(P25-016-24) The Influence of Strain and Sex on High Fat Diet Associated Alterations of Dopamine Neurochemistry in Mice

Objectives: Dopamine (DA) neurochemistry has been found to become disrupted by chronic consumption of a diet high in saturated fat (HFD). Dysregulation of insulin signaling has been identified as a mechanism by which a HFD leads to changes at the dopamine terminal. Our lab has demonstrated that alterations of striatal DA neurochemistry due to a HFD is dependent on strain and biological sex using two models of diet-induced obesity. Unlike the C57B6/J (B6J) strain, the Balb/cJ (Balb/c) model is resistant to HFD-induced glucose intolerance (GI), making it a powerful tool to interrogate how gene-hormone interactions impact the insulin-dependent mechanisms that lead to DA terminal deficits due to a HFD. The purpose of this study was to determine the influence of strain and sex on DA neurochemistry due to a HFD and associated changes in glucose metabolism.

Methods: Male and female mice from B6J and Balb/c strains were randomly assigned to a control fat diet (10% kcal fat/g) or a nutrient matched HFD (60% kcal fat/g) for 12 weeks. Intraperitoneal glucose tolerance testing was conducted at week 11. Ex-vivo fast scan cyclic voltammetry was used to measure electrically evoked DA release and reuptake in the nucleus accumbens (NAc) and striatum.

Results: Blood glucose clearance was greater in HFD-fed Balb/c males (p < 0.001) and females (p < 0.001) compared to B6J counterparts, demonstrating that Balb/c mice were more resistant to HFD-induced GI compared to B6J mice. We found a negative correlation between NAc DA release and GI for B6J (R²= 0.612, p=0.002) and Balb/c (R²= 0.516, p=0.008) males fed a HFD. Striatal DA reuptake was also negatively correlated with GI for HFD-fed B6J males (R²= 0.766, p=0.01). DA reuptake in the NAc (F_1,64 = 6.055, p=0.017) and striatal DA release (F_1,41 = 7.036, p=0.011) was reduced due to a HFD for B6J females. We also found sex-based differences in dopamine release. Specifically, B6J females experienced a more marked blunting of DA release due to a HFD than B6J males (F_{1, 41}= 8.241, p=0.006).

Conclusions: Our study provides evidence that strain and sex influence DA terminal deficits due to a HFD and suggests the extent to which insulin signaling explains the variance of HFD-induced DA alterations is dependent on strain and biological sex.

Funding Sources: This research was funded by the UNC Greensboro Office of Research.