Loss of Krüppel-Like Factor 3 (KLF3/BKLF) Leads to Upregulation of the Insulin-Sensitizing Factor Adipolin (FAM132A/CTRP12/C1qdc2)

Abstract

Krüppel-like factor 3 (KLF3) is a transcriptional regulator that we have shown to be involved in the regulation of adipogenesis in vitro. Here, we report that KLF3-null mice are lean and protected from diet-induced obesity and glucose intolerance. On a chow diet, plasma levels of leptin are decreased, and adiponectin is increased. Despite significant reductions in body weight and adiposity, wild-type and knockout animals show equivalent energy intake, expenditure, and excretion. To investigate the molecular events underlying these observations, we used microarray analysis to compare gene expression in Klf3+/+ and Klf3−/− tissues. We found that mRNA expression of Fam132a, which encodes a newly identified insulin-sensitizing adipokine, adipolin, is significantly upregulated in the absence of KLF3. We confirmed that KLF3 binds the Fam132a promoter in vitro and in vivo and that this leads to repression of promoter activity. Further, plasma adipolin levels were significantly increased in Klf3−/− mice compared with wild-type littermates. Boosting levels of adipolin via targeting of KLF3 offers a novel potential therapeutic strategy for the treatment of insulin resistance.

Adipokines and insulin action

“…37,95,96 Importantly, they demonstrate that the FAM132A promoter is bound and regulated in vivo by KLF3 and show that in Klf3 −/− mice, adipolin levels are significantly elevated. 37 Interestingly, KLF3 recruits the NAD + /NADH-dependent metabolic sensor C-terminal binding protein to regulate gene expression, suggesting a possible mechanism allowing this pathway to respond to metabolic stimuli and energy levels intracellularly. 97,98 While the extent to which the KLF3-adipolin pathway underlies the favorable metabolic phenotype of KLF3 null mice remains to be fully resolved, this discovery provides novel therapeutic potential, perhaps via targeting of signaling molecules that regulate KLF3 activity.…”

“…However, in a recent study, Bell-Anderson et al have elucidated a novel regulatory pathway controlling FAM132A gene expression. 37 In this, and previous work, they describe how mice deficient in the transcriptional repressor Krüppel-like Factor 3 (KLF3/BKLF) are lean due to reduced adiposity, and also demonstrate that loss of KLF3 leads to a favorable metabolic phenotype on a high fat diet, associated with resistance to obesity, improved insulin sensitivity and glucose tolerance. 37,95,96 Importantly, they demonstrate that the FAM132A promoter is bound and regulated in vivo by KLF3 and show that in Klf3 −/− mice, adipolin levels are significantly elevated.…”

“…37 In this, and previous work, they describe how mice deficient in the transcriptional repressor Krüppel-like Factor 3 (KLF3/BKLF) are lean due to reduced adiposity, and also demonstrate that loss of KLF3 leads to a favorable metabolic phenotype on a high fat diet, associated with resistance to obesity, improved insulin sensitivity and glucose tolerance. 37,95,96 Importantly, they demonstrate that the FAM132A promoter is bound and regulated in vivo by KLF3 and show that in Klf3 −/− mice, adipolin levels are significantly elevated. 37 Interestingly, KLF3 recruits the NAD + /NADH-dependent metabolic sensor C-terminal binding protein to regulate gene expression, suggesting a possible mechanism allowing this pathway to respond to metabolic stimuli and energy levels intracellularly.…”

“…[32][33][34] More recently, adipolin (FAM132A/CTRP12 gene) has been associated with improvements in insulin sensitivity and glycaemic control in mouse models of obesity and diabetes. [35][36][37] A summary of the metabolic effects of these adipokines is presented in Table 1.…”

Insulin regulates the novel adipokine adipolin/CTRP12: in vivo and ex vivo effects

“…Furthermore, there are significantly lower concentrations of full-length and total (full-length and globular) adipolin in diet-induced obese mice, leading to an increase in the ratio of globular:full-length adipolin, possibly through upregulation of furin in adipose tissue (Enomoto et al 2012). In addition, genetic studies in mice have shown that the loss of Krüppel-like factor 3 leads to upregulation of adipolin (Bell-Anderson et al 2013); on the other hand, loss of Krüppel-like factor 15 resulted in a decrease in adipolin levels (Enomoto et al 2013).…”