AHNAK deficiency promotes browning and lipolysis in mice via increased responsiveness to β-adrenergic signalling

• DOI: 10.1038/srep23426
• Publication Date: 2016-03-18T10:07:47Z
• Authors: Jae Hoon Shin; Seo Hyun Lee; Yo Na Kim; Il Yong Kim; Youn Ju Kim; Dong Soo Kyeong; Hee Jung Lim; Soo Young Cho; Junhee Choi; Young Jin Wi; Jae-Hoon Choi; Yeo Sung Yoon; Yun Soo Bae; Je Kyung Seong
• Keywords: 0301 basic medicine; Adipose Tissue, White; Lipolysis; Membrane Proteins; Thermogenesis; Dioxoles; Diet, High-Fat; Article; Neoplasm Proteins; Mice; 03 medical and health sciences; Adipose Tissue, Brown; Gene Expression Regulation; Receptors, Adrenergic, beta; Animals; Energy Metabolism; Signal Transduction

AbstractIn adipose tissue, agonists of the β3-adrenergic receptor (ADRB3) regulate lipolysis, lipid oxidation, and thermogenesis. The deficiency in the thermogenesis induced by neuroblast differentiation-associated protein AHNAK in white adipose tissue (WAT) of mice fed a high-fat diet suggests that AHNAK may stimulate energy expenditure via development of beige fat. Here, we report that AHNAK deficiency promoted browning and thermogenic gene expression in WAT but not in brown adipose tissue of mice stimulated with the ADRB3 agonist CL-316243. Consistent with the increased thermogenesis, Ahnak−/− mice exhibited an increase in energy expenditure, accompanied by elevated mitochondrial biogenesis in WAT depots in response to CL-316243. Additionally, AHNAK-deficient WAT contained more eosinophils and higher levels of type 2 cytokines (IL-4/IL-13) to promote browning of WAT in response to CL-316243. This was associated with enhanced sympathetic tone in the WAT via upregulation of adrb3 and tyrosine hydroxylase (TH) in response to β-adrenergic activation. CL-316243 activated PKA signalling and enhanced lipolysis, as evidenced by increased phosphorylation of hormone-sensitive lipase and release of free glycerol in Ahnak−/− mice compared to wild-type mice. Overall, these findings suggest an important role of AHNAK in the regulation of thermogenesis and lipolysis in WAT via β-adrenergic signalling.