Central Insulin Modulates Dopamine Signaling in the Human Striatum

Abstract

Objective Activity in the dopaminergic pathways of the brain is highly sensitive to body weight and metabolic states. Animal studies show that dopamine neurons are important targets for the metabolic hormone insulin with abolished effects in the insulin resistant state, leading to increases in body weight and food intake. In humans, the influence of central acting insulin on dopamine and effects of their interplay are still elusive. Research Design and Methods We investigated whether central administered insulin influences dopaminergic activity in striatal regions and whole-brain neural activity. Using a PET/MRI hybrid scanner, we simultaneously performed [ 11C]-raclopride-PET and resting state fMRI in 10 healthy normal weight men after application of intranasal insulin or placebo on two separate days in a randomized, placebo-controlled, blinded, crossover trial. Results In response to central insulin compared to placebo administration, we observed greater [ 11C]-raclopride binding potential (BPnd) in the bilateral ventral and dorsal striatum. This suggests an insulin-induced reduction in synaptic dopamine levels. Resting-state striatal activity was lower 15 and 30 min after nasal insulin compared to placebo. Functional connectivity of the mesocorticolimbic circuitry associated with differences in dopamine levels: individuals with a stronger insulin-induced effect on dopamine levels showed a stronger increase in functional connectivity 45 min after intranasal insulin. Conclusions This study indicates that central insulin modulates dopaminergic tone in the striatum, which may affect regional brain activity and connectivity. Our results deepen the understanding of the insulin-dopamine interaction and the complex network that underlies the regulation of whole-body metabolism.

Sex differences in central insulin action: Effect of intranasal insulin on neural food cue reactivity in adults with normal weight and overweight

“…Cognitive restraint may enhance the relationship between peripheral insulin sensitivity and central insulin BOLD response to food cues. Central insulin was shown to influence dopamine signaling and reduce hedonic aspects of food [ 9 , 11 , 12 ]. Thus, cognitive restraint could further affect the subjective value and rewarding effect of food.…”

“…A possible explanation could be the role of central insulin action on dopamine signaling. Recent findings demonstrated that intranasal insulin administration directly modulated striatal dopamine levels and functional connectivity of reward pathways in healthy humans [ 9 , 11 , 12 ] and directly modulates dopamine function in the midbrain and nucleus accumbens in animal models [ 17 ]. This leads to the assumption, that central insulin action is not only implicated in the regulation of energy homeostasis, but also in reward processing.…”

Restriction of dietary fat, but not carbohydrate, affects brain reward regions in adults with obesity

“…For example, dopaminergic neurons express insulin receptors (Figlewicz, Evans et al 2003) and insulin decreases synaptic dopamine by increasing clearance from striatal synapses via enhanced dopamine transporter activity (Carvelli, Morón et al 2002, Mebel, Wong et al 2012. Consistent with a decrease in synaptic dopamine, intranasal insulin delivery was recently observed to increase D2BP in humans (Kullmann, Blum et al 2021). Therefore, the lack of effect of the RC diet on brain dopamine remains a mystery.…”

“…We previously showed that the RC diet led to widespread metabolic and endocrine changes compared to the eucaloric baseline diet, including increased fat oxidation as well as decreased energy expenditure and decreased daily insulin secretion, whereas the RF diet did not lead to substantial peripheral metabolic or endocrine changes (Hall, Bemis et al 2015). Therefore, we expected that the RC diet would have a greater effect on brain reward circuitry than the RF diet, especially given insulin’s effects on dopamine levels (Liu and Borgland 2019, Kullmann, Blum et al 2021). Surprisingly, it was the RF diet that significantly decreased both D2BP and neural activity in response to visual food cues in brain reward regions.…”

Acute inorganic nitrate intake increases regional insulin action in the brain: Results of a double-blind, randomized, controlled cross-over trial with abdominally obese men

“…These circuits also showed an increased brain insulin responsiveness after the intake of inorganic nitrate. Both brain circuits are activated by the neurotransmitter dopamine, while insulin inhibits the action of dopamine and has anorexigenic properties by reducing the activation of these reward circuits ( Figlewicz and Sipols, 2010 , Kullmann et al, 2021 ). Interestingly, increased CBF responses to intranasal insulin in the striatum have already been observed in healthy participants ( Kullmann et al, 2021 , Schilling et al, 2014 ).…”