School of Pharmacy and Medical Sciences, Griffith University Gold Coast, Southport, QLD 4217, Australia.
School of Biomedical Sciences, University of Queensland, Brisbane, QLD 4072, Australia.
Life Sci. 2022 Dec 15;311(Pt A):121137. doi: 10.1016/j.lfs.2022.121137. Epub 2022 Oct 28.
Evolving type 2 diabetes (T2D) may influence locomotion and affective state, promoting metabolic dysfunction. We examined behaviour and neurobiology in a model of T2D, testing for benefits with dietary n-3 polyunsaturated fatty acid (PUFA).
Male C57Bl/6 mice received vehicle or 75 mg/kg streptozotocin (STZ) and 21 wks of control or Western diets (43 % fat, 40 % carbohydrate, 17 % protein). Sub-sets received dietary α-linolenic acid (ALA; 10 % of fat intake) for 6 wks. Behaviour was examined via open field and sucrose preference tests, and hippocampal and frontal cortex (FC) leptin and dopamine levels and inflammatory signalling assessed.
T2D mice exhibited weight gain (+15 %), hyperglycemia (+35 %), hyperinsulinemia (+60 %) and insulin-resistance (+80 % higher HOMA-IR), together with anxiety-like behaviour (without anhedonia) that appeared independent of body weight and glycemic status. Cortical leptin declined whereas receptor mRNA increased. Supplementation with ALA did not influence metabolic state, while enhancing locomotion and reducing anxiety-like behaviours in healthy but not T2D mice. Hippocampal dopamine was selectively increased by ALA in T2D mice, with a trend to reduced circulating leptin in both groups. Across all groups, anxiety-like behaviour was associated with declining cortical and hippocampal leptin levels and increasing receptor mRNA, while declining dopamine levels were accompanied by decreased dopamine/serotonin receptor transcripts.
Chronic T2D induced anxiogenesis in mice appears to be independent of metabolic homeostasis but linked to central leptin-resistance, together with disturbed dopamine and serotonin signalling. Despite anxiolytic effects of ALA in healthy mice, no metabolic or behavioural benefits were evident in T2D.
进展性 2 型糖尿病（T2D）可能影响运动和情绪状态，导致代谢功能障碍。我们在 T2D 模型中检查了行为和神经生物学，测试了饮食中 n-3 多不饱和脂肪酸（PUFA）的益处。
雄性 C57Bl/6 小鼠接受 vehicle 或 75mg/kg 链脲佐菌素（STZ）和对照或西方饮食（43%脂肪、40%碳水化合物、17%蛋白质）21 周。部分小鼠接受饮食 α-亚麻酸（ALA；脂肪摄入量的 10%）6 周。通过旷场和蔗糖偏好试验检查行为，并评估海马和额叶皮质（FC）瘦素和多巴胺水平以及炎症信号。
T2D 小鼠表现出体重增加（+15%）、高血糖（+35%）、高胰岛素血症（+60%）和胰岛素抵抗（HOMA-IR 增加 80%），同时伴有焦虑样行为（无快感缺失），似乎与体重和血糖状态无关。皮质瘦素下降，而受体 mRNA 增加。ALA 补充对代谢状态没有影响，而在健康小鼠中增强运动，减少焦虑样行为，但在 T2D 小鼠中没有。ALA 选择性增加 T2D 小鼠的海马多巴胺，两组循环瘦素呈下降趋势。在所有组中，焦虑样行为与皮质和海马瘦素水平下降和受体 mRNA 增加相关，而多巴胺水平下降与多巴胺/血清素受体转录物减少相关。
慢性 T2D 诱导的小鼠焦虑症似乎与代谢稳态无关，但与中枢瘦素抵抗、多巴胺和血清素信号紊乱有关。尽管 ALA 在健康小鼠中有抗焦虑作用，但在 T2D 中没有观察到代谢或行为益处。
