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Kim GH, Szabo A, King EM, et al. Leptin recruits Creb-regulated transcriptional coactivator 1 to improve hyperglycemia in insulin-deficient diabetes. Mol Metab. 2014;4(3):227-36doi: 10.1016/j.molmet.2014.12.006.
Kim, G. H., Szabo, A., King, E. M., Ayala, J., Ayala, J. E., & Altarejos, J. Y. (2015). Leptin recruits Creb-regulated transcriptional coactivator 1 to improve hyperglycemia in insulin-deficient diabetes. Molecular metabolism, 4(3), 227-36. https://doi.org/10.1016/j.molmet.2014.12.006
Kim, Geun Hyang, et al. "Leptin recruits Creb-regulated transcriptional coactivator 1 to improve hyperglycemia in insulin-deficient diabetes." Molecular metabolism vol. 4,3 (2015): 227-36. doi: https://doi.org/10.1016/j.molmet.2014.12.006
Kim GH, Szabo A, King EM, Ayala J, Ayala JE, Altarejos JY. Leptin recruits Creb-regulated transcriptional coactivator 1 to improve hyperglycemia in insulin-deficient diabetes. Mol Metab. 2014 Dec 19;4(3):227-36. doi: 10.1016/j.molmet.2014.12.006. eCollection 2015 Mar. PMID: 25737949; PMCID: PMC4338314.
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Mol Metab. 2014 Dec 19;4(3):227-36. doi: 10.1016/j.molmet.2014.12.006. eCollection 2015 Mar.

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

Molecular metabolism

Geun Hyang Kim, Andras Szabo, Emily M King, Jennifer Ayala, Julio E Ayala, Judith Y Altarejos

Affiliations

  1. Metabolic Disease Program, Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, United States.
  2. Cardiometabolic Phenotyping Core, Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, United States.
  3. Metabolic Disease Program, Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, United States ; Cardiometabolic Phenotyping Core, Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, United States.

PMID: 25737949 PMCID: PMC4338314 DOI: 10.1016/j.molmet.2014.12.006

Abstract

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.

Keywords: Creb-regulated transcriptional coactivator 1; Glucose; Hypothalamus; Leptin; Type 1 diabetes

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