Abstract
ObjectiveIn mouse models, deficiency of TTC39B (T39) decreases hepatic lipogenic gene expression and protects against diet-induced steatohepatitis. While assessing the therapeutic potential of antisense oligonucleotides (ASOs) targeting T39, we discovered an unexpected weight loss phenotype. The objective of this study was to determine the mechanism of the resistance to diet-induced obesity. MethodsTo assess therapeutic potential, we used antisense oligonucleotides (ASO) to knock down T39 expression in a Western or high-fat, high-cholesterol, high-sucrose-diet-fed Ldlr−/− or wild-type mice. ResultsT39 ASO treatment led to decreased hepatic lipogenic gene expression and decreased hepatic triglycerides. Unexpectedly, T39 ASO treatment protected against diet-induced obesity. The reduced weight gain was seen with two different ASOs that decreased T39 mRNA in adipose tissue macrophages (ATMs), but not with a liver-targeted GalNac-ASO. Mice treated with the T39 ASO displayed increased browning of gonadal white adipose tissue (gWAT) and evidence of increased lipolysis. However, T39 knockout mice displayed a similar weight loss response when treated with T39 ASO, indicating an off-target effect. RNA-seq analysis of gWAT showed a widespread increase in type I interferon (IFN)-responsive genes, and knockout of the IFN receptor abolished the weight loss phenotype induced by the T39 ASO. Some human T39 ASOs and ASOs with different modifications targeting LDLR also induced a type I IFN response in THP1 macrophages. ConclusionOur data suggest that extrahepatic targeting of T39 by ASOs in ATMs produced an off-target type 1 IFN response, leading to activation of lipolysis, browning of WAT, and weight loss. While our findings suggest that ASOs may induce off-target type 1 IFN response more commonly than previously thought, they also suggest that therapeutic induction of type 1 IFN selectively in ATMs could potentially represent a novel approach to the treatment of obesity.
Highlights
Obesity is a major risk factor for the development of metabolic diseases, including type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease (NAFLD) [1]
We found that treatment with two different T39 Antisense oligonucleotides (ASOs) in mouse models of dietary obesity induced browning of gonadal white adipose tissue (gWAT) and resistance to dietinduced obesity
T39 is primarily expressed in the stromal vascular fraction (SVF) of adipose tissue, and the ASO appeared to knock down T39 expression in macrophages, causing an induction of type 1 IFN-responsive genes in both the SVF fraction and in adipocytes
Summary
Obesity is a major risk factor for the development of metabolic diseases, including type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease (NAFLD) [1]. T39 deficiency in mouse models resulted in protection from diet-induced steatohepatitis and improved the lipoprotein profile [7]. These findings suggested that T39 might be a novel therapeutic target. This study was initiated to investigate the use of ASOs to knock down T39 expression, reduce fatty liver, and improve lipoprotein cholesterol levels. While T39 ASO treatment reduced fatty liver, it MOLECULAR METABOLISM 34 (2020) 146e156 Ó 2020 The Authors.
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