Perilipin overexpression in mice protects against diet-induced obesity

Abstract

Journal of Lipid ResearchObesity is associated with metabolic dysfunction and increased risk for diabetes, cardiovascular disease, cancer, and early mortality ( 1, 2 ). In both lean and obese states, triacylglycerol is predominately stored within lipid droplets of adipocytes. Perilipin A (PeriA) is the most abundant phosphoprotein on adipocyte lipid droplets and is an important regulator of lipid storage and release (lipolysis) ( 3, 4 ). In the absence of hormonal stimulation (basal state), PeriA functions to inhibit the actions of lipases on stored neutral lipids, thereby maintaining a low rate of constitutive lipolysis (promotes lipid storage) ( 5-10 ). Catecholamines enhance adipocyte lipolysis by stimulating adenylate cyclase activity and consequently activating cAMP-dependent protein kinase A (PKA), which simultaneously phosphorylates perilipin and hormone-sensitive lipase (HSL) ( 3,11,12 ). PKA-dependent phosphorylation of multiple serine residues on perilipin releases CGI-58 from the lipid droplet protein, resulting in enhanced activity of adipose triglyceride lipase (ATGL) ( 13, 14 ) and enhanced HSL accessibility to lipid stores ( 4,5,10,(15)(16)(17). As a result of these combined actions, lipolysis is dramatically increased.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-specifi c 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 catecholaminestimulated lipolysis was decreased and glucose tolerance signifi cantly 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 fi ndings demonstrate a novel role for perilipin expression in adipose tissue metabolism and regulation of obesity and its metabolic complications. -Miyoshi,

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.…”

Pathways commonly dysregulated in mouse and human obese adipose tissue: FAT/CD36 modulates differentiation and lipogenesis

“…50 Its overexpression protects from diet-induced obesity in mice. 51 FAT/ CD36 plays a central role in adipose tissue cell structure and remodeling, angiogenesis and regulates insulin signaling and triglyceride synthesis. 52 FAT/CD36 enhances adipose tissue inflammation and cell death in diet-induced obesity 53 and its expression is upregulated in obese adipose tissue.…”

Not Just Fat: The Structure and Function of the Lipid Droplet

“…Curiously the effect is more robust in females than in males, in both humans and mice (Qi et al 2004;Miyoshi et al 2010), but the reason for the gender difference is not known. It is also noteworthy that not only perilipin-null mice but also perilipin transgenic mice are resistant to diet-induced obesity (Qi et al 2004;Miyoshi et al 2010). These results reflect the multifaceted nature of perilipin function and suggest that obesity is a systemic disease caused by a combination of environmental and genetic factors.…”