title: High-fat diet-induced hyperinsulinemia and tissue-specific insulin resistance in Cry-deficient mice.
abstract: Perturbation of circadian rhythmicity in mammals, either by environmental influences such as shiftwork or by genetic manipulation, has been associated with metabolic disturbance and the development of obesity and diabetes. Circadian clocks are based on transcriptional/translational feedback loops, comprising positive and negative components. Whereas the metabolic effects of deletion of the positive arm of the clock gene machinery, as in Clock- or Bmal1-deficient mice, have been well characterized, inactivation of Period genes (Per1-3) as components of the negative arm have more complex, sometimes contradictory effects on energy homeostasis. The CRYPTOCHROMEs are critical interaction partners of PERs, and simultaneous deletion of Cry1 and -2 results in behavioral and molecular circadian arrhythmicity. We show that, when challenged with a high-fat diet, Cry1/2(-/-) mice rapidly gain weight and surpass that of wild-type mice, despite displaying hypophagia. Transcript analysis of white adipose tissue reveals upregulated expression of lipogenic genes, many of which are insulin targets. High-fat diet-induced hyperinsulinemia, as a result of potentiated insulin secretion, coupled with selective insulin sensitivity in adipose tissue of Cry1/2(-/-) mice, correlates with increased lipid uptake. Collectively, these data indicate that Cry deficiency results in an increased vulnerability to high-fat diet-induced obesity that might be mediated by increased insulin secretion and lipid storage in adipose tissues.
authors.affiliation: Circadian Rhythms Group, Max Planck Institute of Biophysical Chemistry, Göttingen, Germany.
authors.forename: Johanna L
authors.initials: JL
authors.lastname: Barclay
authors.forename: Anton
authors.initials: A
authors.lastname: Shostak
authors.forename: Alexei
authors.initials: A
authors.lastname: Leliavski
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Tsang
authors.forename: Olaf
authors.initials: O
authors.lastname: Jöhren
authors.forename: Helge
authors.initials: H
authors.lastname: Müller-Fielitz
authors.forename: Dominic
authors.initials: D
authors.lastname: Landgraf
authors.forename: Nadine
authors.initials: N
authors.lastname: Naujokat
authors.forename: Gijsbertus T J
authors.initials: GT
authors.lastname: van der Horst
authors.forename: Henrik
authors.initials: H
authors.lastname: Oster
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002153:Calorimetry, Indirect / Q000379:methods; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D056931:Cryptochromes / Q000235:genetics / Q000502:physiology*; D059305:Diet, High-Fat; D006651:Histocytochemistry; D006946:Hyperinsulinism / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015854:Up-Regulation / Q000502:physiology
chemical_list: D001786:Blood Glucose; C538964:Cry1 protein, mouse; C538967:Cry2 protein, mouse; D056931:Cryptochromes; D007328:Insulin; D012333:RNA, Messenger
keywords: circadian clock; cryptochrome; diet-induced obesity; insulin; lipid uptake