title: Targeting of the circadian clock via CK1δ/ε to improve glucose homeostasis in obesity.
abstract: Growing evidence indicates that disruption of our internal timing system contributes to the incidence and severity of metabolic diseases, including obesity and type 2 diabetes. This is perhaps not surprising since components of the circadian clockwork are tightly coupled to metabolic processes across the body. In the current study, we assessed the impact of obesity on the circadian system in mice at a behavioural and molecular level, and determined whether pharmacological targeting of casein kinase 1δ and ε (CK1δ/ε), key regulators of the circadian clock, can confer metabolic benefit. We demonstrate that although behavioural rhythmicity was maintained in diet-induced obesity (DIO), gene expression profiling revealed tissue-specific alteration to the phase and amplitude of the molecular clockwork. Clock function was most significantly attenuated in visceral white adipose tissue (WAT) of DIO mice, and was coincident with elevated tissue inflammation, and dysregulation of clock-coupled metabolic regulators PPARα/γ. Further, we show that daily administration of a CK1δ/ε inhibitor (PF-5006739) improved glucose tolerance in both DIO and genetic (ob/ob) models of obesity. These data further implicate circadian clock disruption in obesity and associated metabolic disturbance, and suggest that targeting of the clock represents a therapeutic avenue for the treatment of metabolic disorders.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Cunningham
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors.forename: Siobhán A
authors.initials: SA
authors.lastname: Ahern
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Smith
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors.forename: Carla S
authors.initials: CS
authors.lastname: da Silva Santos
authors.affiliation: Pfizer Worldwide Research and Development, Cambridge, MA, USA.
authors.forename: Travis T
authors.initials: TT
authors.lastname: Wager
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Bechtold
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001522:Behavior, Animal; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D048149:Casein Kinase 1 epsilon / Q000378:metabolism*; D048148:Casein Kinase Idelta / Q000378:metabolism*; D057906:Circadian Clocks / Q000235:genetics; D002940:Circadian Rhythm; D059305:Diet, High-Fat; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D006066:Gonads / Q000378:metabolism; D006706:Homeostasis; D007031:Hypothalamus / Q000378:metabolism; D007249:Inflammation / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism*; D009928:Organ Specificity / Q000235:genetics; D047493:PPAR alpha / Q000378:metabolism
chemical_list: D047493:PPAR alpha; D056926:CLOCK Proteins; D048149:Casein Kinase 1 epsilon; D048148:Casein Kinase Idelta; D005947:Glucose