Adipose ZFP36 protects against diet-induced obesity and insulin resistance

Highlights•ZFP36 downregulation in adipose tissues of humans and mice is linked to obesity and metabolic disorders.•Adipose ZFP36 deficiency exacerbates diet-induced obesity and metabolic syndrome in mice.•The expansion of adipocytes contributes to adipose tissue hypoxia, leading to adipose tissue dysfunction in obesity.•ZFP36 attenuates hypertrophy of adipocytes in white adipose tissue via RNF128/Sirt1/lipolysis signaling.AbstractAimsObesity, as a worldwide healthcare problem, has become more prevalent. ZFP36 is a well-known RNA-binding protein and involved in the posttranscriptional regulation of many physiological processes. Whether the adipose ZFP36 plays a role in obesity and insulin resistance remains unclear.MethodsThe expression levels of ZFP36 were analyzed in adipose tissues of obese patients, diet-induced obese mice, ob/ob mice and db/db mice. To determine whether adipose ZFP36 protects against the diet-induced obesity, we generated adipose-specific ZFP36 knockout (ZFP36AKO) mice, which were subjected to high-fat-diet (HFD) for 16 weeks. To explore the specific molecular mechanisms of ZFP36 regulating metabolic disorders, we used gene array assay of control and ZFP36-deficient adipose tissue, and assessed the pathways in vitro and vivo.ResultsWestern blotting and RT-PCR were performed to determine the downregulating level of ZFP36 in adipose tissues of obese patients, diet-induced obese mice, ob/ob mice and db/db mice. Relative to control mice, ZFP36AKO mice were more susceptible to HFD-induced obesity, along with insulin resistance, glucose tolerance, and increased metabolic disorders. The obesity of ZFP36AKO mice was attributed to hypertrophy of adipocytes in white adipose tissue via decreased expression of Perilipin1 (PLIN1), adipose triglyceride lipase (ATGL), and hormone-sensitive lipase (HSL). We discovered that ZFP36 oppositely regulated RNF128 expression by repressing the mRNA stability and translation of RNF128, a negative regulator of SIRT1 expression.ConclusionsThis study suggests that ZFP36 in adipose tissue plays an important role in diet-induced obesity, and identifies a novel molecular signaling pathway of ZFP36/RNF128/Sirt1 involved in obesity.Graphical abstract