Coordinated Upregulation of Oxidative Pathways and Downregulation of Lipid Biosynthesis Underlie Obesity Resistance in Perilipin Knockout Mice

Abstract

Obesity is a major risk factor for diabetes and heart disease. We previously reported that the inactivation of the gene for perilipin (plin), an adipocyte lipid droplet surface protein, produced lean and obesity-resistant mice. To dissect the underlying mechanisms involved, we used oligonucleotide microarrays to analyze the gene-expression profile of white adipose tissue (WAT), liver, heart, skeletal muscle, and kidney of plin ؊/؊ and plin ϩ/ϩ mice. As compared with wild-type littermates, the WAT of plin ؊/؊ mice had 270 and 543 transcripts that were significantly up-or downregulated. There was a coordinated upregulation of genes involved in ␤-oxidation, the Krebs cycle, and the electron transport chain concomitant with a downregulation of genes involved in lipid biosynthesis. There was also a significant downregulation of the stearoyl CoA desaturase-1 gene, which has been associated with obesity resistance. Thus, in response to the constitutive activation of lipolysis associated with absence of perilipin, WAT activated pathways to rid itself of the products of lipolysis and activated pathways of energy expenditure that contribute to the observed obesity resistance. The biochemical pathways involved in obesity resistance in plin ؊/؊ mice identified in this study may represent potential targets for the treatment of obesity. Diabetes 52:2666 -2674, 2003 P erilipin (plin) is a member of a family of proteins that coat the surfaces of intracellular neutral lipid storage droplets, mainly in adipocytes and in steroidogenic cells (1,2). Perilipin, in the basal state, prevents access of hormone-sensitive lipase to the lipid droplet (3) and is a major substrate of cAMPdependent protein kinase in adipocytes (4). Specific hormonal or cytokine stimuli, such as catecholamines and tumor necrosis factor-␣, activate lipolysis by phosphorylating perilipin, thereby allowing hormone-sensitive lipase to access the lipid droplet and initiate its lipolytic action (5,6).Plin Ϫ/Ϫ mice are characterized by constitutive lipolysis, normal body weight despite an increase in food consumption, a lean body habitus, and smaller fat depots composed of small adipocytes (7,8). These mice display increased oxygen consumption and are resistant to diet-induced and genetic obesity (7).To explain this phenotype, we hypothesized that there had to be significant changes in the expression of genes involved in pathways for substrate and energy metabolism. We further reasoned that although perilipin is expressed in adipocytes, there should be concomitant changes in other tissues that are important in whole-body metabolism, such as the liver, skeletal muscle, heart, and kidney, to explain the profound changes seen in plin Ϫ/Ϫ mice. To test these hypotheses, we performed oligonucleotide microarray analysis of the above tissues of plin Ϫ/Ϫ mice and compared the data with those obtained from their wild-type littermates. We show a concomitant and coordinated upregulation of multiple genes involved in oxidative catabolic pathways along with downregulation of gene...

C-Reactive Protein Accelerates the Progression of Atherosclerosis in Apolipoprotein E–Deficient Mice

“…Amplification and detection of specific products were performed with the Opticon System (MJ Research). 34 …”

Identification of Mouse Prp19p as a Lipid Droplet-associated Protein and Its Possible Involvement in the Biogenesis of Lipid Droplets

“…Perilipin needs to be polyphosphorylated by protein kinase A for translocation of HSL to the lipid droplets and stimulation of lipolysis (36). Consistent with the role of perilipin as a barrier to lipolysis, adipocytes from perilipin-null mice have an elevated basal rate of lipolysis compared with adipocytes from wild-type mice, but they fail to respond maximally to lipolytic stimuli (37,38). On the contrary, the Prp19p down-regulated adipocyte cells have 35% decreased basal lipolytic activity when compared with the control cells and can fully respond to lipolytic stimuli (Fig.…”

Orchestrated downregulation of genes involved in oxidative metabolic pathways in obese vs. lean high-fat young male consumers

“…Moreover, it has been reported the important contribution of WAT to the control of energy homeostasis with the study of tissue-specific knockout models and the discovery of adipocyte-specific secreted factors that have powerful effects on fuel metabolism (6,39).…”