title: Circadian disruption leads to insulin resistance and obesity.
abstract: BACKGROUND
  Disruption of circadian (daily) timekeeping enhances the risk of metabolic syndrome, obesity, and type 2 diabetes. While clinical observations have suggested that insulin action is not constant throughout the 24 hr cycle, its magnitude and periodicity have not been assessed. Moreover, when circadian rhythmicity is absent or severely disrupted, it is not known whether insulin action will lock to the peak, nadir, or mean of the normal periodicity of insulin action.
  
  
  RESULTS
  We used hyperinsulinemic-euglycemic clamps to show a bona fide circadian rhythm of insulin action; mice are most resistant to insulin during their daily phase of relative inactivity. Moreover, clock-disrupted Bmal1-knockout mice are locked into the trough of insulin action and lack rhythmicity in insulin action and activity patterns. When rhythmicity is rescued in the Bmal1-knockout mice by expression of the paralogous gene Bmal2, insulin action and activity patterns are restored. When challenged with a high-fat diet, arhythmic mice (either Bmal1-knockout mice or wild-type mice made arhythmic by exposure to constant light) were obese prone. Adipose tissue explants obtained from high-fat-fed mice have their own periodicity that was longer than animals on a chow diet.
  
  
  CONCLUSIONS
  This study provides rigorous documentation for a circadian rhythm of insulin action and demonstrates that disturbing the natural rhythmicity of insulin action will disrupt the rhythmic internal environment of insulin sensitive tissue, thereby predisposing the animals to insulin resistance and obesity.
authors: Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235, USA.
authors: Shu-qun
authors: SQ
authors: Shi
authors: Tasneem S
authors: TS
authors: Ansari
authors: Owen P
authors: OP
authors: McGuinness
authors: David H
authors: DH
authors: Wasserman
authors: Carl Hirschie
authors: CH
authors: Johnson
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002940:Circadian Rhythm; D059305:Diet, High-Fat / Q000009:adverse effects; D015309:Glucose Clamp Technique; D007328:Insulin / Q000097:blood*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology*
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; C431792:Arntl2 protein, mouse; D007328:Insulin