332-OR: Pharmacological Inhibition of CREBZF Improves Insulin Resistance by Altering Activation of Macrophage in Adipose Tissue of Diet-Induced Obese Mice

Obesity and type 2 diabetes are associated with chronic inflammation response in adipose tissue, in which macrophage activation and infiltration are hallmark characteristics. However, the molecular mechanism of this association remains largely unknown. Here, we report that CREBZF, a newly characterized transcription factor for insulin-induced lipogenesis, functions as a key regulator in adipose tissue macrophage and couples inflammatory signals to systemic insulin resistance in obesity. Myeloid cell-specific CREBZF knockout (CREBZF MKO) mice were generated by crossing floxed CREBZF mice with LysM-Cre transgenic mice. A small molecule (LIC902) was identified as a CREBZF inhibitor using a luciferase reporter-based high-throughput screening, which is shown to repress expression levels of CREBZF in the macrophage, such as J774. We found that ablation of CREBZF in myeloid cells or administration of LIC902 attenuates insulin resistance and hyperglycemia in mice fed with high-fat high-sucrose (HFHS) diet. Intriguingly, myeloid CREBZF deficiency or LIC902 treatment causes a profound reduction of infiltrated macrophages and reverses M1/M2 imbalance in white adipose tissue of mice fed with HFHS diet, suggesting important roles of CREBZF in regulating macrophage polarization in adipose tissue. CREBZF is capable of potentiating NF-κB signaling in the macrophage as evidenced by increased phosphorylation of p65, whereas CREBZF deficiency or inhibition of CREBZF activity results in the opposite effect. These data indicate that CREBZF plays a critical role in the regulation of innate immune response in the macrophage and maintains whole-body glucose homeostasis. Pharmacological manipulation of CREBZF may provide novel opportunities for treating metabolic diseases such as insulin resistance and type 2 diabetes. Disclosure Y. Liu: None. S. Wei: None. Z. Wang: None. X. Sun: None. Y. Jiang: None. X. Dai: None. Y. Li: None. A. Cui: None. Z. Hu: None. Z. Liu: None. W. Su: None. Z. Zheng: None. D. Ding: None. F. Ma: None. Y. Xue: None. G. Cai: None. Funding National Key Research and Development Program of China (2019YFA0802502); National Natural Science Foundation of China (81925008); Shanghai Science and Technology Commission (19140903300)