Impact of a moderate reduction in protein intake on eating behavior and neuronal activation in the dorsal vagal complex and ventral striatum in rats.

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English. Context and objectives The adjustment of dietary protein intake to requirements is ensured by a very fine brain control that is still poorly understood. It includes the detection of protein intake that relies on essential amino acids (EAA) detection in several part of the brain and integrates protein status and metabolism (Heeley and Blouet 2016) to modulate eating behaviour in consequence. In a recent study, we have shown that a moderate reduction in the protein content of the diet induces hyperphagia and increases the appetence for protein (Champeil-Potokar et al 2021). The hyperphagia reflects the body's need to obtain amino acids whatever the excess in caloric intake. There is no consensus on this so-called "protein leverage" effect, but it may constitute an increase in the risk of obesity when individuals reduce their protein intake by switching to low animal protein diets. It is therefore important to better understand the impact of a low protein diet on the activation of brain areas involved in satiety (dorsal vagal complex, DVC), and reward (Nucleus Accumbens (NAcc) and Olfactory Tubercle (OT)). The aim of the study was to analyse the neuronal activation (c-fos) induced by a low protein (LP) meal or a high protein (HP) meal in the nucleus of the tractus solitarii (NTS), the NAcc and OT, of rats chronically fed with a low protein diet (LP) or with a normal protein diet (NP).Methods6 week-old rats were fed a 6% protein (in percent of energy) diet (LP rats, n=16) or a 20% protein diet (NP rats, n=16) during 2 months. The composition of the 2 diets was similar for lipids (6% of energy as soy oil), fibers, vitamins and minerals; protein source was casein and its variation was compensated by maize starch. LP and NP diets were isocaloric. Rats growth and daily food consumption were followed, and their appetence for protein determined in dietary tests allowing self-selection between pellets containing 6% (LP), 20% (NP) or 55% (HP) protein. Two hours before sacrifice, and after 4h of fasting, rats were given a 5g meal of LP or HP pellets. At sacrifice, brains were fixed, frozen and sliced for immunohistochemistry of neuronal activation (c-fos) in reward areas (NAcc and OT) and in the brain stem DVC to evaluate the impact of the meal. The DVC was also immunolabeled for glia to evaluate microglial activation in the area postrema and the deployment of the astroglial barrier between the AP and NTS. ResultsReduced protein intake in LP rats induced an increase in food consumption (+24%, p<0.01) leading to an increase in body weight (+5%, p<0.01) and visceral adiposity (+30%, p<0.01) compared to NP rats. Choice tests showed a strong (p<0.001) dietary and olfactory preference for high protein (HP) pellets over LP or NP pellets in LP rats as well as in half of the NP rats (NP2). The other half of NP rats (NP1) did not show a preference for HP pellets. Consumption of a meal of HP pellets increased c-fos neuronal activation in the ventromedial region of the NTS as compared to LP pellets whereas LP or HP meal induced similar c-fos activation in the NAcc of LP or NP rats. c-fos activation in the medial OT (encoding the positive valence of odors) tended to increase in LP rats in response to HP vs. LP meal (+38%, p=0.10), and in NP2 vs. NP1 rats (+44%, p=0.10 in response to LP or HP meal). ConclusionOur results show that meal-induced neural activation in the satiety and reward regions varies with meal protein content, animal protein status, and individual appetence for protein.