Angptl8 antisense oligonucleotide improves adipose lipid metabolism and prevents diet-induced NAFLD and hepatic insulin resistance in rodents

Aims/hypothesis Targeting regulators of adipose tissue lipoprotein lipasecould enhance adipose lipid clearance, prevent ectopic lipid accumulation and consequently ameliorate insulin resistanceand type 2 diabetes. Angiopoietin-like 8 (ANGPTL8) is an insulin-regulated lipoprotein lipaseinhibitor strongly expressed in murine adipose tissue. However, Angptl8 knockout mice do not have improved insulin resistance. We hypothesised that pharmacological inhibition, using a second-generation antisense oligonucleotide (ASO) against Angptl8 in adult high-fat-fed rodents, would prevent ectopic lipid accumulation and insulin resistanceby promoting adipose lipid uptake.