Adaptations in brain reward circuitry underlie palatable food cravings and anxiety induced by high-fat diet withdrawal

Abstract

OBJECTIVE:To identify the emotional and motivational processes that reinstate palatable food intake following removal of high-fat diet (HFD) and associated neuroadaptations tied to neurochemical and behavioural changes underlying dopaminergic function. METHODS: Adult male C57Bl6 mice were placed on a HFD (58% kcal fat) or ingredient-matched, low-fat diet (LFD; 11% kcal fat) for 6 weeks. At the end of diet-regimen mice were either maintained on their respective diets, or HFD and LFD were replaced with normal chow (withdrawal). Effort-based operant responding for sucrose and high-fat food rewards was measured along with basal and stress-induced corticosterone levels and anxiety (elevated-plus maze). Protein levels for tyrosine hydroxylase (TH), corticosterone releasing factor type 1 receptor (CRF-R1), brain-derived neurotrophic factor (BDNF), phospho-CREB (pCREB) and DFosB (truncated splice variant of FosB) were assessed in the amygdala, nucleus accumbens (NAc) and ventral tegmental area (VTA) via western immunoblotting. RESULTS: Six weeks of HFD resulting in significant weight gain elicited sucrose anhedonia, anxiety-like behaviour and hypothalamic-pituitary-adrenocortical axis (HPA) hypersensitivity to stress. Withdrawal from HFD but not LFD-potentiated anxiety and basal corticosterone levels and enhanced motivation for sucrose and high-fat food rewards. Chronic high-fat feeding reduced CRF-R1 and increased BDNF and pCREB protein levels in the amygdala and reduced TH and increased DFosB protein in NAc and VTA. Heightened palatable food reward in mice withdrawn from HFD coincided with increased BDNF protein levels in NAc and decreased TH and pCREB expression in the amygdala. CONCLUSION: Anhedonia, anxiety and sensitivity to stressors develops during the course of HFD and may have a key role in a vicious cycle that perpetuates high-fat feeding and the development of obesity. Removal of HFD enhances stress responses and heightens vulnerability for palatable foods by increasing food-motivated behaviour. Lasting changes in dopamine and plasticityrelated signals in reward circuitry may promote negative emotional states, overeating and palatable food relapse.

Decreased rates of operant food self-administration are associated with reward deficits in high-fat feeding mice

“…Our data, taken together with all these antecedents, suggest a situation of HFD-induced anhedonia and are coherent with other findings showing sucrose-induced anhedonia, anxiety-like behavior and hypersensitivity to stress after HFD treatment [50,51].…”

Consumption of palatable food primes food approach behavior by rapidly increasing synaptic density in the VTA

“…This effect could be due to increased interest in SHF or to an increase in risk-taking associated with a potential withdrawal from the food (21). Elevated anxiety has been associated with withdrawal from palatable foods (21,23). However, we did not observe any differences in the time spent or distance traveled in either light or dark compartments between groups, indicating that mice do not appear to have elevated anxiety measures 2 d after exposure to 24-h SHF.…”

High fat diet decreases beneficial effects of estrogen on serotonin-related gene expression in marmosets

“…However, the overall expression of CRF-R1 was two-fold higher in both treatment groups on HFD compared to the same treatments on LFD. In contrast, mice on HFD exhibited a reduction in CRF-R1 in the amygdala (Sharma et al, 2013). We have previously observed a difference in the hypothalamic-adrenal-axis between the response of monkeys and mice (Bethea and Centeno, 2008).…”