Obesity and type 2 diabetes are associated with chronic inflammation response in the adipose tissue, in which macrophage activation and infiltration are hallmark characteristics. However, the molecular mechanism of this association remains largely unknown. Here, we show that CREB/ATF bZIP transcription factor CREBZF as a critical regulator of the adipose macrophage sensing inflammatory signals to cause systemic insulin resistance in obesity. We found that CREBZF was markedly induced in bone-marrow-derived macrophages and J774 macrophage cell lines in response to lipopolysaccharide treatment. To elucidate the function of CREBZF, we generated a myeloid cell-specific CREBZF knockout (CREBZF MKO) mouse by crossing floxed CREBZF mice with LysM-Cre transgenic mice. Myeloid cell-specific CREBZF deficiency in mice largely attenuated high-fat high sucrose (HFHS) diet-induced obesity and insulin resistance and hyperglycemia. CREBZF MKO mice showed a dramatic reduction of infiltrated macrophages in the white adipose tissue and an induction of whole-body energy expenditure. Ablation of CREBZF in myeloid cells caused a potent reduction of M1 macrophages and a concomitant induction of M2 macrophages in the adipose tissue of mice fed with HFHS diet, suggesting an important role of CREBZF in regulating adipose tissue macrophage polarization. Interestingly, CREBZF is capable of potentiating NF-κB signaling as evidenced by increased phosphorylation of IκB and p65 in the macrophage, whereas CREBZF deficiency resulted in opposite effects. These data indicate that CREBZF plays an important role in the regulation of innate immune response in the macrophage, and maintains whole-body energy metabolism and glucose homeostasis. Pharmacologic manipulation of CREBZF activity in the macrophage may provide novel opportunities for treating obesity, insulin resistance and type 2 diabetes.
Z. Hu: None. Y. Liu: None. Z. Liu: None. Z. Zhao: None. A. Cui: None. F. Ma: None. Y. Xue: None. Y. Han: None. F.F. Zhang: None. J. Fan: None. Y. Li: None.
National Key Research and Development Program of China (2017YFC0909601); National Natural Science Foundation of China (31471129, 31671224); Chinese Academy of Sciences (KJZD-EW-G20-02); K.C. Wong Education Foundation (to Y.L.)