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Your brain on high-fat food: why diets may fail

Researchers have discovered that consumption of a high-fat diet (HFD) suppresses the desire to eat healthier, more nutritional food, and that this devaluation of healthy food is rooted in the brain.

It is well known that humans prefer to consume energy-rich, high-fat foods and that exposure to such diets can lead to overconsumption of calories, weight gain, and the numerous health complications that can accompany overweight/obesity. The urge to consume high-fat foods is compounded by an accompanying lack of desire to eat nutritional food that may be perceived as less palatable. However, the reasons behind this remain poorly understood. To determine how high-fat food affects calorie consumption, researchers split adult male and female mice into two groups. Both groups began with unlimited access to a nutritionally balanced standard diet (SD). One group remained on the SD for the duration of the study, while the other group was given unlimited access to both the SD and 60 percent HFD for 8 weeks, followed by removal of the HFD for a 2-week withdrawal period. HFD-exposed mice exhibited an immediate preference for the high-fat food in lieu of the healthier SD, and only the HFD-exposed mice increased total daily calorie consumption and gained weight. Every HFD-exposed mouse displayed a marked reduction in SD consumption, and, remarkably, HFD removal resulted in rapid weight loss and a failure to consume daily required calories from the SD. This self-restricted caloric deprivation indicated that the mice no longer valued SD food. Moreover, after 2 weeks without access to a HFD, body weight and caloric consumption did not recover to baseline levels, indicating a prolonged physiological adaptation. Since several brain circuits, namely in a region of the brain called the hypothalamus, govern the drive to eat, the researchers next recorded activity of brain cells called AgRP neurons in mice transitioned to and from a HFD and compared those to recordings from mice on a SD. Hunger activates AgRP neurons and stimulates the drive to eat; food intake then suppresses AgRP activity. When the researchers presented the mice with a SD, they observed robust inhibition of AgRP activity, followed by similar food intake in each feeding session. However, when mice were provided with a HFD, they had significantly reduced AgRP responses to a SD—indicating that they no longer perceived SD as something that could alleviate their hunger. Notably, SD still did not quiet the hunger signals from AgRP neurons even after a 2-week HFD withdrawal, analogous to a strict diet in humans, emphasizing a prolonged effect from a HFD on this neural signaling system. In addition, the researchers observed changes in the brain chemical dopamine, known to play a critical role in reward pathways. Dopamine release was enhanced in mice that were fed a SD. However, after 1 week of HFD access, the scientists observed reduced dopamine release in response to a SD, further enforcing the concept of devaluation of nutritional food after exposure to a HFD.

Though these findings will need to be confirmed in humans, taken together, they reveal a neural basis behind why we may be driven toward calorie dense, highly palatable, less nutritional food and help explain the challenges of dieting in an obesogenic environment—where such food is readily available. Further research will be critical to developing therapeutics that can potentially target specific brain signaling pathways in response to certain diets.

Mazzone CM, Liang-Guallpa J, Li C,…Krashes MJ. High-fat food biases hypothalamic and mesolimbic expression of consummatory drives. Nat Neurosci 23: 1253-1266, 2020.