Central insulin is thought to act at the neural interface between metabolic and hedonic drives to eat. Here, using pharmacological fMRI, we show that intranasal insulin (INI) changes the value of food cues through modulation of mesolimbic pathways. Overnight fasted participants rated the palatability of food pictures and attractiveness of non-food items (control) after receiving INI or placebo. We report that INI reduces ratings of food palatability and value signals in mesolimbic regions in individuals with normal insulin sensitivity. Connectivity analyses reveal insulinergic inhibition of forward projections from the ventral tegmentum to the nucleus accumbens. Importantly, the strength of this modulation predicts decrease of palatability ratings, directly linking neural findings to behaviour. In insulin-resistant participants however, we observe reduced food values and aberrant central insulin action. These data demonstrate how central insulin modulates the cross-talk between homeostatic and non-homeostatic feeding systems, suggesting that dysfunctions of these neural interactions may promote metabolic disorders.

Central insulin is critically involved in the regulation of hedonic feeding. Insulin resistance in overweight has recently been shown to reduce the inhibitory function of insulin in the human brain. How this relates to effective weight management is unclear, especially in older people, who are highly vulnerable to hyperinsulinemia and in whom neural target systems of insulin action undergo age-related changes. Here, 50 overweight, non-diabetic older adults participated in a double-blind, placebo-controlled, pharmacological functional magnetic resonance imaging study before and after randomization to a 3-month caloric restriction or active waiting group. Our data show that treatment outcome in dieters can be predicted by baseline measures of individual intranasal insulin (INI) inhibition of value signals in the ventral tegmental area related to sweet food liking as well as, independently, by peripheral insulin sensitivity. At follow-up, both INI inhibition of hedonic value signals in the nucleus accumbens and peripheral insulin sensitivity improved with weight loss. These data highlight the critical role of central insulin function in mesolimbic systems for weight management in humans and directly demonstrate that neural insulin function can be improved by weight loss even in older age, which may be essential for preventing metabolic disorders in later life.

Dopaminergic brain structures like the nucleus accumbens (NAc) are thought to encode the incentive salience of palatable foods motivating appetitive behaviour. Animal studies have identified neural networks mediating the regulation of hedonic feeding that comprise connections of the NAc with the ventral tegmental area (VTA) and the lateral hypothalamus (LH). Here, we investigated how structural connectivity of these pathways relates to individual variability in decisions on sweet food consumption in humans. We therefore combined probabilistic tractography on diffusion imaging data from 45 overnight fasted lean to overweight participants with real decisions about high and low sugar food consumption. Across all individuals, sugar preference and connectivity strength were not directly related, however, multiple regression analysis revealed interaction of mesolimbic structure and sugar preference to depend on individuals’ BMI score. In overweight individuals (BMI: ≥25 kg/m², N = 22) higher sugar preference was thereby specifically related to stronger connectivity within the VTA-NAc pathway while the opposite pattern emerged in participants with normal BMI (BMI: <25 kg/m², N = 23). Our structural results complement previous functional findings on the critical role of the human mesolimbic system for regulating hedonic eating in overweight individuals.

One of the strongest drivers of food consumption is pleasure, and with a large variety of palatable food continuously available, there is rarely any necessity to eat something not tasty. The amygdala is involved in hedonic valuation, but its role in valence assignment during food choices is less understood. Given recent evidence for spatially segregated amygdala signatures encoding palatability, we applied a multivariate approach on fMRI data to extract valence-specific signal patterns during an explicit evaluation of food liking. These valence localizers were then used to identify hedonic valuation processes while the same healthy human participants (14 female, 16 male; in overnight fasted state on both scanning days) performed a willingness-to-eat task in a separate fMRI measurement. Valence-specific patterns of amygdala signaling predicted decisions on food consumption significantly. Findings could be validated using the same valence localizers to predict consumption decisions participants made on a separate set of food stimuli that had not been used for localizer identification. Control analyses revealed these findings to be restricted to a multivariate compared with a univariate approach, and to be specific for valence processing in the amygdala. Spatially distributed valuation signals of the amygdala thus appear to modulate appetitive consumption decisions, and may be useful to identify current hedonic valuation processes triggering food choices even when not explicitly instructed.