Circadian regulation of glucose, lipid, and energy metabolism in humans
Introduction
The circadian system organizes metabolism, physiology, and behavior in a daily cycle of circadian rhythms. Circadian derives from the Latin roots circa meaning around and diēm meaning day, and like all daily or diurnal rhythms, circadian rhythms are periodic patterns that repeat themselves approximately every 24 h. However, unlike diurnal rhythms, circadian rhythms are generated endogenously within the organism and perpetuate themselves even in the absence of external time cues (Fig. 1). Such circadian rhythms have evolved over hundreds of millions of years to orchestrate metabolism by temporally separating opposing metabolic processes (such as anabolism and catabolism) and by anticipating recurring feeding-fasting cycles to optimize metabolic efficiency [1], [2], [3].
The circadian system comprises a central pacemaker in the brain and a series of clocks in peripheral tissues throughout the body, including liver, muscle, and adipose tissue. This system of clocks collectively modulates a wide array of metabolic targets, such as glucocorticoids [4], the master energy sensor AMPK [5], rate-limiting steps in fatty acid and cholesterol synthesis [6], [7], and hepatic CREB to modulate gluconeogenesis [8]. The aggregate effect is that an array of metabolic processes—including insulin sensitivity, insulin secretion, cholesterol synthesis, fat oxidation, and energy expenditure—all follow a rhythm across the 24-hour day [2], [3], [9].
In addition to evidence of circadian rhythms in metabolism, data increasingly suggest that disruption of the circadian system increases the risk of metabolic diseases [9], [10], [11], [12]. In rodent studies, clock gene mutants often display obese or diabetic phenotypes and possess defects in core metabolic pathways such as insulin secretion and gluconeogenesis [3], [13], [14], [15], [16], [17]. Moreover, misalignment of circadian rhythms in rodents often makes them hyperphagic, insulin resistant, and hyperlipidemic [9], [10], [11], [12]. In human trials, circadian misalignment similarly elevates glucose, insulin, and triglyceride levels [18], [19], [20] and lowers energy expenditure [21]. Therefore, understanding these rhythms is important for timing when to eat, sleep, be exposed to bright light, be physically active, and even when to take medications to reduce the risk of metabolic diseases [22], [23], [24].
While there is ample mechanistic data in animal models demonstrating the wide-sweeping role of the circadian system in metabolism, there are comparatively fewer trials in humans. Given that rodents differ in several key ways from humans—such as being nocturnal, polyphasic (sleeping more than once per day), and having high metabolic rates per body weight—it is unclear how, and to what degree, circadian and diurnal research in rodents translates into humans. In this review, we synthesize evidence for circadian regulation of metabolism in humans. In Section 2, we provide an overview of the architecture of the circadian system and protocols for measuring circadian rhythms in humans. In Section 3, we summarize the evidence for circadian and diurnal rhythms in glucose, lipid, and energy metabolism in humans. In Section 4, we conclude by discussing how circadian alignment or misalignment with three external factors—light, sleep, and food intake—affects metabolism and the risk of metabolic diseases.
Section snippets
Architecture of the Circadian System
The circadian system consists of two parts: (1) a central clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus and (2) a series of peripheral clocks located in virtually all other tissues of the body, including the liver, pancreas, gastrointestinal tract, skeletal muscle, and adipose tissue (Fig. 2). The central clock is thought to regulate metabolism through diffusible factors (primarily cortisol and melatonin) and synaptic projections (including via the autonomic nervous
Diurnal Studies
The first evidence for circadian regulation of glucose metabolism emerged in the late 1960’s and 1970’s when several studies reported diurnal variations in glucose tolerance [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47]. Since then, more than a dozen human studies have reported the existence of a diurnal rhythm in oral glucose tolerance, typically peaking in the morning, with impairments in glucose tolerance in the afternoon and evening [33], [34], [35]
Circadian Misalignment and Translational Implications
Diurnal rhythms in metabolism are driven not only by the circadian system but also by environmental and behavioral factors, including light, sleep, food intake, and physical activity. Increasing evidence suggests that when these external rhythms are out-of-sync with endogenous circadian rhythms—such as through exposure to bright light at night, sleeping during the daytime, or eating at night (Fig. 4)—several facets of metabolism are impaired. Here, we review evidence that circadian misalignment
Discussion
Although circadian regulation of metabolism is less well-characterized in humans than in rodents, there is clear evidence of circadian rhythms in multiple aspects of metabolism, including glucose, insulin, glucose tolerance, lipid levels, energy expenditure, and appetite. The rhythms in glucose metabolism appear to be driven by diurnal variations in multiple metabolic pathways, including peripheral insulin sensitivity, β-cell responsiveness, insulin clearance, and glucose effectiveness.
Author Contributions
EP and CMP conceived of and designed the review article. All authors performed the literature review; analyzed and interpreted the data; wrote multiple subsections of the manuscript; and revised the manuscript for intellectual content. All authors approved the final manuscript.
Role of the Funding Source
EP was supported by grant AR7/2016 from Sapienza University of Rome, Italy. CMP was supported by KL2TR001419 from the National Center for Advancing Translational Sciences of the National Institutes of Health. This content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding sources had no involvement in any aspect of the research.
Conflicts of Interest
None.
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