Abstract
Obese states characterized by chronic inflammation are closely linked to the development of metabolic dysfunction. We identified adipolin/CTRP12 as an insulin-sensitizing and anti-inflammatory adipokine. Although obese conditions down-regulate adipolin expression, its molecular mechanism is largely unknown. Here we show that the transcriptional regulator Krüppel-like factor (KLF) 15 is involved in the regulation of adipolin expression in adipocytes. White adipose tissue from diet-induced obese (DIO) mice showed decreased expression of KLF9 and KLF15 among several KLFs, which was accompanied by reduced expression of adipolin. In cultured 3T3L1 adipocytes, treatment with TNFα significantly reduced the mRNA levels of KLF9, KLF15 and adipolin. Adenovirus-mediated overexpression of KLF15 but not KLF9 reversed TNFα-induced reduction of adipolin expression in adipocytes. Conversely, gene targeting ablation of KLF15 attenuated adipolin expression in adipocytes. Expression of KLF15 but not KLF9 enhanced the promoter activity of adipolin in HEK293 cells. Pretreatment of 3T3L1 adipocytes with the JNK inhibitor SP600125, but not p38 MAPK inhibitor SB203580 blocked the inhibitory effects of TNFα on adipolin and KLF15 expression. These data suggest that adipose inflammation under conditions of obesity suppresses adipolin expression via JNK-dependent down-regulation of KLF15 in adipocytes.
Highlights
Obesity is closely associated with the development of various metabolic disorders including insulin resistance and type 2 diabetes [1,2,3]
To investigate whether obesity modulates the expression Kruppel-like factor (KLF) in adipose tissue, the mRNA levels of KLF3, KLF9, KLF10, KLF13 and KLF15 were evaluated in epididymal adipose tissue of diet-induced obese (DIO) and control lean mice by RT-PCR methods
KLF9 and KLF15 mRNA levels were significantly reduced in adipose tissue from DIO mice compared with those from control mice (Figure 1A)
Summary
Obesity is closely associated with the development of various metabolic disorders including insulin resistance and type 2 diabetes [1,2,3]. We found that adipolin/C1q/ TNF-related protein (CTRP) 12 functions as an anti-inflammatory adipokine that is abundantly expressed in fat tissue [17]. Consistent with our findings, another report demonstrated that adipolin ameliorates glucose metabolism in obese and diabetic mice [18]. Adipolin expression is reduced in fat tissue in obese mice [17,18]. It is plausible that adipose tissue inflammation in obese states is involved in the regulation of adipolin expression. The precise mechanism of how obese states reduce adipolin expression in fat tissue has not been fully clarified
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