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...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2015-03-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877814002075 |
| _version_ | 1818931600294936576 |
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| author | Geun Hyang Kim Andras Szabo Emily M. King Jennifer Ayala Julio E. Ayala Judith Y. Altarejos |
| author_facet | Geun Hyang Kim Andras Szabo Emily M. King Jennifer Ayala Julio E. Ayala Judith Y. Altarejos |
| author_sort | Geun Hyang Kim |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T04:19:10Z |
| format | Article |
| id | doaj.art-065278a9ff98498fa67e12f95d2e2608 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-20T04:19:10Z |
| publishDate | 2015-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-065278a9ff98498fa67e12f95d2e26082022-12-21T19:53:40ZengElsevierMolecular Metabolism2212-87782015-03-014322723610.1016/j.molmet.2014.12.006Leptin recruits Creb-regulated transcriptional coactivator 1 to improve hyperglycemia in insulin-deficient diabetesGeun Hyang Kim0Andras Szabo1Emily M. King2Jennifer Ayala3Julio E. Ayala4Judith Y. Altarejos5Metabolic Disease Program, Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, United StatesMetabolic Disease Program, Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, United StatesCardiometabolic Phenotyping Core, Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, United StatesCardiometabolic Phenotyping Core, Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, United StatesMetabolic Disease Program, Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, United StatesMetabolic Disease Program, Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, United StatesObjective: 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.http://www.sciencedirect.com/science/article/pii/S2212877814002075LeptinType 1 diabetesGlucoseHypothalamusCreb-regulated transcriptional coactivator 1 |
| spellingShingle | Geun Hyang Kim Andras Szabo Emily M. King Jennifer Ayala Julio E. Ayala Judith Y. Altarejos Leptin recruits Creb-regulated transcriptional coactivator 1 to improve hyperglycemia in insulin-deficient diabetes Molecular Metabolism Leptin Type 1 diabetes Glucose Hypothalamus Creb-regulated transcriptional coactivator 1 |
| title | Leptin recruits Creb-regulated transcriptional coactivator 1 to improve hyperglycemia in insulin-deficient diabetes |
| title_full | Leptin recruits Creb-regulated transcriptional coactivator 1 to improve hyperglycemia in insulin-deficient diabetes |
| title_fullStr | Leptin recruits Creb-regulated transcriptional coactivator 1 to improve hyperglycemia in insulin-deficient diabetes |
| title_full_unstemmed | Leptin recruits Creb-regulated transcriptional coactivator 1 to improve hyperglycemia in insulin-deficient diabetes |
| title_short | Leptin recruits Creb-regulated transcriptional coactivator 1 to improve hyperglycemia in insulin-deficient diabetes |
| title_sort | leptin recruits creb regulated transcriptional coactivator 1 to improve hyperglycemia in insulin deficient diabetes |
| topic | Leptin Type 1 diabetes Glucose Hypothalamus Creb-regulated transcriptional coactivator 1 |
| url | http://www.sciencedirect.com/science/article/pii/S2212877814002075 |
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