| First Author | Kim GH | Year | 2015 |
| Journal | Mol Metab | Volume | 4 |
| Issue | 3 | Pages | 227-36 |
| PubMed ID | 25737949 | Mgi Jnum | J:220979 |
| Mgi Id | MGI:5637614 | Doi | 10.1016/j.molmet.2014.12.006 |
| Citation | Kim GH, et al. (2015) Leptin recruits Creb-regulated transcriptional coactivator 1 to improve hyperglycemia in insulin-deficient diabetes. Mol Metab 4(3):227-36 |
| abstractText | OBJECTIVE: Leptin alleviates hyperglycemia in rodent models of Type 1 diabetes by activating leptin receptors within the central nervous system. Here we delineate whether non-canonical leptin signaling through the Creb-regulated transcriptional coactivator 1 (Crtc1) contributes to leptin-dependent improvements in diabetic glucose metabolism. METHODS: We employed mice with a targeted genetic disruption of Crtc1, tracer dilution techniques and neuroanatomical studies to interrogate whether Crtc1 enables leptin to improve glucose metabolism in streptozotocin-induced (STZ) diabetes. RESULTS: Here we show that leptin improves diabetic glucose metabolism through Crtc1-dependent and independent mechanisms. We find that leptin reduces diabetic hyperglycemia, hepatic gluconeogenic gene expression and selectively increases glucose disposal to brown adipose tissue and heart, in STZ-diabetic Crtc1 (WT) mice but not Crtc1 (+/-) mice. By contrast, leptin decreases circulating glucagon levels in both STZ-diabetic Crtc1 (WT) and Crtc1 (+/-) mice. We also demonstrate that leptin promotes Crtc1 nuclear translocation in pro-opiomelanocortin (Pomc) and non-Pomc neurons within the hypothalamic arcuate nucleus (ARC). Accordingly, leptin's ability to induce Pomc gene expression in the ARC is blunted in STZ-diabetic Crtc1 (+/-) mice. CONCLUSIONS: Our study reveals that Crtc1 functions as a conduit for leptin's glucoregulatory actions in insulin-dependent diabetes. This study also highlights a new role for Crtc1 in modulating peripheral glucose metabolism. |
