title: 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.
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest School of Medicine , Winston-Salem, North Carolina 27157, United States.
authors.forename: Steve C
authors.identifier: 0000-0002-7093-6774
authors.initials: SC
authors.lastname: Fordahl
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest School of Medicine , Winston-Salem, North Carolina 27157, United States.
authors.forename: Sara R
authors.initials: SR
authors.lastname: Jones
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D019540:Area Under Curve; D001562:Benzimidazoles / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism*; D059305:Diet, High-Fat; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000187:drug effects; D004563:Electrochemistry; D004566:Electrodes; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005215:Fasting; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009714:Nucleus Accumbens / Q000166:cytology*; D011728:Pyridones / Q000494:pharmacology; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; C504983:BMS 536924; D001562:Benzimidazoles; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D011728:Pyridones; D011972:Receptor, Insulin; D004298:Dopamine; D000077191:Wortmannin
keywords: DAT; Voltammetry; dopamine; high fat diet; insulin resistance; obesity