Circadian metabolism in the light of evolution

Abstract

Circadian rhythm, or daily oscillation, of behaviors and biological processes is a fundamental feature of mammalian physiology that has developed over hundreds of thousands of years under the continuous evolutionary pressure of energy conservation and efficiency. Evolution has fine-tuned the body's clock to anticipate and respond to numerous environmental cues in order to maintain homeostatic balance and promote survival. However, we now live in a society in which these classic circadian entrainment stimuli have been dramatically altered from the conditions under which the clock machinery was originally set. A bombardment of artificial lighting, heating, and cooling systems that maintain constant ambient temperature; sedentary lifestyle; and the availability of inexpensive, high-calorie foods has threatened even the most powerful and ancient circadian programming mechanisms. Such environmental changes have contributed to the recent staggering elevation in lifestyle-influenced pathologies, including cancer, cardiovascular disease, depression, obesity, and diabetes. This review scrutinizes the role of the body's internal clocks in the hard-wiring of circadian networks that have evolved to achieve energetic balance and adaptability, and it discusses potential therapeutic strategies to reset clock metabolic control to modern time for the benefit of human health.

Figure 1.

Interplay between the cell-autonomous clock and metabolism. The core biological clock, present in every cell in the body, consists of an autoregulatory transcriptional feedback loop. The activating arm (highlighted in green) is comprised of the transcriptional regulators BMAL1 and CLOCK, which heterodimerize and induce the expression of the inhibitory arm (highlighted in red). The inhibitory arm contains Rev-erb, CRY, and PER factors. Rev-erb acts to suppress transcription of Bmal1, whereas CRY and PER directly inhibit the activating function of BMAL1/CLOCK heterodimer complexes. Members of both activating and inhibitory arms of the clock coordinate metabolic programming through the transcriptional control of clock-controlled genes (CCG) involved in a wide array of bioenergetic networks. The metabolic output resulting from this regulation feeds back on individual clock components, linking the energetic fitness of the cell with circadian functionality. Various nodes in this sustained molecular loop are subject to further control by intracellular oscillations of key metabolites, including heme, NAD⁺, and AMP.

Figure 2.

Impact of modern environments on evolutionarily programmed circadian functions. Sunlight, temperature, physical activity, and food intake serve as basic entraining cues, or zeitgebers, that coordinate tissue-specific circadian processes to cumulatively define whole organismal physiology. Among these zeitgebers, light is the chief synchronization cue and acts to reset the master clock (A) in the hypothalamic SCN each day, which then relays signaling to peripheral tissues. Evolutionarily fine-tuned, tissue-specific circadian processes discussed in this review are depicted, including: B, heat production by brown adipose; C, energy storage by white adipose; D, fuel source management between carbohydrate and lipid substrates in the liver; E, distribution or circulation of blood-borne factors, hormones, and metabolites by the heart; F, control of blood glucose levels by the pancreas; G, capacity for movement and activity by skeletal muscle; and H, food processing and nutrient extraction by the gut microbiome. A combination of light pollution from artificial light sources, sedentary lifestyles largely lacking physical activity, continuous access to high-calorie foods, and living conditions maintained at constant ambient temperature have all contributed to the disruption of circadian fitness.