Networks of neurons control feeding and activity patterns by integrating internal metabolic signals of energy balance with external environmental cues such as time-of-day. Proper circadian alignment of feeding behavior is necessary to prevent metabolic disease, and thus it is imperative that molecular players that maintain neuronal coordination of energy homeostasis are identified. Here, we demonstrate that mice lacking the p75 neurotrophin receptor, p75NTR, decrease their feeding and food anticipatory behavior (FAA) in response to daytime, but not nighttime, restricted feeding. These effects lead to increased weight loss, but do not require p75NTR during development. Instead, p75NTR is required for fasting-induced activation of neurons within the arcuate hypothalamus. Indeed, p75NTR specifically in AgRP neurons is required for FAA in response to daytime restricted feeding. These findings establish p75NTR as a novel regulator gating behavioral response to food scarcity and time-of-day dependence of circadian food anticipation.
Keywords: AgRP; food anticipation; mouse; neuroscience; neurotrophin; p75NTR.
In many animals, specific types of neurons, such as the hypothalamic hunger neurons, are tasked with regulating food consumption, integrating internal signals of hunger. In general, individuals eat if food becomes available when they are hungry; if food is absent, they will start moving to find new resources. Finally, if food always comes at the same time, animals will increase their activity just before it is delivered. Neurotrophins are a family of proteins that have many essential roles in the brain. In recent years, they have been shown to interact with the circadian clock, the built-in mechanism that helps animals stay synchronized with the cycle of day and night. A protein known as p75NTR is present in nerve cells, including hypothalamic hunger neurons: there, it helps to relay messages from a neurotrophin which, amongst other roles, controls food intake. However, it was unclear whether p75NTR played a role in regulating feeding behaviors, especially in a circadian manner. To investigate this question, Podyma et al. genetically engineered a group of mice lacking p75NTR, and a group missing the protein only in their hypothalamic hunger neurons. Both types of mutants had abnormal control of their feeding behavior: compared to normal mice, they fed less (and lost more weight) after they had been deprived of food overnight, or when they faced food shortage over multiple days. In addition, the mutants failed to move more before being fed. However, these feeding patterns were only affected during daytime, while they were preserved at night. These results reveal a new role for p75NTR in hypothalamic hunger neurons. Dissecting the biological processes that control food intake is key since obesity levels are increasing around the world. In particular, the relationship between food intake and the circadian clock is an important avenue of research as time-restricted diets (where food intake is only allowed during specific periods of the day) are growing in popularity.
© 2020, Podyma et al.