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

• Published in: Diabetologia 2018-06, Vol.61 (6), p.1435-1446
• Main Authors: Vatner, Daniel F., Goedeke, Leigh, Camporez, Joao-Paulo G., Lyu, Kun, Nasiri, Ali R., Zhang, Dongyan, Bhanot, Sanjay, Murray, Susan F., Still, Christopher D., Gerhard, Glenn S., Shulman, Gerald I., Samuel, Varman T.
• Format: Article
• Language: English
• Subjects: Adipose tissue; Adipose Tissue - metabolism; AKT protein; Angiopoietin; Angiopoietin-like Proteins - genetics; Animals; Antisense oligonucleotides; Body Composition; Body fat; Calorimetry; Calorimetry, Indirect; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diet, High-Fat; Disease resistance; Energy balance; Fatty liver; Gene expression; Glucose; Glucose tolerance; Glucose Tolerance Test; Human Physiology; Insulin; Insulin Resistance; Internal Medicine; Intolerance; Kinases; Lipase; Lipid Metabolism; Lipoprotein lipase; Liver diseases; Male; Medicine; Medicine & Public Health; Metabolic Diseases; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease - metabolism; Oligonucleotides, Antisense - genetics; Peptide Hormones - genetics; Phosphorylation; Protein kinase; Protein kinase C; Rats; Rats, Sprague-Dawley; Rodents; Steatosis; Surgery; Therapeutic applications
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-018-4579-1

Aims/hypothesis Targeting regulators of adipose tissue lipoprotein lipase could enhance adipose lipid clearance, prevent ectopic lipid accumulation and consequently ameliorate insulin resistance and type 2 diabetes. Angiopoietin-like 8 (ANGPTL8) is an insulin-regulated lipoprotein lipase inhibitor 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 resistance by promoting adipose lipid uptake. Methods ANGPTL8 expression was assessed by quantitative PCR in omental adipose tissue of bariatric surgery patients. High-fat-fed Sprague Dawley rats and C57BL/6 mice were treated with ASO against Angptl8 and insulin sensitivity was assessed by hyperinsulinaemic–euglycaemic clamps in rats and glucose tolerance tests in mice. Factors mediating lipid-induced hepatic insulin resistance were assessed, including lipid content, protein kinase Cε (PKCε) activation and insulin-stimulated Akt phosphorylation. Rat adipose lipid uptake was assessed by mixed meal tolerance tests. Murine energy balance was assessed by indirect calorimetry. Results Omental fat ANGPTL8 mRNA expression is higher in obese individuals with fatty liver and insulin resistance compared with BMI-matched insulin-sensitive individuals. Angptl8 ASO prevented hepatic steatosis, PKCε activation and hepatic insulin resistance in high-fat-fed rats. Postprandial triacylglycerol uptake in white adipose tissue was increased in Angptl8 ASO-treated rats. Angptl8 ASO protected high-fat-fed mice from glucose intolerance. Although there was no change in net energy balance, Angptl8 ASO increased fat mass in high-fat-fed mice. Conclusions/interpretation Disinhibition of adipose tissue lipoprotein lipase is a novel therapeutic modality to enhance adipose lipid uptake and treat non-alcoholic fatty liver disease and insulin resistance. In line with this, adipose ANGPTL8 is a candidate therapeutic target for these conditions.