Publication Date:
2015-11-07
Description:
The mammalian transcription factors CLOCK and BMAL1 are essential components of the molecular clock that coordinate behavior and metabolism with the solar cycle. Genetic or environmental perturbation of circadian cycles contributes to metabolic disorders including type 2 diabetes. To study the impact of the cell-autonomous clock on pancreatic beta cell function, we examined pancreatic islets from mice with either intact or disrupted BMAL1 expression both throughout life and limited to adulthood. We found pronounced oscillation of insulin secretion that was synchronized with the expression of genes encoding secretory machinery and signaling factors that regulate insulin release. CLOCK/BMAL1 colocalized with the pancreatic transcription factor PDX1 within active enhancers distinct from those controlling rhythmic metabolic gene networks in liver. We also found that beta cell clock ablation in adult mice caused severe glucose intolerance. Thus, cell type-specific enhancers underlie the circadian control of peripheral metabolism throughout life and may help to explain its dysregulation in diabetes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669216/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669216/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Perelis, Mark -- Marcheva, Biliana -- Ramsey, Kathryn Moynihan -- Schipma, Matthew J -- Hutchison, Alan L -- Taguchi, Akihiko -- Peek, Clara Bien -- Hong, Heekyung -- Huang, Wenyu -- Omura, Chiaki -- Allred, Amanda L -- Bradfield, Christopher A -- Dinner, Aaron R -- Barish, Grant D -- Bass, Joseph -- ES05703/ES/NIEHS NIH HHS/ -- K01 DK105137/DK/NIDDK NIH HHS/ -- P01 AG011412/AG/NIA NIH HHS/ -- P01AG011412/AG/NIA NIH HHS/ -- P60 DK020595/DK/NIDDK NIH HHS/ -- P60DK020595/DK/NIDDK NIH HHS/ -- R01 DK090625/DK/NIDDK NIH HHS/ -- R01 ES005703/ES/NIEHS NIH HHS/ -- R01DK090625/DK/NIDDK NIH HHS/ -- T32 DK007169/DK/NIDDK NIH HHS/ -- T32 GM007281/GM/NIGMS NIH HHS/ -- T32 HL007909/HL/NHLBI NIH HHS/ -- T32GM07281/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Nov 6;350(6261):aac4250. doi: 10.1126/science.aac4250.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. ; Center for Genetic Medicine, Northwestern University, Chicago, IL 60611, USA. ; Medical Scientist Training Program, University of Chicago, Chicago, IL 60637, USA. Graduate Program in the Biophysical Sciences, University of Chicago, Chicago, IL 60637, USA. James Franck Institute, University of Chicago, Chicago, IL 60637, USA. ; McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 52705, USA. ; Graduate Program in the Biophysical Sciences, University of Chicago, Chicago, IL 60637, USA. James Franck Institute, University of Chicago, Chicago, IL 60637, USA. Department of Chemistry, University of Chicago, Chicago, IL 60637, USA. ; Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. j-bass@northwestern.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26542580" target="_blank"〉PubMed〈/a〉
Keywords:
ARNTL Transcription Factors/genetics/metabolism
;
Animals
;
CLOCK Proteins/metabolism
;
Circadian Rhythm/*genetics
;
Diabetes Mellitus, Type 2/genetics/metabolism
;
Enhancer Elements, Genetic/*physiology
;
Exocytosis/genetics
;
*Gene Expression Regulation
;
Glucose Intolerance
;
Homeodomain Proteins/metabolism
;
Humans
;
Insulin/*secretion
;
Insulin-Secreting Cells/*secretion
;
Liver/metabolism
;
Male
;
Mice
;
Mice, Inbred C57BL
;
Trans-Activators/metabolism
;
Transcription, Genetic
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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