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. 2017 Feb 15;8(2):290-299.
doi: 10.1021/acschemneuro.6b00308. Epub 2017 Jan 3.

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

Steve C Fordahl  1 , Sara R Jones  1
Affiliations

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

Steve C Fordahl et al. ACS Chem Neurosci. .

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.

Keywords: DAT; Voltammetry; dopamine; high fat diet; insulin resistance; obesity.

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Conflict of interest statement

Notes

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Increased body weight and impaired blood glucose clearance. (A) Experimental design showing mice with 6 week dietary exposure to high-fat diet (HF) or a control chow diet, followed by an i.p. glucose tolerance test (IPGTT) which measures glucose clearance to identify insulin sensitivity, and slice voltammetry (Volt) in the nucleus accumbens core (NAc). Access to a high-fat diet significantly increases body weight (B) and blood glucose levels following a 5 h fast (C), compared to controls. Blood glucose clearance was also significantly impaired in high-fat-diet-fed mice, compared to controls, following a bolus injection of glucose (2g/kg) (D), quantified by area under the curve (AUC) (E). (*p < 0.05, **p < 0.01, ***p < 0.001.)
Figure 2
Figure 2
Dopamine release and reuptake. Dopamine (DA) release (A) was similar between dietary groups; however, greater DA release was correlated with reduced glucose clearance in chow-fed control mice, as indicated by a greater area under the curve (AUC) showing slower glucose clearance following an i.p. glucose tolerance test (IPGTT) (B). The maximal rate of DA reuptake (Vmax) was lower in mice fed a high-fat diet (C), and negatively correlated with glucose clearance (D). Insulin increased DA release in control mice, but not in slices from high-fat-fed mice, measured as percent change from baseline (BL) DA release (E), and visualized with representative line traces following 30 nM insulin (F). (*p < 0.05, ***p < 0.001.)
Figure 3
Figure 3
Insulin enhanced dopamine clearance is absent in high-fat diet-fed mice. Representative line traces and color plots depicting evoked DA release normalized to peak height show that insulin (1 μM), dashed lines (–––), increases Vmax compared to baseline, solid lines (—), in NAc slices from control chow-fed mice (A), but not in slices from high-fat (HF)-fed mice (B), or in slices from control mice pretreated with 100 nM wortmannin (Wort), a PI3-kinase inhibitor that blocks downstream insulin signaling (C). Below the representative line traces are corresponding color plots showing the oxidation and reductions peaks of dopamine at +0.6 and −0.4 V, respectively. (D) Slices from high fat-fed mice and slices from control mice pretreated with Wort were resistant to insulin’s effect on Vmax in slices from control mice, and insulin significantly increased Vmax at physiological concentrations in control, but not high-fat-fed (E, inset). (*p < 0.05, ***p < 0.001.)
Figure 4
Figure 4
Insulin receptor function, not receptor number, modulates dopamine reuptake. Pretreating slices from chow-fed control mice with BMS 536924 (300 nM), a small molecule inhibitor of insulin receptor autophosphorylation blocks insulin-induced increases on dopamine (DA) release (A) and Vmax (C), recreating the high-fat (HF)-fed phenotype. Conversely, insulin’s effect on Vmax and DA release can be restored in slices from high fat-fed mice by pretreating them with TCS 401, a protein tyrosine 1B inhibitor that sensitizes downstream insulin signaling (B, D). No difference in NAc insulin receptor protein content was found between controls and high fat mice (E). (*p < 0.05; **p < 0.01.)
Figure 5
Figure 5
Voltammetry recording locations. Mouse brain atlas pictures from Franklin and Paxinos (2008) show placement of the carbon fiber electrode for voltammetry recordings. All recordings were grouped ventral to the anterior commissure in the area contained by the yellow circles. Reproduced with permission from ref . Copyright 2008 Elsevier.
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