The Krüppel-like Factor KLF2 Inhibits Peroxisome Proliferator-activated Receptor-γ Expression and Adipogenesis

Abstract

Obesity is an important public health problem associated with a number of disease states such as diabetes and arteriosclerosis. As such, an understanding of the mechanisms governing adipose tissue differentiation and function is of considerable importance. We recently reported that the Krü ppel-like zinc finger transcription factor KLF15 can induce adipocyte maturation and GLUT4 expression. In this study, we identify that a second family member, KLF2/Lung Krü ppel-like factor (LKLF), as a negative regulator of adipocyte differentiation. KLF2 is highly expressed in adipose tissue, and studies in cell lines and primary cells demonstrate that KLF2 is expressed in preadipocytes but not mature adipocytes. Constitutive overexpression of KLF2 but not KLF15 potently inhibits peroxisome proliferator-activated receptor-␥ (PPAR␥) expression with no effect on the upstream regulators C/EBP␤ and C/EBP␦. However, the expression of C/EBP␣ and SREBP1c/ADD1 (adipocyte determination and differentiation factor-1/sterol regulatory element-binding protein-1), two factors that feedback in a positive manner to enhance PPAR␥ function, was also markedly reduced. In addition, transient transfection studies show that KLF2 directly inhibits PPAR␥2 promoter activity (70% inhibition; p < 0.001). Using a combination of promoter mutational analysis and gel mobility shift assays, we have identified a binding site within the PPAR␥2 promoter, which mediates this inhibitory effect. These data identify a novel role for KLF2 as a negative regulator of adipogenesis.

Krüppel-like factor KLF9 regulates PPARγ transactivation at the middle stage of adipogenesis

“…36 In another report, KLF9 competed with Sp1 for the BTE sequence in the cytochrome P4501A1 promoter. 34 Importantly, a previous work identified that KLF2 bound to a GC box at the proximal region of the PPARg2 promoter in preadipocytes and at the early stage of differentiation, 15 which is just the KLF9-binding site-II identified in the present experiment (Figures 4 and 5). Thus, it is reasonable to speculate that the endogenous KLF2 binds to this specific region on the PPARg2 promoter in pre-adipocytes, which made the PPARg2 promoter unavailable for the ectopic KLF9 proteins.…”

“…14 Previous reports showed that KLF proteins had different expression patterns during adipogenesis and several KLFs had been proved to either promote or inhibit this process. [15][16][17][18][19][20][21] Krü ppel-like factor 9 (KLF9), previously designated as basic transcription element-binding protein-1 (BTEB1), was initially isolated from a rat liver cDNA library. 22 KLF9 was further identified to be important for development and other physiological functions.…”

Prostaglandin F2α inhibits adipocyte differentiation via a Gαq‐Calcium‐Calcineurin‐Dependent signaling pathway

“…HDACs are enzymes that play an important role in the regulation of gene expression and are best known for their role in repressing gene transcription via interaction with transcriptional repressors [Ng and Bird, 2000]. Interestingly, both HDACs and transcriptional repressors have previously been implicated in the regulation of adipocyte differentiation: HDAC-1 has been shown to associate with the C/EBPa promoter and play an important role in preventing C/EBPa expression in unstimulated preadipocytes [Wiper-Bergeron et al, 2003], while a number of transcriptional repressors have been implicated in the regulation of adipogenesis via the direct inhibition of both C/EBPa and PPARg gene expression [Tong et al, 2000;Yun et al, 2002;Banerjee et al, 2003;Shi et al, 2003]. Hence, it is tempting to speculate that one potential mechanism by which the PGF2a-calcineurin signaling pathway may inhibit adipocyte differentiation is by inducing the expression and/or activity of an HDAC-associated transcriptional repressor that is either able to directly inhibit the expression of the PPARg and C/EBPa genes, or alternatively, acts indirectly, by inhibiting the expression of a gene(s) that is normally required to promote the expression of PPARg and C/ EBPa.…”

Obesity and polymorphisms in genes regulating human adipose tissue

“…44 The Kruppel-like zincfinger transcription factor KLF2 is a negative regulator of adipocyte differentiation. 45 Common KLF2 polymorphisms are not associated with obesity in a population-based sample composed of 1155 French individuals. 46 Transgenic mice with adipose-tissue-specific overexpression of Wingless-type MMTV integration site family, member 10B (WNT10B) display a 50% reduction in body fat.…”