High fat diet allows food-predictive stimuli to energize action performance in the absence of hunger, without distorting insulin signaling on accumbal cholinergic interneurons

Abstract

Obesity can disrupt how food-predictive stimuli control action performance and selection. These two forms of control recruit cholinergic interneurons (CIN) located in the nucleus accumbens core (NAcC) and shell (NAcS), respectively. Given that obesity is associated with insulin resistance in this region, we examined whether interfering with CIN insulin signaling disrupts how food-predictive stimuli control actions. To interfere with insulin signaling we used a high-fat diet (HFD) or genetic excision of insulin receptor (InsR) from cholinergic cells. HFD left intact the capacity of food-predictive stimuli to energize performance of an action earning food when mice were tested hungry. However, it allowed this energizing effect to persist when the mice were tested sated. This persistence was linked to NAcC CIN activity but was not associated with distorted CIN insulin signaling. Accordingly, InsR excision had no effect on how food-predicting stimuli control action performance. Next, we found that neither HFD nor InsR excision altered the capacity of food-predictive stimuli to guide action selection. Yet, this capacity was associated with changes in NAcS CIN activity. These results indicate that insulin signaling on accumbal CIN does not modulate how food-predictive stimuli control action performance and selection. However, they show that HFD allows food-predictive stimuli to energize performance of an action earning food in the absence of hunger.

Diet and obesity effects on cue-driven food-seeking: insights from studies of Pavlovian-instrumental transfer in rodents and humans

“…Together, these studies support the notion that diet (and/or predisposition to obesity) was abolishing the selectivity of the food-seeking response. In contrast, in another recent study mice fed a high-fat diet for 8 weeks did not show any impairments in sPIT (Gladding et al, 2023). However, these mice were returned to a chow diet for 5 weeks prior to behavioral testing, and it is possible that this diet switch ameliorated the effects of the high-fat diet on choice behavior.…”

“…The third study likewise found no differences in choice behavior between individuals with obesity versus individuals of healthy-weight ( Meemken and Horstmann, 2019 ). Thus, while there is evidence for sPIT being abolished ( Kosheleff et al, 2018 ; Derman and Ferrario, 2020 ), enhanced ( Lehner et al, 2017 ; Watson et al, 2017 ), or left intact ( Meemken and Horstmann, 2019 ; Gladding et al, 2023 ) across different obesity models, the link to excess weight is weak. Moreover, it is not possible from these studies to disentangle the effects of weight gain itself and the dietary choices that might have caused the weight gain.…”

“…A recent study found that gPIT abnormally persisted in mice previously fed a high-fat diet relative to a chow-fed control group when they were tested under conditions of satiety (Gladding et al, 2023). Specifically, mice were fed a chow or high-fat diet for 8 weeks followed by a standard chow 2023) are translatable, it could suggest that when the ability for motivational state to control cue-driven food-seeking is lost, eating in the absence of hunger could increase and subsequently promote weight gain.…”

“…A recent study found that gPIT abnormally persisted in mice previously fed a high-fat diet relative to a chow-fed control group when they were tested under conditions of satiety ( Gladding et al, 2023 ). Specifically, mice were fed a chow or high-fat diet for 8 weeks followed by a standard chow diet for 5 weeks, which ameliorated diet-induced weight gain such that body weight did not differ between groups when Pavlovian and instrumental training commenced.…”

“…In everyday life, humans are exposed to food-predictive cues across the full spectrum of hunger to satiety. If the results of Gladding et al (2023) are translatable, it could suggest that when the ability for motivational state to control cue-driven food-seeking is lost, eating in the absence of hunger could increase and subsequently promote weight gain. It will be important for future studies to further replicate and elucidate these effects, but this is not without its challenges.…”