| First Author | Zhang J | Year | 2011 |
| Journal | Endocrinology | Volume | 152 |
| Issue | 5 | Pages | 1829-38 |
| PubMed ID | 21406501 | Mgi Jnum | J:173968 |
| Mgi Id | MGI:5050607 | Doi | 10.1210/en.2010-0828 |
| Citation | Zhang J, et al. (2011) Inhibition of glyceroneogenesis by histone deacetylase 3 contributes to lipodystrophy in mice with adipose tissue inflammation. Endocrinology 152(5):1829-38 |
| abstractText | We have reported that the nuclear factor-kappaB (NF-kappaB) induces chronic inflammation in the adipose tissue of p65 transgenic (Tg) mice, in which the NF-kappaB subunit p65 (RelA) is overexpressed from the adipocyte protein 2 (aP2) gene promoter. Tg mice suffer a mild lipodystrophy and exhibit deficiency in adipocyte differentiation. To understand molecular mechanism of the defect in adipocytes, we investigated glyceroneogenesis by examining the activity of cytosolic phosphoenolpyruvate carboxykinase (PEPCK) in adipocytes. In aP2-p65 Tg mice, Pepck expression is inhibited at both the mRNA and protein levels in adipose tissue. The mRNA reduction is a consequence of transcriptional inhibition but not alteration in mRNA stability. The Pepck gene promoter is inhibited by NF-kappaB, which enhances the corepressor activity through activation of histone deacetylase 3 (HDAC3) in the nucleus. HDAC3 suppresses Pepck transcription by inhibiting the transcriptional activators, peroxisome proliferator-activated receptor-gamma, and cAMP response element binding protein. The NF-kappaB activity is abolished by Hdac3 knockdown or inhibition of HDAC3 catalytic activity. In a chromatin immunoprecipitation assay, HDAC3 interacts with peroxisome proliferator-activated receptor-gamma and cAMP response element binding protein in the Pepck promoter when NF-kappaB is activated by TNF-alpha. These results suggest that HDAC3 mediates NF-kappaB activity to repress Pepck transcription. This mechanism is responsible for inhibition of glyceroneogenesis in adipocytes, which contributes to lipodystrophy in the aP2-p65 Tg mice. |
