Current Biology . . . How long meat you eat at night is dopamine in the brain's biological clock center.

In the past few decades, thanks to the painstaking efforts of countless scientists, we have made continuous progress in the cause and treatment of obesity.however, the problem of obesity still exists and is increasing day by day, and our understanding of obesity is still not comprehensive.scientists have revealed a variety of causes of obesity, including genetics, dietary patterns, gut microbiota, etc.however, the most obvious and well-known cause of obesity is eating too much.in the field of studying eating behavior, it is generally believed that there are two common but interactive regulatory mechanisms in our body that control eating behavior: homeostatic regulation and hedonic regulation.homeostasis is to tell you that it's time to eat when the body is short of energy, and then, when you eat enough food, the system will tell you that it's time to stop.but sometimes, today's meal is so delicious that the reward regulation system can't stop your body, so you eat too much.the two mechanisms are very easy to understand. However, the physiological regulation mechanism behind them, even how the two systems interact, are still poorly understood.most people may have had the experience of receiving food pictures from their friends late at night. They also know that if they get up at that time, turn on the refrigerator, and stick to a week's running clock in vain.in recent years, scientists have been discussing that not only eating more, but also when to eat can affect the formation of obesity.on January 2, 2020, a team from Ali D. g ü ler and cooperative Laboratory of the University of Virginia published an article entitled "dopamine signaling in the supreme nucleus enables weight gain associated with hedonic feeding" in current biology.this study revealed the important role of dopamine type 1 receptor-mediated dopamine signaling pathway in the regulation of eating time, food intake and weight gain in the hypothalamus.the main conclusions of this paper are as follows: 1. Dopamine receptor type 1 knockout mice maintain normal dietary discipline even when they eat high-fat diet. Many laboratories have confirmed that feeding wild-type mice with high-fat diet will lead to overeating and obesity of mice, and researchers have confirmed again.however, unlike previous studies, the researchers paid extra attention to the feeding time of mice.it is worth noting that mice are nocturnal. Under normal laboratory conditions, wild-type mice will consume 80% of the total daily food in the evening (active period) and the remaining 20% in the daytime (rest period) (for the convenience of understanding, we will not use "day" and "night" to describe the experimental conclusion).the researchers found that the percentage of mice fed high-fat rat diets increased to 40% during rest time (and thus reduced to 60% during active periods).instead of looking at the proportion, the researchers found that the calorie intake of mice fed high-fat rat food was the same as that of mice fed normal rat food during the activity period. The part they ate more occurred in the rest period, and the excessive intake of calories led to the obesity of mice. it's just like we eat three meals normally, but we still eat a lot of snacks. high fat rat food is rewarding for mice. What if some hands and feet were used to control the reward system in the brain of mice? Dopamine signaling pathway mediated by dopamine type 1 receptor (DRD1) is widely believed to play an important role in the regulation of reward related behaviors in mice. the researchers used DRD1 knockout mice, gave them the same normal or high-fat diet as above, and observed their eating behavior. the researchers found that the knockout mice maintained a normal diet rhythm, normal energy intake, and normal body weight regardless of the food. therefore, the dopamine signaling pathway mediated by DRD1 does play a key role in the diet irregularity and obesity of mice caused by high-fat diet. DRD1 mediated dopamine signaling pathway in nucleus accumbens does not lead to obesity. After understanding the effect of DRD1 mediated dopamine signaling pathway on obesity, researchers want to find out in more detail which neural circuits in the brain regulate this process. DRD1 is expressed in the nucleus accumbens of the brain and receives dopamine from the ventral tegmental area, which is a widely studied neural pathway regulating reward related behaviors. so the researchers first targeted the nucleus accumbens. in the DRD1 knockout mice, Cre recombinase was introduced at the same time of DRD1 gene knockout. In this way, there would be no DRD1 in the DRD1 expressing cells, but Cre recombinase was contained. through the CRE loxP recombination system, researchers can selectively operate on DRD1 cells in specific brain regions. by using adeno-associated virus vector, the gene fragment containing DRD1, which can only be expressed in the presence of Cre recombinase, was transferred to the nucleus accumbens of DRD1 knockout mice. in these mice (referred to as "nucleus accumbens re expression"), DRD1 mediated dopamine signaling in the nucleus accumbens returned to normal, while this pathway was still absent in all other places. the researchers fed the same two kinds of food to the accumbent nucleus re expression mice. it was found that the mice in the high-fat rat diet had more calories during the rest period, as if they were wild-type mice. however, interestingly, these mice consumed less calories during the active period (wild-type mice did not change), which led to the fact that if you only looked at the total calorie intake in one day, they still maintained at normal levels, did not eat more and did not gain weight. therefore, it seems that only changing the diet rhythm is not enough to cause obesity, and overeating is the culprit, while DRD1 in nucleus accumbens is not enough to regulate the process of excessive intake of high-fat food. The DRD1 mediated dopamine signaling pathway in the suprachiasmatic nucleus is what we are looking for. Researchers found that when fed with high-fat food, not only the feeding rhythm of mice changed, but also the glucose metabolism rhythm of mice, and the expression level of circadian clock regulating genes in peripheral tissues also changed. this makes people think of a series of neural circuits in the brain that regulate biological rhythms. the suprachiasmatic nucleus in hypothalamus is a key brain area regulating mammalian biological rhythm. It receives information from the retina to light, generates circadian rhythm signals and transmits them to the whole body, which enables the body to have a series of rhythmic behaviors, including sleeping, eating, body temperature, etc. in the past studies, scientists have known that DRD1 exists in the suprachiasmatic nucleus, and that these DRD1 neurons play an important role in the development and rhythm formation of the suprachiasmatic nucleus itself, but few people have directly linked it with eating behavior. however, the researchers showed that exposure to high-fat food for a short time alone was enough to increase dopamine release in the suprachiasmatic nucleus. therefore, this led the researchers to believe that dopamine in the suprachiasmatic nucleus is indeed involved in food intake and weight regulation. using the same gene editing technique, the researchers put DRD1 back into the suprachiasmatic nucleus of DRD1 knockout mice. this time, when the mice were fed a high-fat diet, they returned to their wild-type behavior - eating at normal levels during activity, overeating during breaks, and then becoming obese. this proves that DRD1 mediated dopamine signaling pathway in the suprachiasmatic nucleus alone is enough to make mice overeat high-fat food and become obese. the dopamine type 1 receptor cells in the nucleus accumbens (left) and suprachiasmatic nucleus (right) were labeled with fluorescence. Conclusion: the dopamine signal mediated by DRD1 is not uncommon in the brain, and it has been repeatedly proved to be involved in the regulation of eating behavior in some other brain regions. however, this signal pathway in the suprachiasmatic nucleus alone is enough to play such an important role in the regulation of eating behavior and subsequent weight changes, which is unexpected even in the eyes of the researchers' laboratory itself. and for the part of nucleus accumbens studies, it is also emphasized that only changing the time of eating, but not changing the total daily food intake, is not enough to change the weight of mice. the core idea used in this work is to selectively restore specific brain regions in the case of whole-body gene knockout, which proves the "Sufficiency", that is, the brain region itself is enough to perform a certain function. however, there are always "backup" in organisms, that is, multiple brain regions work together to perform the same function. but to prove that this brain region is unique in controlling this function, i.e. "necessity", it is necessary to modify a certain brain area selectively under all normal conditions. this is also the work that has not been completed for the time being. We also look forward to the future work of the authors. original link: plate maker: Xiaoxian