ArticleMolecular metabolism2020
Antisense oligonucleotide treatment produces a type I interferon response that protects against diet-induced obesity.
Article in Molecular metabolism, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 18 citations in OpenAlex.
- An RNA thermogenic therapy to preserve lean mass and enhance metabolic health during GLP-1 weight loss.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Maternal high fat diet induces circadian clock-independent endocrine alterations impacting the metabolism of the offspring.iScience · 2024Article
- Role of IFN-α in Rheumatoid Arthritis.Current rheumatology reports · 2024Review
- Friend or foe for obesity: How hepatokines remodel adipose tissues and translational perspective.Genes & diseases · 2023Review
- Review
- An intranasal ASO therapeutic targeting SARS-CoV-2.Nature communications · 2022Article
- Shared genetic loci for body fat storage and adipocyte lipolysis in humans.Scientific reports · 2022Article
- TTC39B destabilizes retinoblastoma protein promoting hepatic lipogenesis in a sex-specific fashion.Journal of hepatology · 2022Article
- Antisense Oligonucleotide Technologies to Combat Obesity and Fatty Liver Disease.Frontiers in physiology · 2022Review
- Antisense oligonucleotide-mediated knockdown of Mpzl3 attenuates the negative metabolic effects of diet-induced obesity in mice.Physiological reports · 2021Article
- Where in the (lncRNA) World IsCirculation research · 2021Article
- Peripheral blood transcriptome profiling enables monitoring disease progression in dystrophic mice and patients.EMBO molecular medicine · 2021Article
- Review
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
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
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.