Guangdong Provincial Key Laboratory of Animal Nutrition Control, Guangzhou, Guangdong 510642, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China.
Guangdong Provincial Key Laboratory of Animal Nutrition Control, Guangzhou, Guangdong 510642, China; National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China.
Pharmacol Res. 2021 Jul;169:105659. doi: 10.1016/j.phrs.2021.105659. Epub 2021 May 8.
The rising prevalence of obesity and being overweight is a worldwide health concern. Food reward dysregulation is the basic factor for the development of obesity. Dopamine (DA) neurons in the ventral tegmental area (VTA) play a vital role in food reward. Toll-like receptor 4 (TLR4) is a transmembrane pattern recognition receptor that can be activated by saturated fatty acids. Here, we show that the deletion of TLR4 specifically in DA neurons increases body weight, increases food intake, and decreases food reward. Conditional deletion of TLR4 also decreased the activity of DA neurons while suppressing the expression of tyrosine hydroxylase (TH) in the VTA, which regulates the concentration of DA in the nucleus accumbens (NAc) to affect food reward. Meanwhile, AAV-Cre-GFP mediated VTA-specific TLR4-deficient mice recapitulates food reward of DAT-TLR4-KO mice. Food reward could be rescued by re-expressing TLR4 in VTA DA neurons. Moreover, effects of intra-VTA infusion of lauric acid (a saturated fatty acid with 12 carbon) on food reward were abolished in mice lacking TLR4 in DA neurons. Our study demonstrates the critical role of TLR4 signaling in regulating the activity of VTA DA neurons and the normal function of the mesolimbic DA system that may contribute to food reward.
肥胖和超重的患病率不断上升是一个全球性的健康问题。食物奖赏失调是肥胖发展的基本因素。腹侧被盖区（VTA）中的多巴胺（DA）神经元在食物奖赏中起着至关重要的作用。Toll 样受体 4（TLR4）是一种跨膜模式识别受体，可被饱和脂肪酸激活。在这里，我们表明 TLR4 在 DA 神经元中的特异性缺失会增加体重、增加食物摄入并降低食物奖赏。TLR4 的条件性缺失还降低了 VTA 中 DA 神经元的活性，同时抑制了酪氨酸羟化酶（TH）的表达，后者调节核壳（NAc）中 DA 的浓度以影响食物奖赏。同时，AAV-Cre-GFP 介导的 VTA 特异性 TLR4 缺失小鼠重现了 DAT-TLR4-KO 小鼠的食物奖赏。在 VTA DA 神经元中重新表达 TLR4 可以挽救食物奖赏。此外，在缺乏 TLR4 的 DA 神经元的小鼠中，VTA 内灌流月桂酸（一种具有 12 个碳原子的饱和脂肪酸）对食物奖赏的影响被消除。我们的研究表明 TLR4 信号在调节 VTA DA 神经元的活性和中边缘多巴胺系统的正常功能方面起着关键作用，这可能有助于食物奖赏。
