Satiety Associated with Calorie Restriction and Time-Restricted Feeding: Central Neuroendocrine Integration

Abstract

This review focuses on summarizing current knowledge on how time-restricted feeding (TRF) and continuous caloric restriction (CR) affect central neuroendocrine systems involved in regulating satiety. Several interconnected regions of the hypothalamus, brainstem, and cortical areas of the brain are involved in the regulation of satiety. Following CR and TRF, the increase in hunger and reduction in satiety signals of the melanocortin system [neuropeptide Y (NPY), proopiomelanocortin (POMC), and agouti-related peptide (AgRP)] appear similar between CR and TRF protocols, as do the dopaminergic responses in the mesocorticolimbic circuit. However, ghrelin and leptin signaling via the melanocortin system appears to improve energy balance signals and reduce hyperphagia following TRF, which has not been reported in CR. In addition to satiety systems, CR and TRF also influence circadian rhythms. CR influences the suprachiasmatic nucleus (SCN) or the primary circadian clock as seen by increased clock gene expression. In contrast, TRF appears to affect both the SCN and the peripheral clocks, as seen by phasic changes in the non-SCN (potentially the elusive food entrainable oscillator) and metabolic clocks. The peripheral clocks are influenced by the primary circadian clock but are also entrained by food timing, sleep timing, and other lifestyle parameters, which can supersede the metabolic processes that are regulated by the primary circadian clock. Taken together, TRF influences hunger/satiety, energy balance systems, and circadian rhythms, suggesting a role for adherence to CR in the long run if implemented using the TRF approach. However, these suggestions are based on only a few studies, and future investigations that use standardized protocols for the evaluation of the effect of these diet patterns (time, duration, meal composition, sufficiently powered) are necessary to verify these preliminary observations.

Keywords: calorie restriction; circadian rhythms; hypothalamus; light-entrainable oscillator; peripheral oscillators; satiety; time-restricted feeding.

FIGURE 1

An integrated overview of the brain regions and peripheral hormones involved in hunger and satiety. Right box panels depict the interaction of peripheral gut hormones with specific brain regions. Several hunger (ghrelin and orexin) and satiety (leptin, insulin, GLP-1, amylin, PYY, CCK, GIP) peptide hormones cross the blood–brain barrier and elicit responses in the regions alluded via unique receptor activation. Left panel: Black arrows in the non-hypothalamic region indicate neural projection connections in the mesocorticolimbic system (which includes the VTA/SNPC, Amg, NAc, PVT, and prefrontal cortex), dark-red arrows depict the DVC, made up of DMNC and NTS, in the hypothalamus: the blue dotted line indicates connections between the LHA and extrahypothalamic areas, the blue dashed line indicates the connections from the PVN to extrahypothalamic areas; black lines indicate intrahypothalamic connections between nuclei; bidirectional arrows suggest neural projections going both directions. Created with Biorender.com, Toronto, Ontario. Amg, amygdala; ARC, arcuate nucleus; BNST, bed nuclei of stria terminalis; CCK, cholecystokinin; DaMH, dorsal medial hypothalamus; DMNV, dorsal motor nucleus of the vagus; DVC, dorsal vagal complex; GIP, gastrointestinal peptide; GLP-1, glucagon-like-peptide 1; LHA, lateral hypothalamus; NAc, nucleus accumbens; NTS, nucleus tractus solitarius; PBN, parabrachial nucleus; PP, pancreatic polypeptide; PVN, paraventricular nucleus; PVT, paraventricular thalamus; PYY, peptide YY; SCN, suprachiasmatic nucleus; VMH, ventral medial hypothalamus; VTA/SNPC, ventral tegmental area/substantia nigra pars compacta.

FIGURE 2

Effect of CR and TRF on peripheral and central clocks involved in hunger and satiety. Left: time restriction; right:—calorie restriction. An overview of mechanisms suggested to be involved in TRF and CR compared with ad libitum food consumption and their eventual effect on FAA and food choice (highly palatable foods, etc.). This depicts the integration of satiety and hunger signals (blue and green boxes originating from the gut) with the non-SCN and SCN clocks in the brain. During ad libitum feeding, the light-dark cycle entrains the light-entrainable oscillators in the SCN, while food cues and peripheral clocks are regulated and reset by the SCN-clock. Hunger systems may be less “stimulated” following TRF, in contrast to CR, while satiety systems are equally suppressed following both regimes. Following TRF, the food-entrainable and peripheral clocks become stronger, and induce resetting of the SCN-clock. In the case of CR, the SCN-clock resets the food-entrainable and peripheral clocks. Combined, the integrated mechanism suggests that the overall lack of increase in hunger and stronger regulation by peripheral metabolic and food-entrainable non-SCN clocks may mean that TRF could aid in adherence to specific food intake regimes such as CR. Different color arrows used to indicate entrainment (brown and red), feedback of peripheral satiety signals to the brain (blue and green), interactions between SCN, non-SCN, and peripheral clocks (black, light blue). Dashed arrows indicate a reduction in strength of physiological signal compared with no-CR or no-TRF. Created with Biorender.com. CR, calorie restriction; FAA, food anticipatory activity; GI, gastrointestinal; SCN, suprachiasmatic nucleus; TRF, time-restricted feeding.