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

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 i...

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Detalles Bibliográficos
Autores principales: Kim, Geun Hyang, Szabo, Andras, King, Emily M., Ayala, Jennifer, Ayala, Julio E., Altarejos, Judith Y.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338314/
https://www.ncbi.nlm.nih.gov/pubmed/25737949
http://dx.doi.org/10.1016/j.molmet.2014.12.006
Descripción
Sumario: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.