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Diabetologia. 2018 Jun;61(6):1435-1446. doi: 10.1007/s00125-018-4579-1. Epub 2018 Mar 1.

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

Author information

1
Department of Internal Medicine, Yale University School of Medicine, P.O. Box 208020, New Haven, CT, 06520, USA. daniel.vatner@yale.edu.
2
Department of Internal Medicine, Yale University School of Medicine, P.O. Box 208020, New Haven, CT, 06520, USA.
3
Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT, 06520, USA.
4
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, 06520, USA.
5
Ionis Pharmaceuticals, Carlsbad, CA, 92008, USA.
6
Obesity Institute, Geisinger Health System, Danville, PA, 17822, USA.
7
Department of Internal Medicine, Yale University School of Medicine, P.O. Box 208020, New Haven, CT, 06520, USA. varman.samuel@yale.edu.
8
Veterans Affairs Medical Center, 950 Campbell Ave, BLG 5 3rd floor, West Haven, CT, 06516, USA. varman.samuel@yale.edu.

Abstract

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.

KEYWORDS:

Angiopoietin-like 8; Antisense oligonucleotide; Ectopic lipid; Insulin resistance; Lipoprotein lipase; NAFLD

PMID:
29497783
PMCID:
PMC5940564
DOI:
10.1007/s00125-018-4579-1
[Indexed for MEDLINE]
Free PMC Article

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