Multi-Modal Regulation of Circadian Physiology by Interactive Features of Biological Clocks

Abstract

The circadian clock is a fundamental biological timing mechanism that generates nearly 24 h rhythms of physiology and behaviors, including sleep/wake cycles, hormone secretion, and metabolism. Evolutionarily, the endogenous clock is thought to confer living organisms, including humans, with survival benefits by adapting internal rhythms to the day and night cycles of the local environment. Mirroring the evolutionary fitness bestowed by the circadian clock, daily mismatches between the internal body clock and environmental cycles, such as irregular work (e.g., night shift work) and life schedules (e.g., jet lag, mistimed eating), have been recognized to increase the risk of cardiac, metabolic, and neurological diseases. Moreover, increasing numbers of studies with cellular and animal models have detected the presence of functional circadian oscillators at multiple levels, ranging from individual neurons and fibroblasts to brain and peripheral organs. These oscillators are tightly coupled to timely modulate cellular and bodily responses to physiological and metabolic cues. In this review, we will discuss the roles of central and peripheral clocks in physiology and diseases, highlighting the dynamic regulatory interactions between circadian timing systems and multiple metabolic factors.

Circadian Rhythm Sleep-Wake Disorders

“…Cellular and bodily rhythms are highly influenced by physiologic and metabolic stimuli such as diet, exercise, metabolites, gut microbial products, ions, and gaseous molecules (which has been demonstrated in cellular and animal models). Functional circadian oscillators act as a multimodal mechanism that includes individual neurons and fibroblasts of the brain and peripheral organs 6 . Physiologic and metabolic cues, such as proteins and metabolites, prompt a timely response from these oscillators.…”

“…These cues may have different oscillations in individual tissues, but they can be reprogrammed. The external stimuli that allow for reprogramming include sleep deprivation, aging, the timing of food, and a high-fat diet ( figure 8-4 6 ).…”

“…Food intake in the circadian evening or night is associated with a greater amount of body fat, obesity, and decreased effectiveness of weight loss treatments for adults and children 3 . Intestinal microbiota depletion can disrupt peripheral clocks, with subsequent alterations in corticosteroid levels that can contribute to metabolic disorders 6 …”

Homo sapiens May Incorporate Daily Acute Cycles of “Conditioning–Deconditioning” to Maintain Musculoskeletal Integrity: Need to Integrate with Biological Clocks and Circadian Rhythm Mediators

“…Additional studies with such rats may provide further insights into factors regulating the integrity of the biological clocks, exercise-dependent mediators and responsiveness to such obesity-inducing diets. As disruption of circadian rhythms and biological clock integrity by shift work can influence health at multiple levels [ 120 , 121 ], such studies could have an impact at multiple levels.…”

Circadian modulation by time-restricted feeding restores brain transcription and slows amyloid deposition in a mouse model of Alzheimer’s disease

“…The mechanisms through which TRF conveys the observed benefits have not been fully elucidated and are likely pleiotropic. The alterations brought about by TRF may result from changes in metabolite interactions, bioenergetic pathway responses, modulation of circadian rhythm timing and strength, epigenetic modifications, and effects on food-anticipatory activity and reward circuits [22][23][24][25][26][27][28] .…”