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Animal Models

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 ΔFosB (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 ΔFosB 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 Heightened palatable food reward in mice withdrawn from HFD coincided with increased BDNF protein levels in NAc and decreased TH and pCREB expression in the amygdala.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 plasticity-related signals in reward circuitry may promote negative emotional states, overeating and palatable food relapse.

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Acknowledgements

This project was supported by grants to SF from the Natural Sciences and Engineering Research Council of Canada (No.355881), Canadian Diabetes Association (OG-2-09-2835-SF) and Canadian Foundation for Innovation. SS is supported by a postdoctoral fellowship from the CIHR Neuroinflammation Training Program and MFF by a PhD fellowship from the Canadian Diabetes Association.

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Correspondence to S Fulton.

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Sharma, S., Fernandes, M. & Fulton, S. Adaptations in brain reward circuitry underlie palatable food cravings and anxiety induced by high-fat diet withdrawal. Int J Obes 37, 1183–1191 (2013). https://doi.org/10.1038/ijo.2012.197

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