The Time Of Day We Eat Is Associated with Diet-Induced Obesity

Post by Flora Moujaes 

What's the science? 

Worldwide obesity has nearly tripled since 1975: currently over 13% of the world’s adult population is obese. This increase in obesity is correlated with the more widespread availability of highly processed energy-dense rewarding foods that encourage snacking outside of regular meal times. However, it is not just the number of calories consumed that are important for understanding weight gain, but also when they are consumed. Proper maintenance of energy throughout the day requires that meals are synchronized with daily metabolic rhythms. For example, even if two mice consume the same number of calories, eating food at different times (e.g. snacking) could lead to obesity in one mouse but not the other. This issue is particularly prevalent in modern society as the central pacemaker is under constant dysregulation by artificial light. This week in Current Biology, Grippo et al. investigate the mechanisms through which the increased availability of energy-dense food and feed times lead to diet-induced obesity. 

How did they do it? 

To explore the mechanisms underlying diet-induced obesity, mice were either fed a diet comparable to that eaten in the wild, or had unlimited access to a high fat, high sugar diet. To examine the involvement of dopamine in diet-induced obesity, the cre-lox recombinase enzyme (an enzyme that allows you to knock out genes solely in subsets of cells e.g. the brain) was used to knock out the Drd1 gene in the brain. This gene encodes the D1 subtype of the dopamine receptor, which is the most abundant dopamine receptor in the central nervous system. These mice are referred to as the ‘knockout’ mice. Finally, to explore exactly where in the brain dopamine is involved in diet-induced obesity, the researchers selectively restored Drd1 expression in (1) the nucleus accumbens or (2) the suprachiasmatic nucleus (SCN). The nucleus accumbens was chosen as it is the reward processing center of the brain. The SCN was chosen as it is the main biological clock: the SCN receives light cues from the eyes and interprets them as the time of day, as well as cues when the body consumes and metabolizes food.

What did they find?

Researchers first showed that unlimited access to energy-dense food led to obesity. While mice fed a diet akin to that eaten in the wild maintained normal eating and exercise schedules and proper weight, mice with unlimited access to energy-dense food rapidly developed obesity, diabetes, and metabolic diseases. However, knockout mice with impaired dopamine D1 receptor functioning were resistant to weight gain following exposure to unlimited energy-dense food. Researchers also found that unlimited access to energy-dense food led to eating at irregular times. As nocturnal animals, mice usually eat 80% of their food during the night when exposed to a healthy diet, however mice with unlimited access to energy-dense food only ate 60% of their food during the night. In contrast, knockout mice with impaired dopamine D1 receptor functioning did not change their feeding times following exposure to unlimited energy-dense food. Taken together, these data suggest that D1 is important for the overconsumption of energy-dense food, predominantly during rest, leading to obesity.

Mice with restored D1 dopamine receptor functioning in the nucleus accumbens did not gain weight when exposed to unlimited energy-dense food - while they did increase their consumption of food during rest, they did not increase their overall calorie intake and therefore, did not become obese. In contrast, mice with restored D1 dopamine receptor functioning in the central circadian clock (SCN) did gain a substantial amount of weight when exposed to unlimited energy-dense food. Both their consumption of food at rest and overall calorie intake was significantly increased. Overall, this indicates that dopamine D1 receptor functioning in the central circadian clock (SCN) is crucial for diet-induced obesity. 

What's the impact? 

This study uncovered a novel mechanism for understanding how energy-dense diets lead to obesity, defining a connection between the reward and circadian pathways in the regulation of pathological calorie consumption. The authors demonstrate that dopaminergic signalling within the central circadian clock (SCN) disrupts the timing of feeding, resulting in an overconsumption of food, which leads to obesity, diabetes, and metabolic disease. This research not only has significant clinical implications by furthering our understanding of the mechanisms that underlie obesity but also helps to explain the growing popularity and effectiveness of diets that involve time-restricted feeding (e.g. intermittent fasting).

Grippo et al. Dopamine Signaling in the Suprachiasmatic Nucleus Enables Weight Gain Associated with Hedonic Feeding. Current Biology (2020). Access the original scientific publication here.