[HTML][HTML] Leptin recruits Creb-regulated transcriptional coactivator 1 to improve hyperglycemia in insulin-deficient diabetes

GH Kim, A Szabo, EM King, J Ayala, JE Ayala… - Molecular …, 2015 - Elsevier
GH Kim, A Szabo, EM King, J Ayala, JE Ayala, JY Altarejos
Molecular metabolism, 2015Elsevier
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 …
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 Crtc1WT mice but not Crtc1+/− mice. By contrast, leptin decreases circulating glucagon levels in both STZ-diabetic Crtc1WT 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.
Elsevier