Submitted to: PLoS One
Publication Type: Peer reviewed journal
Publication Acceptance Date: 10/26/2010
Publication Date: 11/26/2010
Citation: Sawada, T., Miyoshi, H., Shimada, K., Suzuki, A., Okamatsu-Ogura, Y., Perfield, J., Kondo, T., Nagi, S., Shimizu, C., Yoshioka, N., Greenberg, A., Kimura, K., Koike, T. 2010. Perilipin overexpression in white adipose tissue induces a brown fat-like phenotype. PLoS One. 5(11)e14006. Interpretive Summary: In both animals and humans fat is stored within fat cell cells in a specific compartment within the cell called lipid droplets. Our laboratory discovered a protein called perilipin that coats the surface of lipid droplets and regulates the breakdown of stored fat. To understand how the amount of the protein perilipin regulates body weight and fat storage we developed mice using genetic techniques to increase the amount of the protein, perilipin specifically in fat cells of mice. Previously, we demonstrated these mice which have increased expression of perilipin in their fat cells have smaller fat cells and when fed a high caloric diet they gain less weight than mice which express less perilipin in their fat cells. In new studies we find that the mice that have increased levels of perilipin in their fat cells have an increased metabolic rate which means that they have increased ability to burn food calories. Mice and human have two types of fat cells, one type called white adipocytes whose function is to predominately store fat while another type of fat cell called brown fat cells express a protein called uncoupling protein 1(UCP1) which increases the ability of brown fat cells to more efficiently burn fat. In the mice which expressed more perilipin in their fat cells, we observed that many of the white cells now also expressed the UCP1 protein. Thus we found that increased levels of perilipin may result in reduced body fat accumulation and increased fat burning.
Technical Abstract: BACKGROUND: Perilipin 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 FINDINGS: When 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 beta-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. CONCLUSIONS: These 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