Bmal1 is required for beta cell compensatory expansion, survival and metabolic adaptation to diet-induced obesity in mice

Kuntol Rakshit, Tu Wen Hsu, Aleksey V Matveyenko

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Aims/hypothesis: 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 CreERT 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. Conclusion/interpretation: 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.

Original languageEnglish (US)
Pages (from-to)734-743
Number of pages10
JournalDiabetologia
Volume59
Issue number4
DOIs
StatePublished - Apr 1 2016

Fingerprint

Obesity
Diet
Circadian Clocks
High Fat Diet
Insulin Resistance
Insulin
Glucose
Type 2 Diabetes Mellitus
Glucose Intolerance
Tamoxifen
Hyperglycemia
Genetic Recombination
Fluorescent Antibody Technique
Fasting
Homeostasis
Transcription Factors
Maintenance
Cell Proliferation

Keywords

  • Beta cell
  • Beta cell expansion
  • Beta cell failure
  • BMAL1
  • Circadian clock
  • Clock genes
  • High fat diet

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

Cite this

Bmal1 is required for beta cell compensatory expansion, survival and metabolic adaptation to diet-induced obesity in mice. / Rakshit, Kuntol; Hsu, Tu Wen; Matveyenko, Aleksey V.

In: Diabetologia, Vol. 59, No. 4, 01.04.2016, p. 734-743.

Research output: Contribution to journalArticle

@article{0e16f0f6fe6a45d0aeb3392d68ac39bc,
title = "Bmal1 is required for beta cell compensatory expansion, survival and metabolic adaptation to diet-induced obesity in mice",
abstract = "Aims/hypothesis: 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 CreERT 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. Conclusion/interpretation: 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.",
keywords = "Beta cell, Beta cell expansion, Beta cell failure, BMAL1, Circadian clock, Clock genes, High fat diet",
author = "Kuntol Rakshit and Hsu, {Tu Wen} and Matveyenko, {Aleksey V}",
year = "2016",
month = "4",
day = "1",
doi = "10.1007/s00125-015-3859-2",
language = "English (US)",
volume = "59",
pages = "734--743",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Springer Verlag",
number = "4",

}

TY - JOUR

T1 - Bmal1 is required for beta cell compensatory expansion, survival and metabolic adaptation to diet-induced obesity in mice

AU - Rakshit, Kuntol

AU - Hsu, Tu Wen

AU - Matveyenko, Aleksey V

PY - 2016/4/1

Y1 - 2016/4/1

N2 - Aims/hypothesis: 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 CreERT 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. Conclusion/interpretation: 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.

AB - Aims/hypothesis: 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 CreERT 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. Conclusion/interpretation: 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.

KW - Beta cell

KW - Beta cell expansion

KW - Beta cell failure

KW - BMAL1

KW - Circadian clock

KW - Clock genes

KW - High fat diet

UR - http://www.scopus.com/inward/record.url?scp=84959479091&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84959479091&partnerID=8YFLogxK

U2 - 10.1007/s00125-015-3859-2

DO - 10.1007/s00125-015-3859-2

M3 - Article

C2 - 26762333

AN - SCOPUS:84959479091

VL - 59

SP - 734

EP - 743

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 4

ER -