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.
Highlights
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
To assess the impact of diet-induced obesity (DIO) on behavioural and physiological rhythms, adult male C57BL/6J mice were maintained on normal chow (NC) or high fat diet (HFD) (60% energy from fat) for 16wk, leading to pronounced weight gain and white adipose tissue (WAT) accumulation (Supplementary Fig. S1)
The impact of HFD feeding on circadian rhythms in behaviour, as well as clock gene expression in central and peripheral tissues has been examined in a number of studies (e.g.5,25–32)
Summary
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. 24 hour rhythms are evident in virtually all aspects of our physiology including sleep/wake cycles, feeding behaviour, metabolism, and immune response[1] In mammals, these rhythms are orchestrated by a master circadian clock housed within the suprachiasmatic nuclei (SCN) of the hypothalamus, and a coordinated network of semi-autonomous clocks operating throughout the brain and peripheral tissues of the body. Our current studies highlight a highly tissue- and gene-specific impact of HFD-feeding on the molecular clockwork, and show that pharmacological targeting of CK1δ/ɛ improves glucose tolerance in diet-induced and genetic models of obesity
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