Interplay of peripheral clock genes with energy balance and nutrients: Role of hormonal pathways

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Circadian clocks are endogenous oscillators, present in the hypothalamus as well as in peripheral tissues that regulate daily rhythms in physiology, metabolism and behavior. The fundamental mechanism of circadian clocks is cell-autonomous: clock genes and proteins form regulatory networks that generate rhythms on the molecular level. Their deletion not only leads to clock dysfunction but also to obesity and metabolic dysfunction. Clock genes modulate endocrine rhythms, body weight and temperature, fat metabolism and fat cell differentiation, xenobiotic metabolism, amongst other processes. On the other hand, metabolic cues - such as meal timing particularly under conditions of energy restriction – themselves regulate clock gene expression in adipose tissue, liver and intestine. We recently identified the incretin GIP as a novel cue modulating clock gene expression in humans. Our subproject’s aim is to correlate clock gene expression and function to hormonal and metabolic regulation in humans, animal models and tissue culture cells. Since clock gene expression is substantially altered by caloric restriction in animals, we particularly focus on conditions of energy restriction and subsequent weight maintenance/regain in the Z project. In addition, we will test meal timing for effects on human clock gene expression in PBMCs and adipose tissue. In animal models we will characterize (i) the specific role of GIP on food entrained circadian rhythms using GIP treatment and GIP-receptor deficient mice and (ii) the effect of diet-induced obesity on circadian clock properties in relevant peripheral tissues. Moreover we will characterize clock gene regulation by incretins and appetite regulating hormones in adipocyte tissue culture cells using a circadian luciferase reporter system as well as gene expression studies. Our experiments will show whether clock gene expression/function is correlated with and altered by caloric restriction and involved in the counter-regulation of weight regain. We will attempt to identify hormonal cues involved and develop strategies for weight maintenance based on the regulation of clock genes.