Neurobiological Consequences of High-Fat High-Sugar Diets on the Mesocorticolimbic System: a Narrative Review

Abstract Purpose of Review This narrative review aims to examine the neurobiological consequences of high-fat, high-sugar (HFHS) diets on the mesocorticolimbic reward system. Emphasis is placed on how dopamine and opioid signaling interact to drive maladaptive behaviors such as compulsive eating and food addiction. Recent Findings High-fat, high-sugar (HFHS) diets have a profound impact on the mesocorticolimbic reward system, altering the function of both dopamine and opioid signaling. Evidence from animal and human studies shows that acute consumption of HFHS foods produces supra-additive effects, boosting dopamine release in the Ventral Tegmental Area-Nucleus Accumens (VTA-NAc) pathway and enhancing pleasure through µ-opioid receptor activation, which reinforces repeated intake. Chronic exposure, however, results in maladaptive neuroplasticity, including downregulation of D2 receptors, weakened dopamine signaling, synaptic desensitization, and structural impairments in the prefrontal cortex. These changes parallel neural adaptations observed in substance use disorders, manifesting as tolerance, loss of control, and cue-induced craving. The opioid system also contributes to stress-related comfort eating. In contrast, individual variability in response to treatments such as the opioid antagonist naltrexone has been linked to genetic factors, including Opioid Receptor Mu 1 (OPRM1) polymorphisms. Summary HFHS diets profoundly reshape the brain’s reward circuitry, promoting tolerance, craving, and compulsive consumption that mirror substance addiction. These findings support the conceptualization of food addiction as a neurobiological condition and highlight the importance of personalized treatment approaches. A better understanding of dopaminergic and opioid system interactions will inform targeted interventions to prevent and manage diet-related obesity and eating disorders.