The Top Six Most Asked Questions About Enol

To investigate a role for IRF4 in mature adipocytes, we began by asking whether IRF4 is nutritionally regulated. Twenty-four hours of fasting resulted in dramatic induction of IRF4 at both the messenger RNA (mRNA) (Figure?1A) and protein (Figure?1B) level in white adipose tissue (WAT) and brown adipose tissue (BAT), with subsequent downregulation after refeeding. This effect is not seen in spleen, one of the few tissues other than fat that expresses significant levels of IRF4. The time course for this effect is relatively swift, with significant upregulation of Irf4 mRNA within 6?hr of food withdrawal, and repression within an hour of refeeding ( Figure?S1A available online). We noted similar regulation of IRF4 in subcutaneous and epididymal WAT depots ( Figure?S1B). We next sought to determine whether this was a rodent-specific Enol effect or whether it could be relevant to humans. Biopsy samples were obtained from the subcutaneous fat of male volunteers before and after 72?hr of fasting (see Table S1 for clinical characteristics). Indeed, IRF4 mRNA rose significantly with fasting in five of seven patients ( Figure?1C; p?FDA-approved Drug Library in vivo mature adipocyte per se. Adipose tissue is insulin sensitive, while spleen is not; the fact that IRF4 expression is regulated in the former but not the latter suggested to us that insulin might repress IRF4. This proved to be the case, as cultured 3T3-L1 adipocytes treated with insulin showed a dose- and time-dependent reduction in Irf4 mRNA levels ( Figure?1D and Figure?S1C). To determine whether insulin plays a similar role in?vivo, we examined adipose tissue from mice treated with streptozotocin, which SNS032 causes �� cell failure and insulinopenia. In these animals, Irf4 mRNA expression in WAT rose significantly, and decreased when insulin was replaced ( Figure?1E). Similarly, Irf4 mRNA levels were elevated in mice lacking insulin receptors exclusively in adipose tissue (so-called fat-specific insulin receptor knockout [FIRKO] mice [ Bluher et?al., 2002]) ( Figure?1F). Taken together, these findings indicate that insulin is a potent repressor of IRF4 expression and implicate the rise and fall of insulin during feeding and fasting as a dominant determinant of IRF4 levels in fat. Consistent with this notion, IRF4 expression is repressed in whole WAT of three different rodent models of obesity, a hyperinsulinemic state ( Figure?S1D). As previously reported ( Joken et?al., 2007?and?Kershaw et?al., 2007), there was also a significant reduction of ATGL mRNA in whole WAT of high-fat diet-induced obesity and ob/ob mice compared to controls ( Figure?S1D).