Inhibition of ADRP prevents diet-induced insulin resistance

Abstract

Diets with high fat content induce steatosis, insulin resistance, and type 2 diabetes. The lipid droplet protein adipose differentiation-related protein (ADRP) mediates hepatic steatosis, but whether this affects insulin action in the liver or peripheral organs in diet-induced obesity is uncertain. We fed C57BL/6J mice a high-fat diet and simultaneously treated them with an antisense oligonucleotide (ASO) against ADRP for 4 wk. Glucose homeostasis was assessed with clamp and tracer techniques. ADRP ASO decreased the levels of triglycerides and diacylglycerol in the liver, but fatty acids, long-chain fatty acyl CoAs, ceramides, and cholesterol were unchanged. Insulin action in the liver was enhanced after ADRP ASO treatment, whereas muscle and adipose tissue were not affected. ADRP ASO increased the phosphorylation of insulin receptor substrate (IRS)1, IRS2, and Akt, and decreased gluconeogenic enzymes and PKCepsilon, consistent with its insulin-sensitizing action. These results demonstrate an important role for ADRP in the pathogenesis of diet-induced insulin resistance.

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.…”

“…Additionally, we observed Ppar␣ and Cpt1a to be down 50% in the Plin2-null. This was surprising but is similar to what has been observed with anti-Plin2 antisense oligonucleotide treatment (17).…”

“…Previous studies using antisense oligonucleotides targeting PLIN2 in ob/ob mice and in mice fed high fat diets suggested that SREBP target genes might be altered upon loss of PLIN2 (11,12,17). In this study, we show that both SREBP-1 and SREBP-2 target genes do indeed experience extreme alterations with loss of PLIN2.…”

“…De novo lipogenesis is a major pathway in development of NAFLD both in humans and rodents fed longterm high fat, high carbohydrate diets. Additionally, reduction of hepatic Plin2 gene expression through the use of anti-Plin2 oligonucleotides in mouse models fed a long-term high fat diet has shown that de novo lipogenic gene expression is reduced (17). Given the improved glucose tolerance and previous gene expression studies in Plin2 antisense oligonucleotide mice, we suspected that SREBP-1 target genes would be reduced in Plin2-null animals.…”

“…This could possibly be due to incomplete knock-out of the PLIN2 protein (50) and/or differences in dietary sucrose. Additionally, the majority of studies examining the effect on hepatic TG accumulation with the loss of Plin2 have been performed in the context of leptin deficiency (11,18) and high fat diet-only feeding studies (12,17). Thus, complete characterization of the gene, protein, and lipid profile changes on control diet represents a novel area of study with regard to the role of PLIN2 in normal hepatic lipid metabolism.…”