High-Fat-Diet-Induced Deficits in Dopamine Terminal Function Are Reversed by Restoring Insulin Signaling

Abstract

Systemically released insulin crosses the blood-brain barrier and binds to insulin receptors on several neural cell types, including dopaminergic neurons. Insulin has been shown to decrease dopamine neuron firing in the ventral tegmental area (VTA), but potentiate release and reuptake at dopamine terminals in the nucleus accumbens (NAc). Here we show that prolonged consumption of a high fat diet blocks insulin’s effects in the NAc, but insulin’s effects are restored by inhibiting protein tyrosine phosphatase 1B, which supports insulin receptor signaling. Mice fed a high fat diet (60% kcals from fat) displayed significantly higher fasting blood glucose 160 mg/dL, compared to 101 mg/dL for control-diet-fed mice, and high-fat-diet-fed mice showed reduced blood glucose clearance after an intraperitoneal glucose tolerance test. Using fast scan cyclic voltammetry to measure electrically evoked dopamine in brain slices containing the NAc core, high-fat-diet-fed mice exhibited slower dopamine reuptake compared to control-diet-fed mice (2.2 ± 0.1 and 2.67 ± 0.15 μM/s, respectively). Moreover, glucose clearance rate was negatively correlated with Vmax. Insulin (10 nM to 1 μM) dose dependently increased reuptake rates in control-diet-fed mice compared with in the high-fat-diet group; however, the small molecule insulin receptor sensitizing agent, TCS 401 (300 nM), restored reuptake in high-fat-diet-fed mice to control-diet levels, and a small molecule inhibitor of the insulin receptor, BMS 536924 (300 nM), attenuated reuptake, similar to high-fat-diet-fed mice. These data show that a high-fat diet impairs dopamine reuptake by attenuating insulin signaling at dopamine terminals.

Persistent effects of obesity: a neuroplasticity hypothesis

“…[141][142][143] Indeed, obese rats fed a HFD for a month exhibited elevated plasma insulin levels indicative of insulin resistance and also showed reduced striatal DAT expression, 159 similar to the observed insulin resistance, impaired blood glucose clearance, and reduced dopamine clearance prevalent in mice fed a HFD for 6 weeks. 158 Inhibition of protein tyrosine phosphtase 1B-and subsequent promotion of phosphorylation of insulin receptor tyrosine residues-promoted the insulin receptor signaling cascade and effectively rescued dopamine reuptake, 158 supporting the link between insulin resistance and changes observed in the dopamine system. Even in the absence of obesity, mice fed high-fructose corn syrup for several months had impaired blood glucose clearance and impaired dopamine release in the dorsal striatum.…”

Interactions between insulin and diet on striatal dopamine uptake kinetics in rodent brain slices

“…Although absolute values for V max differ among experimental paradigms, the 25–30% decreases reported for CPu and NAc with these diets parallel decreases obtained under non‐depolarizing conditions using synaptosomes and B max (maximal binding) for surface DAT expression with either shorter food deprivation (Patterson et al ., ) or the same FR and OB diets examined here (Zhen et al ., ; Jones et al ., ). Notably, a lower V max was also seen in FSCV studies in striatal slices from mice on a high‐fat only diet (normal sugar), although the decrease was <20% from control, and not accompanied by a change in peak evoked [DA] o (Fordahl & Jones, ). Whether these slight differences from the present results reflect diet or species differences has not been addressed.…”

“…These data mirror the influence of these diets on DAT‐mediated 3 [H]‐DA uptake in striatal synaptosomes (Jones et al ., ). The enhancing effect of insulin on DA release and uptake in mouse striatal slices is also lost with a chronic high‐fat diet (Fordahl & Jones, ). Together, these results support the notion that diet‐regulated levels of brain insulin set the tone for acute InsR‐pathway mediated DA signaling.…”

“…Indeed, peak evoked extracellular dopamine (DA) concentration ([DA] o ) detected by fast‐scan cyclic voltammetry (FSCV) in striatal slices is decreased by either food restriction (FR) or a high‐fat/high‐sugar obesogenic (OB) diet vs. ad‐libitum (AL) feeding (Stouffer et al ., ). Among other factors, the pancreatic hormone insulin has been shown to regulate DA release and uptake in reward‐related pathways (Mebel et al ., ; Labouebe et al ., ; Stouffer et al ., ; Fordahl & Jones, ). Insulin receptors (InsRs) are expressed in midbrain DA neurons (Figlewicz et al ., ), and mediate the effects of insulin on DA neurons in the ventral tegmental area (VTA) to decrease feeding behavior (Mebel et al ., ; Labouebe et al ., ).…”

“…Insulin receptors (InsRs) are expressed in midbrain DA neurons (Figlewicz et al ., ), and mediate the effects of insulin on DA neurons in the ventral tegmental area (VTA) to decrease feeding behavior (Mebel et al ., ; Labouebe et al ., ). In addition, physiological concentrations of insulin (i.e., 10–30 n m ) that are typically reached in the CSF and brain after feeding (Strubbe et al ., ; Banks & Kastin, ; Woods et al .,, 2003; Banks, ) enhance evoked [DA] o throughout the rat striatal complex with the greatest effect in the ventral striatum (Stouffer et al ., ; Fordahl & Jones, ), which also has the highest levels of InsR expression (Werther et al ., ; Schulingkamp et al ., ).…”