Antisense reduction of 11β-hydroxysteroid dehydrogenase type 1 enhances energy expenditure and insulin sensitivity independent of food intake in C57BL/6J mice on a Western-type diet.
We recently reported that inhibition of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) by antisense oligonucleotide (ASO) improved hepatic lipid metabolism independent of food intake. In that study, 11β-HSD1 ASO-treated mice lost weight compared with food-matched control ASO-treated mice, suggesting treatment-mediated increased energy expenditure. We have now examined the effects of 11β-HSD1 ASO treatment on adipose tissue metabolism, insulin sensitivity, and whole-body energy expenditure. We used an ASO to knock down 11β-HSD1 in C57BL/6J mice consuming a Western-type diet (WTD). The 11β-HSD1 ASO-treated mice consumed less food, so food-matched control ASO-treated mice were also evaluated. We characterized body composition, gene expression of individual adipose depots, and measures of energy metabolism. We also investigated glucose/insulin tolerance as well as acute insulin signaling in several tissues. Knockdown of 11β-HSD1 protected against WTD-induced obesity by reducing epididymal, mesenteric, and subcutaneous white adipose tissue while activating thermogenesis in brown adipose tissue. The latter was confirmed by demonstrating increased energy expenditure in 11β-HSD1 ASO-treated mice. The 11β-HSD1 ASO treatment also protected against WTD-induced glucose intolerance and insulin resistance; this protection was associated with smaller cells and fewer macrophages in epididymal white adipose tissue as well as enhanced in vivo insulin signaling. Our results indicate that ASO-mediated inhibition of 11β-HSD1 can protect against several WTD-induced metabolic abnormalities. These effects are, at least in part, mediated by increases in the oxidative capacity of brown adipose tissue.
Department of Medicine, Columbia University, New York, NY 10032, USA.
Guoping
G
Li
Antonio
A
Hernandez-Ono
Rosanne M
RM
Crooke
Mark J
MJ
Graham
Henry N
HN
Ginsberg
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001823:Body Composition / Q000235:genetics / Q000502:physiology; D004435:Eating / Q000235:genetics / Q000502:physiology*; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology*; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
D007328:Insulin; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1