Therapeutic Inhibition of miR-33 Promotes Fatty Acid Oxidation but Does Not Ameliorate Metabolic Dysfunction in Diet-Induced Obesity.

Abstract

OBJECTIVE:

miR-33 has emerged as an important regulator of lipid homeostasis. Inhibition of miR-33 has been demonstrated as protective against atherosclerosis; however, recent studies in mice suggest that miR-33 inhibition may have adverse effects on lipid and insulin metabolism. Given the therapeutic interest in miR-33 inhibitors for treating atherosclerosis, we sought to test whether pharmacologically inhibiting miR-33 at atheroprotective doses affected metabolic parameters in a mouse model of diet-induced obesity.

APPROACH AND RESULTS:

High-fat diet (HFD) feeding in conjunction with treatment of male mice with 10 mg/kg control anti-miR or anti-miR33 inhibitors for 20 weeks promoted equivalent weight gain in all groups. miR-33 inhibitors increased plasma total cholesterol and decreased serum triglycerides compared with control anti-miR, but not compared with PBS-treated mice. Metrics of insulin resistance were not altered in anti-miR33-treated mice compared with controls; however, respiratory exchange ratio was decreased in anti-miR33-treated mice. Hepatic expression of miR-33 targets Abca1 and Hadhb were derepressed on miR-33 inhibition. In contrast, protein levels of putative miR-33 target gene SREBP-1 or its downstream targets genes Fasn and Acc were not altered in anti-miR33-treated mice, and hepatic lipid accumulation did not differ between groups. In the adipose tissue, anti-miR33 treatment increased Ampk gene expression and markers of M2 macrophage polarization.

CONCLUSIONS:

We demonstrate in a mouse model of diet-induced obesity that therapeutic silencing of miR-33 may promote whole-body oxidative metabolism but does not affect metabolic dysregulation. This suggests that pharmacological inhibition of miR-33 at doses known to reduce atherosclerosis may be a safe future therapeutic.

• Authors: Denuja Karunakaran, Laura Richards, Michele Geoffrion, Danyk Barrette, Ryan J Gotfrit, Mary-Ellen Harper, Katey J Rayner
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 35 Issue 12 Pg. 2536-43 (Dec 2015) ISSN: 1524-4636 [Electronic] United States
• PMID: 26427794 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 American Heart Association, Inc.

Chemical References

• ABCA1 protein, mouse
• ATP Binding Cassette Transporter 1
• Biomarkers
• Blood Glucose
• Fatty Acids
• Insulin
• MicroRNAs
• Mirn33 microRNA, mouse
• Oligonucleotides, Antisense
• Triglycerides
• Cholesterol
• Hadhb protein, mouse
• Mitochondrial Trifunctional Protein, beta Subunit
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (genetics, metabolism)
• ATP Binding Cassette Transporter 1 (genetics, metabolism)
• Adipose Tissue (metabolism)
• Animals
• Biomarkers (blood)
• Blood Glucose (metabolism)
• Cholesterol (blood)
• Diet, High-Fat
• Disease Models, Animal
• Fatty Acids (metabolism)
• Insulin (blood)
• Insulin Resistance
• Liver (metabolism)
• Macrophages (metabolism)
• Male
• Mice, Inbred C57BL
• MicroRNAs (genetics, metabolism)
• Mitochondrial Trifunctional Protein, beta Subunit (genetics, metabolism)
• Obesity (genetics, metabolism, therapy)
• Oligonucleotides, Antisense (genetics, metabolism)
• Oxidation-Reduction
• Phenotype
• Time Factors
• Triglycerides (blood)
• Weight Gain