Targeted disruption of the basic Krüppel-like factor gene (Klf3) reveals a role in adipogenesis

Krüppel-like factors (KLFs) recognize CACCC and GC-rich sequences in gene regulatory elements. Here, we describe the disruption of the murine basic Krüppel-like factor gene <i>(Bklf or Klf3). Klf3</i> knockout mice have less white adipose tissue, and their fat pads contain smaller and fewer cells. Adipocyte differentiation is altered in murine embryonic fibroblasts from <i>Klf3 </i>knockouts. <i>Klf3</i> expression was studied in the 3T3-L1 cellular system. Adipocyte differentiation is accompanied by a decline in <i>Klf3</i> expression, and forced overexpression of <i>Klf3</i> blocks 3T3-L1 differentiation. <i>Klf3</i> represses transcription by recruiting C-terminal binding protein (CtBP) corepressors. CtBPs bind NADH and may function as metabolic sensors. A Klf3 mutant that does not bind CtBP cannot block adipogenesis. Other KLFs, Klf2, Klf5, and Klf15, also regulate adipogenesis, and functional CACCC elements occur in key adipogenic genes, including in the <i>C/ebp</i>α promoter. We find that <i>C/ebp</i>α is derepressed in <i>Klf3</i> and <i>Ctbp</i> knockout fibroblasts and adipocytes from <i>Klf3</i> knockout mice. Chromatin immunoprecipitations confirm that Klf3 binds the <i>C/ebp</i>α promoter in vivo. These results implicate Klf3 and CtBP in controlling adipogenesis.<br />