Abstract
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.
Highlights
Obesity is a major risk factor for the development of type II diabetes
Co-expression of CRTC2/3 and p65 potentiated effects of FSK and TNFα on IL8 reporter activity. These results indicate that NF-κB and CREB/cAMP Responsive Transcriptional Coactivators (CRTCs) pathways co-regulate the expression of CXCL1 and CXCL2 (CXCL1/2) and perhaps other genes in adipocytes
Based on the proposed effects of CRTC2/3 on CXCL1/2 expression and insulin resistance, we evaluated whether depletion of CRTC2/3 in adipose tissue modulates the effects of High Fat Diet (HFD) on insulin signaling and glucose metabolism
Summary
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. Sustained low-grade inflammation in this setting impairs triglyceride and glucose metabolism Following their migration to WAT depots in response to circulating cytokines and chemokines, neutrophils promote infiltration of macrophages[2,3], which in turn release TNFα and other pro-inflammatory cytokines that enhance insulin resistance[4,5,6], in part via the induction of NF-κB. SIK2 is the most highly expressed of the three SIK family members in adipose tissue; and its downregulation in adipocytes of obese individuals is thought to contribute to insulin resistance[12,13]. CAMP signaling is itself associated with reduced inflammation in adipose tissue[15,16], the adipocyte CREB/CRTC pathway has paradoxically been found to enhance insulin resistance in obesity[17,18,19]. Our results demonstrate an unexpected link between CREB/CRTC and cytokine signaling pathways in modulating adipose tissue function
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