Peptide Biology Laboratories, The Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.
Department of Clinical Nutrition, Osaka Prefecture University, Habikino, Habikino City, Osaka, Japan.
Commun Biol. 2021 Oct 22;4(1):1214. doi: 10.1038/s42003-021-02735-5.
Obesity is a major risk factor for the development of type II diabetes. Increases in adipose tissue mass trigger insulin resistance via the release of pro-inflammatory cytokines from adipocytes and macrophages. CREB and the CRTC coactivators have been found to promote insulin resistance in obesity, although the mechanism is unclear. Here we show that high fat diet feeding activates the CREB/CRTC pathway in adipocytes by decreasing the expression of SIK2, a Ser/Thr kinase that phosphorylates and inhibits CRTCs. SIK2 levels are regulated by the adipogenic factor C/EBPα, whose expression is reduced in obesity. Exposure to PPARγ agonist rescues C/EBPα expression and restores SIK2 levels. CRTC2/3 promote insulin resistance via induction of the chemokines CXCL1/2. Knockout of CRTC2/3 in adipocytes reduces CXCL1/2 expression and improves insulin sensitivity. As administration of CXCL1/2 reverses salutary effects of CRTC2/3 depletion, our results demonstrate the importance of the CREB/CRTC pathway in modulating adipose tissue function.
肥胖是 II 型糖尿病发展的一个主要危险因素。脂肪组织质量的增加会通过脂肪细胞和巨噬细胞释放促炎细胞因子引发胰岛素抵抗。已经发现 CREB 和 CRTC 共激活因子促进肥胖中的胰岛素抵抗，尽管其机制尚不清楚。在这里，我们发现高脂饮食通过降低丝氨酸/苏氨酸激酶 SIK2 的表达来激活脂肪细胞中的 CREB/CRTC 通路，SIK2 会磷酸化并抑制 CRTCs。SIK2 的水平受脂肪形成因子 C/EBPα 的调节，肥胖时 C/EBPα 的表达减少。暴露于过氧化物酶体增殖物激活受体 γ 激动剂可恢复 C/EBPα 的表达并恢复 SIK2 的水平。CRTC2/3 通过诱导趋化因子 CXCL1/2 促进胰岛素抵抗。在脂肪细胞中敲除 CRTC2/3 可降低 CXCL1/2 的表达并改善胰岛素敏感性。由于 CXCL1/2 的给药可逆转 CRTC2/3 耗竭的有益作用，因此我们的结果表明 CREB/CRTC 通路在调节脂肪组织功能方面具有重要作用。
