Using place preference and diet choice experiments, we aim at distinguishing homeostatic from hedonic aspects of circadian appetite regulation. Since food intake is regulated via complex neuronal circuits involving several brain areas 2, 15, we hypothesize that homeostatic and hedonic aspects of appetite are regulated by spatially discrete CNS clocks, resulting in diet-dependent daily food intake patterns. ![]() While it is still a matter of debate whether the VTA harbors a functional circadian clock, basal neuronal activity and gene expression patterns in this area show daily oscillations 27, 28, 29, 30, 31, 32, 33, 34, 35. Further, optogenetic activation of VTA/NAc connections stimulates food reward-related behavior 24, 26. Intake of energy-dense, palatable food activates VTA/NAc connections promoting dopamine release 18, 22, 23 while low dopamine levels suppress the motivation to eat 24, 25. There is accumulating evidence that the VTA is a key structure in the regulation of hedonic behaviors. While MBH clocks have been implicated in the regulation of rhythmic homeostatic intake behavior, it is less clear how hedonic aspects of appetite are controlled across the day 19, 20, 21. In addition, central reward circuits, especially dopaminergic projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), affect the motivation to eat independent of homeostatic requirements 15, 16, 17, 18. Nuclei of the mediobasal hypothalamus (MBH) receive peripheral information about the energy state of the body to adjust food intake to homeostatic energetic requirements 2. The underlying mechanisms of how circadian disruption promotes metabolic abnormalities, however, are still poorly understood. Thus, consumption of energy-dense food impairs metabolic control in a two-fold way, promoting obesity and its comorbidities in mammals 3, 14. Accordingly, food intake during the rest phase leads to a state of internal circadian desynchrony promoting obesity, diabetes mellitus type 2 and other metabolic disorders in rodents 7, 8, 9 and humans 10, 11, 12, 13. Shifts in meal timing, however, can reset clocks of metabolically active tissues and uncouple them from the light-controlled SCN 5, 6. ![]() When food intake and environmental light conditions are aligned, a master circadian pacemaker located in the suprachiasmatic nucleus (SCN) synchronizes subordinated cellular clocks throughout the body to the environmental light/dark cycle 4. Besides increasing the risk of caloric overconsumption, ad libitum access to energy-dense food disrupts the regulation of endogenous circadian clocks 3 evolved to anticipate and adapt to daily recurring environmental changes induced by the rotation of the earth around its axis. This environment facilitates a behavioral trend toward a dissociation of caloric intake from energy demands, promoting obesity and related metabolic disorders 1, 2. Modern societies are exposed to an obesity-promoting environment, with virtually unlimited access to and choice of different palatable, high-caloric foods and beverages. These findings assign a functional role of VTA clocks in modulating palatable feeding behaviors and identify a potential therapeutic route to counteract hyperphagy in an obesogenic environment. Mice with disrupted clock function in the VTA lose their hedonic overconsumption rhythms without affecting homeostatic intake. ![]() This hedonic appetite rhythm is driven by endogenous circadian clocks in dopaminergic neurons of the ventral tegmental area (VTA). While homeostatic intake peaks in the active phase, conditioned place preference and choice experiments show an increased sensitivity to overeating on palatable food during the rest phase. We developed a paradigm to reveal differential timing in the regulation of food intake behavior in mice. In addition to promoting overconsumption, palatable diets dampen daily intake patterns, further augmenting metabolic disruption. Unlimited access to calorie-dense, palatable food is a hallmark of Western societies and substantially contributes to the worldwide rise of metabolic disorders.
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