Submitted to: Journal of Lipid Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/22/2009
Publication Date: 5/20/2010
Citation: Miyoshi, H., Souza, S.C., Endo, M., Sawada, T., Perfield, J.W., Shimizu, C., Stancheva, Z., Nagai, S., Strissel, K.J., Yoshioka, N., Obin, M.S., Koike, T., Greenberg, A.S. 2010. Perilipin overexpression in mice protects against diet-induced obesity. Journal of Lipid Research. 51(5):975-982. Interpretive Summary: Obesity is occurring at epidemic levels in humans and increasing the risk of developing diabetes, heart disease, and cancer. Understanding the factors produced in our body that regulate body weight and body fat accumulation will allow us to develop nutritional approaches that will ameliorate obesity and the associated medical complications. Fat is primarily stored within fat cells in the body. Our laboratory has discovered that within fat cells, fat is actually stored within a specific compartment of the cell which we have termed ‘fat droplets’. We have discovered a protein, specifically coating the fat droplets in fat cells, which we have named perilipin. We have little understanding of the consequences of whether different levels of perilipin expression regulate body weight. To address this question we were able to develop mice that expressed increased amounts of perilipin specifically in fat cells. We know from prior research studies that mice, when fed a diet high in fat, become obese. To determine whether perilipin overexpression protects against the development of obesity in mice, we provided a high fat diet to mice which do not have increased levels of perilipin. We observed that mice, which overexpress perilipin in fat cells, were protected against the development of obesity as compared to mice which do not overexpress perilipin. Additionally, mice which expressed high amounts of perilipin had improved blood glucose levels. These data suggests that nutritional approaches, which increase amounts of perilipin in fat cells, may ameliorate obesity and its associated complications such as diabetes.
Technical Abstract: Perilipin A is the most abundant phosphoprotein on adipocyte lipid droplets and is essential for lipid storage and lipolysis. Perilipin null mice exhibit diminished adipose tissue, elevated basal lipolysis, reduced catecholamine-stimulated lipolysis, and increased insulin resistance. To understand the physiological consequences of increased perilipin expression in vivo, we generated transgenic mice that overexpressed either human or mouse perilipin using the adipocyte-specific aP2 promoter/enhancer. Phenotypes of female transgenic and wild-type mice were characterized on chow and high-fat diets (HFDs). When challenged with an HFD, transgenic mice exhibited lower body weight, fat mass, and adipocyte size than wild-type mice. Expression of oxidative genes was increased and lipogenic genes decreased in brown adipose tissue of transgenic mice. Basal and catecholamine-stimulated lipolysis was decreased and glucose tolerance significantly improved in transgenic mice fed a HFD. Perilipin overexpression in adipose tissue protects against HFD-induced adipocyte hypertrophy, obesity, and glucose intolerance. Alterations in brown adipose tissue metabolism may mediate the effects of perilipin overexpression on body fat, although the mechanisms by which perilipin overexpression alters brown adipose tissue metabolism remain to be determined. Our findings demonstrate a novel role for perilipin expression in adipose tissue metabolism and regulation of obesity and its metabolic complications.