Obesity dysregulates feeding-evoked response dynamics in hypothalamic satiety neurons.

Melanocortin-4 receptor-expressing neurons in the paraventricular nucleus of the hypothalamus (PVHMC4R) integrate hunger-promoting and hunger-suppressing signals to regulate satiety. Food consumption-evoked responses in PVHMC4R neurons increase gradually during meal consumption to promote satiety, and disrupting this process drives massive obesity. These critical satiety neurons are strongly affected by a high-fat diet, yet the impact on their functional properties remains unknown. We used fiber photometry to track PVHMC4R neurons' responses to the consumption of drops of milkshake in animals fed a chow diet or a high-fat diet (HFD), both after obesity was established and after its reversal. PVHMC4R neurons in HFD-fed animals showed greater consumption-evoked responses than chow-fed animals at the early stages of meal consumption, and these responses did not increase further during the meal. HFD-fed animals also showed reduced licking vigor and motivation to consume milkshake. Switching HFD-fed obese animals to a normal chow diet (NCD) re-engaged the motivation to consume milkshake, partially restored early-meal neural responses to a lower level, but did not restore the increase in consumption-evoked response magnitude across the meal. These findings highlight functional alterations in hypothalamic satiety-promoting neurons in obesity and provide insight into the pathological neural consequences of an obesogenic environment.