title: Bmal1 is required for beta cell compensatory expansion, survival and metabolic adaptation to diet-induced obesity in mice.
abstract: OBJECTIVE
  Obesity and consequent insulin resistance are known risk factors for type 2 diabetes. A compensatory increase in beta cell function and mass in response to insulin resistance permits maintenance of normal glucose homeostasis, whereas failure to do so results in beta cell failure and type 2 diabetes. Recent evidence suggests that the circadian system is essential for proper metabolic control and regulation of beta cell function. We set out to address the hypothesis that the beta cell circadian clock is essential for the appropriate functional and morphological beta cell response to insulin resistance.
  
  
  METHODS
  We employed conditional deletion of the Bmal1 (also known as Arntl) gene (encoding a key circadian clock transcription factor) in beta cells using the tamoxifen-inducible CreER(T) recombination system. Upon adulthood, Bmal1 deletion in beta cells was achieved and mice were exposed to either chow or high fat diet (HFD). Changes in diurnal glycaemia, glucose tolerance and insulin secretion were longitudinally monitored in vivo and islet morphology and turnover assessed by immunofluorescence. Isolated islet experiments in vitro were performed to delineate changes in beta cell function and transcriptional regulation of cell proliferation.
  
  
  RESULTS
  Adult Bmal1 deletion in beta cells resulted in failed metabolic adaptation to HFD characterised by fasting and diurnal hyperglycaemia, glucose intolerance and loss of glucose-stimulated insulin secretion. Importantly, HFD-induced beta cell expansion was absent following beta cell Bmal1 deletion indicating impaired beta cell proliferative and regenerative potential, which was confirmed by assessment of transcriptional profiles in isolated islets.
  
  
  CONCLUSIONS
  Results of the study suggest that the beta cell circadian clock is a novel regulator of compensatory beta cell expansion and function in response to increased insulin demand associated with diet-induced obesity.
authors.affiliation: Department of Physiology and Biomedical Engineering, Mayo Clinic School of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.|Department of Medicine, Division of Endocrinology, University of California Los Angeles, David Geffen School of Medicine, Los Angeles, CA, USA.
authors.forename: Kuntol
authors.initials: K
authors.lastname: Rakshit
authors.affiliation: Department of Medicine, Division of Endocrinology, University of California Los Angeles, David Geffen School of Medicine, Los Angeles, CA, USA.
authors.forename: Tu Wen
authors.initials: TW
authors.lastname: Hsu
authors.affiliation: Department of Physiology and Biomedical Engineering, Mayo Clinic School of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. Matveyenko.Aleksey@mayo.edu.|Department of Medicine, Division of Endocrinology, University of California Los Angeles, David Geffen School of Medicine, Los Angeles, CA, USA. Matveyenko.Aleksey@mayo.edu.
authors.forename: Aleksey V
authors.initials: AV
authors.lastname: Matveyenko
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D002940:Circadian Rhythm / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D005260:Female; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D009765:Obesity / Q000209:etiology / Q000378:metabolism*
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D056926:CLOCK Proteins
keywords: BMAL1; Beta cell; Beta cell expansion; Beta cell failure; Circadian clock; Clock genes; High fat diet