Abstract 14903: Activating Transcription Factor 3 Regulates High-Fat Diet-Induced Adipocytes Hypertrophy and Lipid Metabolism in Mice
Obesity is a severe and complicated health issue related to lifestyle and dietary modifications, and is highly associated with cardiovascular diseases. Activating transcription factor 3 (ATF3) is a member of the ATF/cAMP-response element-binding protein family of transcriptional factors. It can be induced by stress condition in a variety of tissues, including adipocytes. Here we demonstrated that ATF3 can regulate lipid metabolism in high-fat-diet (HFD)-induced obesity in mice. ATF3-/- mice (KO) were given HFD for 16 weeks, with body weights significantly increased as compared to B6 wild-type (WT) littermate mice (KO: 41.3±0.98 gm vs. WT: 34.3±0.9 gm, p<0.05, n=6). The obese ATF3-/- mice then received AAV8-mediated gene transfer of ATF3 (AAV8-ATF3) at 16 weeks, in which decrease body weights were observed in the AAV8-ATF3 mice as compared to ATF3-/- mice receiving AAV8-GFP (AAV8-ATF3: 36.5±0.7 gm, p<0.05, n=6). Histology demonstrated increased adipocyte cell diameter in ATF3-/- mice, in which such enlargement of adipocytes can be reversed by AAV8-ATF3 therapy (AAV8-GFP: 88.2±7.6 μm vs AAV8-ATF3: 59.7±1.3 μm, p<0.05, n=6). Further signaling analysis showed that phosphorylation of AMPK and ERK were inhibited in adipose tissue of HFD-fed ATF3-/- mice compared to WT mice, whereas AAV8-ATF3 therapy can enhance adiponectin receptor-1 expression, suppressed inflammatory marker ICAM-1 and serum resistin levels, thus rescue the obese phenotype seen in these mice. We further investigate the role of ATF3 in 3T3-L1 adipocytes. ATF3-overexpressing adipocytes exhibited less lipid accumulation with diminished expression of adipogenic markers (including C/EBP-alpha, PPAR-gamma, adiponectin, leptin and resistin), and lipogenic markers (including ACC1, ACC2, FAS, DGAT1 and DGAT2) as compared to the control cells. Inflammation-related genes like ICAM1, IL-6, MCP1 and TNF-alpha, and lipid droplet coat protein, perilipin, were found downregulated in ATF3-overexpressing adipocytes.These results suggest that ATF3 inhibits 3T3-L1 preadipocyte differentiation and lipid droplet formation in adipocyte through downregulation on both adipogenic and lipogenic pathways, thus confirm that ATF3 regulates adipocyte hypertrophy and lipid metabolism in mice.
Author Disclosures: C. Cheng: None. H. Ku: None. T. Tseng: None. P. Lai: None. H. Lin: None.
- © 2014 by American Heart Association, Inc.