. Expression of RIP140, a regulator of white adipocyte differentiation, and the lipid droplet protein FSP27 was decreased in the transgenic mice. Importantly, FSP27 has been shown to control gene expression of these crucial metabolic regulators. Overexpression of PeriA in 3T3-L1 adipocytes also reduced FSP27 expression and diminished lipid droplet size.ConclusionsThese findings demonstrate that overexpression of PeriA in white adipocytes reduces lipid droplet size by decreasing FSP27 expression and thereby inducing a brown adipose tissue-like phenotype. Our data suggest that modulation of lipid droplet proteins in white adipocytes is a potential therapeutic strategy for the treatment of obesity and its related disorders.

Defective Adipose Lipolysis and Altered Global Energy Metabolism in Mice with Adipose Overexpression of the Lipolytic Inhibitor G0/G1 Switch Gene 2 (G0S2)

“…However, our evidence suggests that G0S2 is capable of blunting lipolysis and thermogenic response in BAT without inducing its transdifferentiation to WAT. In mice with adipose overexpression of perilipin-1, decreased basal and catecholamine-stimulated lipolysis was observed along with a brown fat-like phenotype in WAT (36,37). Therefore, additional factors/mechanisms may be involved in the regulation of adipocyte plasticity in response to lipolytic alterations.…”

Ceramide kinase deficiency improves diet‐induced obesity and insulin resistance

“…For example, perilipin, a coat protein of lipid droplets in adipocytes, is abundant in small adipocytes [13]. The adipose tissue of CERK-/-mice expressed perilipin at levels higher than those observed in WT mice ( Fig.…”

The role of lipid droplets in metabolic disease in rodents and humans

“…Potentially, differences in rates of constitutive lipolysis and fat oxidation in adipocytes may at least in part explain the differential susceptibility of Plin1- and FSP27/Cidec-null mice to insulin resistance. Of potential relevance is our observation that overexpressing human or mouse Plin1 in female mice protects against the development of obesity and obesity-associated insulin resistance while increasing expression of oxidative genes in adipose tissue (83,84). Overexpression of Plin1 potently reduces expression of FSP27 in adipocytes, which may partly explain the protection against obesity and insulin resistance.…”