Interplay between diet, exercise and the molecular circadian clock in orchestrating metabolic adaptations of adipose tissue

Abstract

Disruption of circadian rhythmicity induced by prolonged light exposure, altered sleep patterns and shift work is associated with the development of obesity and related metabolic disorders, including type 2 diabetes and cardiovascular diseases. White and brown adipose tissue activity shows circadian rhythmicity, with daily variations in the regulation of metabolic processes such as lipolysis, glucose and lipid uptake, and adipokine secretion. The role of the circadian clock in the regulation of energy homeostasis has raised interest in clock-related strategies to mitigate metabolic disturbances associated with type 2 diabetes, including 'resynchronizing' metabolism through diet or targeting a particular time of a day to potentiate the effect of a pharmacological or physiological treatment. Exercise is an effective intervention to prevent insulin resistance and type 2 diabetes. Beyond its effect on skeletal muscle, exercise training also has a profound effect on adipose tissue. Adipose tissue partly mediates the beneficial effect of exercise on glucose and energy homeostasis, via its metabolic and endocrine function. The interaction between zeitgeber time and diet or exercise is likely to influence the metabolic response of adipose tissue and therefore impact the whole-body phenotype. Understanding the impact of circadian clock systems on human physiology and how this is regulated by exercise in a tissue-specific manner will yield new insights for the management of metabolic disorders.

Keywords: Adipokine; Adipose tissue; Circadian Rhythm; Energy Homeostasis; Exercise; Nutrition; Type 2 Diabetes.

Figure 1

Circadian regulation of metabolic and endocrine function of adipose tissue and the contribution to glucose and lipid oscillations in plasma White adipocyte tissue lipolysis and lipid storage undergo diurnal oscillations. Adipokines such as adiponectin and leptin are released into circulation in a circadian pattern and peak at different times of the day. Brown adipose tissue displays a circadian rhythm of glucose and fatty acid uptake, with higher thermogenesis activity in the active phase. On the molecular level, the intrinsic clock influences adipocyte function via direct regulation of the expression of several genes, including the lipolytic enzymes ATGL and HSL, the fat storage factor PPARγ and the thermogenic protein UCP1. This schematic representation is mainly derived from experimental evidence from mouse models and therefore it requires additional corroboration in humans. The peak in leptin level in humans is identified by the red triangle.

Figure 2

Exercise adaptation of adipose tissue and regulation by circadian factors Evidence in mouse models and humans suggests that adipose tissue responds to exercise training by metabolic and genomic remodelling. Acute exercise induces lipolysis and inflammation. Exercise training leads to a profound remodelling of the metabolic and endocrine profile of adipose tissue. Skeletal muscle and adipose tissue communicate during exercise and play a role in adaptation to exercise training. Several physiological and metabolic processes are regulated in a circadian pattern, in response to hormonal, neuronal or feeding patterns or the molecular clock machinery. Changes in the molecular clock function can influence adipose tissue physiology, which in turn could potentiate the adaptive response to exercise. ^*Evidence from mouse models. PGC‐1α, peroxisome proliferator‐activated receptor γ coactivator 1α.