Circadian clocks are important regulators of physiology and behavior. In the brain, circadian clocks have been described in many centers of the central reward system. They affect neurotransmitter signaling, neuroendocrine circuits, and the sensitivity to external stimulation. Circadian disruption affects reward signaling, promoting the development of behavioral and substance use disorders. In this review, we summarize our current knowledge of circadian clock-reward crosstalk. We show how chronodisruption affects reward signaling in different animal models. We then translate these findings to circadian aspects of human reward (dys-) function and its clinical implications. Finally, we devise approaches to and challenges in implementing the concepts of circadian medicine in the therapy of substance use disorders.

Physiological processes, including metabolism and immune responses, are generated by the circadian clock, driven by clock genes. Disrupting circadian rhythms through a high-fat diet promotes obesity and inflammation. Studies show that deleting the clock gene, brain, and muscle ARNT-like 1 (Bmal1) in adipose tissue leads to overeating and weight gain. We now show that Bmal1 deletion in neutrophils protects against diet-induced obesity and reduces inflammatory macrophage infiltration into epididymal white adipose tissue (eWAT), despite increased food intake over 20 weeks of a high-fat diet. This protection is linked to enhanced energy expenditure, increased UCP1 expression in iBAT, improved insulin sensitivity, and altered expression of genes encoding chemokine receptors CXCR2, CXCR4, and the ligand Cxcl2 in eWAT. Our findings reveal a key role of Bmal1 in neutrophils in regulating high-fat diet-induced adipose inflammation and emphasize circadian regulation's importance in immuno-metabolic function.

Objective: The circadian clock anticipates daily repetitive events to adapt physiological processes. In mammals, the circadian system consists of a master clock in the suprachiasmatic nucleus (SCN), which synchronizes subordinate tissue clocks, including extra-SCN central nervous system (CNS) clocks involved in functions such as sleep and appetite regulation. Appetite is controlled by both homeostatic and non-homeostatic (hedonic) circuits. Homeostatic appetite addresses energy needs, while hedonic feeding targets cravings for palatable, calorie-dense foods. The adipokine leptin is a major appetite regulator, interacting with the circadian clock. Although leptin's role in satiation through its action in the mediobasal hypothalamus (MBH) is well established, its involvement in the circadian regulation of feeding remains poorly understood. We hypothesized that circadian gating of leptin signaling in the CNS controls homeostatic and hedonic appetite across the day.

Methods: We analyzed food intake rhythms in mice with a loss of leptin (ob/ob mice) or clock function (Per1/2 or Bmal1 KO) and in mice with specific disruption of leptin circadian gating in the CNS (ObRb.Bmal1).

Results: We found that in leptin-deficient mice hedonic appetite increases specifically in the early rest phase. In contrast, clock-deficient Per1/2 mutant mice exhibit blunted rhythms in both hedonic and homeostatic appetite control. Finally, when clock function is disrupted in leptin-sensitive neurons only, mice display a lower sensitivity to palatable food, along with reduced initial weight gain and adipose hypertrophy under obesogenic diet conditions.

Conclusions: Our data describe a local clock-controlled central leptin gating mechanism that modulates hedonic food intake rhythms and impacts metabolic homeostasis.

Multiple sclerosis (MS) is an autoimmune inflammatory and neurodegenerative disease of the central nervous system (CNS) with increasing incidence and prevalence. MS is associated with inflammatory and metabolic disturbances that, as preliminary human and animal data suggest, might be mediated by disruption of circadian rhythmicity. Nutrition habits can influence the risk for MS, and dietary interventions may be effective in modulating MS disease course. Chronotherapeutic approaches such as time-restricted eating (TRE) may benefit people with MS by stabilizing the circadian clock and restoring immunological and metabolic rhythms, thus potentially counteracting disease progression. This review provides a summary of selected studies on dietary intervention in MS, circadian rhythms, and their disruption in MS, including clock gene variations, circadian hormones, and retino-hypothalamic tract changes. Furthermore, we present studies that reported diurnal variations in MS, which might result from circadian disruption. And lastly, we suggest how chrononutritive approaches like TRE might counteract MS disease activity.

Time-restricted eating (TRE) is a promising strategy to improve metabolic outcomes. However, it remains unclear whether TRE has cardiometabolic benefits in an isocaloric setting and whether its effects depend on the eating timing. We conducted a randomized crossover trial in 31 women with overweight or obesity to directly compare the effects of a 2-week early TRE (eTRE; eating from 8:00 to 16:00) and a 2-week late TRE (lTRE; eating from 13:00 to 21:00) on insulin sensitivity, cardiometabolic risk factors, and the internal circadian phase. During the restricted 8-hour eating period, participants were asked to consume their habitual food quality and quantity. Insulin sensitivity did not differ between (-0.07; 95% CI, -0.77 to 0.62; P = 0.60) or within (eTRE: 0.31; 95% CI, -0.14 to 0.76; P = 0.11; lTRE: 0.19; 95% CI, -0.22 to 0.60; P = 0.25) interventions. Twenty-four-hour glucose, lipid, inflammatory, and oxidative stress markers showed no clinically meaningful between- or within-intervention differences. Participants demonstrated high timely adherence (eTRE, 96.5%; lTRE, 97.7%), unchanged dietary composition and physical activity, minor daily calorie deficit (eTRE, -167 kilocalories/day), and weight loss (eTRE, -1.08 kilograms; lTRE, -0.44 kilograms). In lTRE, the circadian phase in blood monocytes (24 minutes; 95% CI, -5 to 54 minutes; P = 0.10) and sleep midpoint (15 minutes; 95% CI, 7 to 23 minutes; P< 0.001) occurred later compared with eTRE. Overall, in an intended isocaloric setting, neither eTRE nor lTRE improves insulin sensitivity or other cardiometabolic traits, despite a shift of internal circadian clocks.

Caloric restriction prolongs lifespan and preserves health across species, with feeding times synchronized to day–night cycles further maximizing benefits. However, the mechanisms linking diet, diurnal rhythms, and lifespan remain unclear. In mice, the time point most strongly tied to dietary effects on lifespan coincides with the peak of glucocorticoid secretion (ZT12, lights-off). Caloric restriction raises circulating glucocorticoid hormone levels, implicating these signals as candidate mediators for its benefits. Here we show that in the liver, the glucocorticoid receptor (GR) is required for the metabolic response to caloric restriction. Hepatocyte-specific GR mutant males fail to mount this response, indicating that increased glucocorticoid amplitude is necessary for the adaptation. Using multiomics, we find that nutrient deprivation elicits a nuclear switch from active STAT signaling to increased FOXO1 activity, enabling GR to activate diet-specific gene expression programs. Our results suggest that glucocorticoid rhythms are crucial for caloric restriction-induced metabolic reprogramming.