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AHNAK ablation promotes browning of white adipose tissue and counteracts obesity
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- Authors
- Advisor
- 성제경
- Major
- 수의과대학 수의학과
- Issue Date
- 2016-02
- Publisher
- 서울대학교 대학원
- Keywords
- obesity ; adipogenesis ; BMP4/SMAD1 ; energy expenditure ; browning ; lipolysis ; thermogenesis ; b-adrenergic signaling ; Ahnak
- Description
- 학위논문 (박사)-- 서울대학교 대학원 : 수의과대학 수의학과, 2016. 2. 성제경.
- Abstract
- AHNAK, a large size-phosphoprotein, plays a crucial role in the cell adhesion, proliferation and calcium signaling. Recently emerging evidence has suggested that AHNAK expression is altered in obese condition. Nevertheless, the role of AHNAK during adipose tissue development remains unclear. The objective of this study was to determine the molecular mechanism of AHNAK in adipogenesis and glucose homeostasis. In this study, AHNAK KO mice displayed resistance to diet-induced obesity due to reduction of fat accumulation. We found that adipogenesis from adipose derived mesenchymal stem cells (ADSCs) was severely impaired in AHNAK KO mice, which could contribute to whole-body fat accumulation. We also observed that loss of AHANK led to a decreased BMP4/SMAD1 signaling, resulting in decreased expression of key regulators for adipocyte differentiation. AHNAK directly interacts with Smad1 on the PPAR2 transcription activity. Concomitantly, AHNAK KO mice displayed a better degree of metabolic profiles, including improved glucose tolerance, enhanced insulin sensitivity, and higher energy expenditure without alteration in food intake and physical activity. Taken together, Ahnak plays a crucial role in body fat accumulation by regulation of adipose tissue development through interaction with Smad1 protein and can be involved in metabolic homeostasis.
Changes in brown adipose tissue (BAT) activity and energy expenditure through thermogenesis would be a promising therapeutic target against obesity. In adipose tissue, agonists of the b3-adrenergic receptor (ADRB3) regulate lipolysis, lipid oxidation, and thermogenesis. AHNAK deficiency induced thermogenesis in white adipose tissue (WAT) of mice fed high-fat diet, suggesting that AHNAK may stimulate energy expenditure via the 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 increased thermogenesis, AHNAK KO mice exhibited an increase in energy expenditure, accompanied by elevated mitochondrial biogenesis in WAT depots in response to CL-316243. CL-316243 activated PKA signaling and enhanced lipolysis, as evidenced by increased phosphorylation of hormone sensitive lipase and release of free glycerol in AHNAK KO mice compared to the wild-type mice. AHNAK deficient WAT contains more eosinophil and type 2 cytokines (IL-4/IL-13) to promote browning of WAT and mitochondrial biogenesis in response to CL. This is associated with enhanced sympathetic tone in WAT via upregulation of adrb3 and tyrosine hydroxylase (TH) expression in AHNAK KO mice in response to b-adrenergic activation. Overall, these findings suggest an important role of AHNAK in the regulation of thermogenesis and lipolysis in WAT via b-adrenergic signaling.
- Language
- English
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