11β-HSD1 reduces metabolic efficacy and adiponectin synthesis in hypertrophic adipocytes

Abstract

Mitochondrial dysfunction in hypertrophic adipocytes can reduce adiponectin synthesis. We investigated whether 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) expression is increased in hypertrophic adipocytes and whether this is responsible for mitochondrial dysfunction and reduced adiponectin synthesis. Differentiated 3T3L1 adipocytes were cultured for up to 21 days. The effect of AZD6925, a selective 11b-HSD1 inhibitor, on metabolism was examined. db/db mice were administered 600 mg/kg AZD6925 daily for 4 weeks via gastric lavage. Mitochondrial DNA (mtDNA) content, mRNA expression levels of 11b-Hsd1 and mitochondrial biogenesis factors, adiponectin synthesis, fatty acid oxidation (FAO), oxygen consumption rate and glycolysis were measured. Adipocyte hypertrophy in 3T3L1 cells exposed to a long duration of culture was associated with increased 11b-Hsd1 mRNA expression and reduced mtDNA content, mitochondrial biogenesis factor expression and adiponectin synthesis. These cells displayed reduced mitochondrial respiration and increased glycolysis. Treatment of these cells with AZD6925 increased adiponectin synthesis and mitochondrial respiration. Inhibition of FAO by etomoxir blocked the AZD6925-induced increase in adiponectin synthesis, indicating that 11b-HSD1-mediated reductions in FAO are responsible for the reduction in adiponectin synthesis. The expression level of 11b-Hsd1 was higher in adipose tissues of db/db mice. Administration of AZD6925 to db/db mice increased the plasma adiponectin level and adipose tissue FAO. In conclusion, increased 11b-HSD1 expression contributes to reduced mitochondrial respiration and adiponectin synthesis in hypertrophic adipocytes.

White adipose tissue mitochondrial metabolism in health and in obesity

“…If adipose tissue and its mitochondria are dysfunctional and the storage capacity of adipocytes is compromised, FFA spill over to ectopic sites in the liver, muscle, and pancreas causing dysfunction and insulin resistance . Mitochondrial dysfunction also reduces the synthesis of adiponectin . Adipose tissue dysfunction has been recognized as an important contributor to obesity‐related disorders and can increase the risk of developing insulin resistance and metabolic complications of obesity .…”

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