Perilipin-2-null mice are protected against diet-induced obesity, adipose inflammation, and fatty liver disease

Abstract

This article is available online at http://www.jlr.org type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD) ( 2 ). Obesity-associated NAFLD in particular is associated with development of hyperlipidemia, insulin resistance, hyperglycemia ( 3 ), and increased risk of liver cancer ( 4, 5 ). In tissues, neutral lipids such as triacylglycerol are stored in cytoplasmic lipid droplets (CLDs), which are specialized organelle-like structures that function in intracellular traffi cking and metabolism of lipids ( 6 ). Alterations in CLD properties are increasingly recognized to be associated with metabolic abnormalities and disruptions of normal cellular and tissue functions ( 7 ).Perilipins (PLINs) are a family of genes encoding fi ve CLD-associated proteins in mammals that are implicated in the regulation of storage and hydrolysis of neutral lipids ( 7,8 ). Prior studies investigating reduced expression of perilipin1 (Plin1) in mice demonstrated that it is required for normal adipose lipid storage ( 9-11 ), whereas reduced perilipin-2 (Plin2) expression prevents hepatic lipid accumulation in response to high-fat diet (HFD) feeding (12)(13)(14). Although Plin1-null mice are also resistant to obesity and many of its attendant metabolic abnormalities ( 9, 10 ), there is limited understanding of the contributions of Plin2, or other PLIN family members, to obesity or other metabolic disorders.Defi ning the roles of Plin2 in obesity and metabolism has been complicated by observations that existing Plin2-defi cient mice produce a truncated product that is biologically active ( 15 ), and that the short-term-diet models used previously did not adequately investigate Plin2 regulation Abstract The cytoplasmic lipid droplet (CLD) protein perilipin-2 (Plin2) is expressed in multiple nonadipose tissues, where it is thought to play a role in regulating their lipid storage properties. However, the extent to which Plin2 functions in nutrient utilization and metabolism, or how it infl uences the consequences of over-feeding, remains unclear. In this study, we demonstrate that the absence of Plin2 prevents high-fat diet(HFD)-induced obesity in male and female mice. This response is associated with increased formation of subcutaneous beige adipocyte cells with uncoupling protein 1 expression, and amelioration of infl ammatory foci formation in white adipose tissue and steatosis in the liver. Experiments demonstrate that Plin2 loss results in reduced energy intake and increased physical activity in response to HFD feeding. Our study provides the fi rst evidence that Plin2 contributes to HFD-induced obesity by modulating food intake, and that its absence prevents obesity-associated adipose tissue infl ammatory foci and liver steatosis. Obesity, resulting from increased calorie consumption and decreased energy expenditure, remains a major public health concern for children and adults in the United States ( 1 ), through its strong etiological links to several metabolic complications, including metabolic syndrome,

Perilipin-2 Deletion Impairs Hepatic Lipid Accumulation by Interfering with Sterol Regulatory Element-binding Protein (SREBP) Activation and Altering the Hepatic Lipidome

“…1E). Collectively, these results agree with previous conclusions that PLIN2-deletion protects against insulin resistance associated with diet or genetically induced obesity (13,17,18). Interestingly, we also observed a 25% reduction (p ϭ 0.0056) in fasting serum FFA for Plin2-null mice fed the control diet.…”

“…We first examined Plin2, Plin3, and Plin5 gene expression in both WT and Plin2-null mice fed WD or CD for 30 weeks. As established previously (13), Plin2 gene expression is not detected in livers of Plin2-null mice (Fig. 2E).…”

“…Plin2-null mice were generated as described previously (13). Mice were housed at the University of Colorado Anschutz Medical Campus animal facility at ambient temperatures (22-24°C) on a 14:10-h light/dark cycle.…”

“…Upon completion of the feeding experiments, the body composition of each animal was determined by quantitative magnetic resonance imaging (EchoMRI-900 Whole-body Composition Analyzer; Echo Medical Systems, Houston, TX), and mice were euthanized by CO 2 exposure and cardiac puncture. Intraperitoneal glucose tolerance testing was performed as described previously (13). 18-Hour fasted serum FFA analy-sis was performed using a standard FFA calorimetric detection kit (ZenBio Inc.) with 5 l of serum per reaction.…”

“…We previously generated mice with whole-body knock-out of PLIN2 (Plin2-null) (13). These animals are resistant to obesity, adipose tissue inflammation, and liver steatosis (NAFLD) when raised on a high fat diet.…”