Comportements anxiodépressifs et motivation alimentaire en contexte d'obésité : impacts des acides gras saturés sur le noyau accumbens

Obesity increases the odds for mood disorders such as depression and anxiety and, in turn, negative affect influences feeding behaviours. Part of the reward circuitry, the nucleus accumbens integrates dopaminergic signaling with cortical inputs and translates this information into goal-oriented behaviours. In rodents, high-fat feeding promotes dopaminergic adaptations in the nucleus accumbens and imaging studies reveal blunted recruitment of this brain region during palatable food consumption in human obesity. Alterations in nucleus accumbens dopamine signaling disrupt reward function and heavily contribute to the motivational deficits commonly observed in depression. Diet-induced obesity results from chronic overconsumption of energy-dense foods, such as those with a high fat content, yet distinct dietary fatty acids influence metabolic health and mood differently. While monounsaturated fatty acids, predominant in the Mediterranean diet, have overall benefits for features of the metabolic syndrome, saturated fatty acids, enriched in animal-derived products and processed foods, have pro-inflammatory actions and their consumption correlates with depressive symptoms. Thus, we hypothesized that obesity induced by a saturated, but not monounsaturated, high-fat diet promotes anxiety and depressive behaviours in mice via molecular adaptations in the nucleus accumbens. In order to test this hypothesis, we placed male and female mice on either a saturated or monounsaturated high-fat diet or a control low-fat diet and assessed the role of nucleus accumbens inflammation in mediating the expression of an anxiodepressive phenotype. In our first study, only involving male mice, we found that, despite similar weight gain and overall adiposity, only mice fed the saturated high-fat diet displayed metabolic impairments and anxiodepressive behaviours. In addition, these impairments were accompanied by enhanced levels of inflammatory markers in the nucleus accumbens and region-specific viral mediated inhibition of the pro-inflammatory nuclear factor kappa-b pathway was sufficient to prevent the expression of anxiodepressive behaviours as well as compulsive sucrose-seeking. In our second study, female mice were placed on the same 3 diets and we also observed an anxiodepressive phenotype specific to the saturated high-fat diet. In contrast to the males, inflammation was not associated to the increase in anxiodepressive behaviours. Instead, elevated circulating levels of estrogen and diminished expression of estrogen receptor beta in the nucleus accumbens distinguished mice on the saturated high-fat diet from the others. In our third study, we induced obesity and anxiodepressive behaviours in male mice by exposing them to the saturated high-fat diet. Via a chemogenetic approach, we blocked the depressive phenotype induced by saturated high-fat feeding by activating neurons of the nucleus accumbens expressing the type 1 dopamine receptor. In addition, we evidenced differential effects of these neurons, under conditions of saturated high-fat feeding, as anxiety behaviours were enhanced by this same manipulation. In our fourth study, we assess the potential of a novel glucagon-like peptide-1/dexamethasone co-agonist to reduce motivation for high-fat/high-sugar rewards in male mice. We found that this co-agonist could acutely inhibit operant response for palatable foods under both chow and withdrawal from high-fat/high-sucrose diet conditions. Prolonged treatment with this compound in diet-induced obese mice successfully reduced body weight and food intake, without promoting anxiodepressive behaviours as well as cognitive impairment. Overall, our work supports a role for the nucleus accumbens in the greater susceptibility to anxiety and depression in obese individuals. We demonstrate that diet composition in fatty acids, and not just fat content, influences metabolic and mood impairments in obesity. Our data suggests this relationship to be mediating by distinct molecular mechanisms in a sex-specific manner. Finally, these studies may orient the development of novel therapeutic approaches addressing both the metabolic and motivational components of obesity.

Keyphrases: dopamine, inflammation, diet-induced obesity,, saturated fatty acids, nucleus accumbens, anxiety