Circadian and Metabolic Effects of Light: Implications in Weight Homeostasis and Health

Abstract

Daily interactions between the hypothalamic circadian clock at the suprachiasmatic nucleus (SCN) and peripheral circadian oscillators regulate physiology and metabolism to set temporal variations in homeostatic regulation. Phase coherence of these circadian oscillators is achieved by the entrainment of the SCN to the environmental 24-h light:dark (LD) cycle, coupled through downstream neural, neuroendocrine, and autonomic outputs. The SCN coordinate activity and feeding rhythms, thus setting the timing of food intake, energy expenditure, thermogenesis, and active and basal metabolism. In this work, we will discuss evidences exploring the impact of different photic entrainment conditions on energy metabolism. The steady-state interaction between the LD cycle and the SCN is essential for health and wellbeing, as its chronic misalignment disrupts the circadian organization at different levels. For instance, in nocturnal rodents, non-24 h protocols (i.e., LD cycles of different durations, or chronic jet-lag simulations) might generate forced desynchronization of oscillators from the behavioral to the metabolic level. Even seemingly subtle photic manipulations, as the exposure to a "dim light" scotophase, might lead to similar alterations. The daily amount of light integrated by the clock (i.e., the photophase duration) strongly regulates energy metabolism in photoperiodic species. Removing LD cycles under either constant light or darkness, which are routine protocols in chronobiology, can also affect metabolism, and the same happens with disrupted LD cycles (like shiftwork of jetlag) and artificial light at night in humans. A profound knowledge of the photic and metabolic inputs to the clock, as well as its endocrine and autonomic outputs to peripheral oscillators driving energy metabolism, will help us to understand and alleviate circadian health alterations including cardiometabolic diseases, diabetes, and obesity.

Keywords: desynchronization; metabolism; obesity; photic entrainment; suprachiasmatic nucleus.

Figure 1

Circadian rhythms are driven by a vast network of oscillators regulated by multiple interconnected feedback loops that, in turn, synchronize the entire organism. Here, we show a simplified system with three interconnected components: the hypothalamus, brain stem/spinal cord, and the periphery (including behavioral rhythms as feeding/fasting and activity/rest). In the hypothalamus, the suprachiasmatic nucleus (SCN) sends synchronizing signals to different hypothalamic areas such as the medial preoptic (MPO), paraventricular (PVN), dorsomedial (DMH), and the arcuate (ARC) nuclei. All these are interconnected and send feedback information to the SCN. In addition, PVN efferences connect to two main endocrine outputs: (1) a polysynaptic pathway relaying in the superior cervical ganglion (SCG) which controls the production and release of melatonin from the pineal gland via its sympathetic innervation and (2) the secretion of corticotrophin-releasing hormone, acting on the pituitary for the release of adrenocorticotropic hormone (HPA axis) and controlling adrenal glucocorticoids (corticosterone in rodents). The SCN exert a circadian control on PVN outputs for most autonomic nervous system (ANS) functions, driven at the brain stem/medulla through parasympathetic motoneurons in the vagal dorsal motor nucleus (DMV), and by sympathetic motoneurons in the intermediolateral column (IML). The nucleus tractus solitarius (NTS) acts as an integrative center for signals coming from the hypothalamus, peripheral ANS reflexes transmitted to the DMN and the IML, and feedback to the hypothalamus (not shown). Blood-borne factors like glucose, feeding/fasting regulatory hormones and, factors derived from physical exercise, can modulate circadian rhythms at peripheral organs, as well as regulate the ANS feedback to the hypothalamus.

Figure 2

Schematic changes found in mice and rats chronically exposed to different lighting protocols which might induce circadian and metabolic alterations. Actograms double plotted at modulo 24 h show alterations in the behavioral activity rhythm. Compared to standard light:dark (LD) conditions: (1) LD_LAN (light at night) promotes a dispersed rhythm increasing both general and feeding activity bouts at the light phase, together with reduced suprachiasmatic nucleus (SCN) and liver clock-genes amplitude; (2) LL generates behavioral arrhythmicity with loss of the feeding/fasting rhythm, also with dampened amplitude of SCN and liver clock-genes rhythms; (3) forced desynchrony protocols (i.e., chronic jetlag—CJL—and T cycles) generate two activity components at the behavioral and SCN clock-gene (regional) levels, with disrupted daily feeding/fasting rhythms, and with liver clock genes out of phase. Dampened melatonin rhythms occur both under LL and LD_LAN, while this rhythm is out of phase under forced desynchronization. All lighting protocols promote a decrease in the insulin sensitivity rhythm, and an increased weight gain respect to LD.

Figure 3

The figure schematizes how nocturnal light exposure, together with a misaligned feeding pattern with respect to the regular activity/rest rhythm, generate metabolic disruptions in nocturnal rodents and human subjects. Humans under nightwork schedules tend to invert by 180° their activity/rest rhythm, increasing nocturnal feeding and light exposure during the night. When receiving light at night, nocturnal rodents alter their feeding pattern increasing episodes throughout the day. These changes desynchronize pancreatic and liver circadian functions regulating nutrient balance and caloric usage/storage, mainly by reducing postprandial glucose tolerance, and decreasing glucose usage. As main outcomes of these alterations, increased basal glycemia, free fatty acids, and adipose tissue are generally observed. When chronically established, this misalignment between the circadian clock activity, its photic inputs, and behavioral/physiological/metabolic outputs can lead to metabolic syndrome and obesity.