Geiger Brenda M, Behr Gerald G, Frank Lauren E, Caldera-Siu Angela D, Beinfeld Margery C, Kokkotou Efi G, Pothos Emmanuel N
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
FASEB J. 2008 Aug;22(8):2740-6. doi: 10.1096/fj.08-110759. Epub 2008 May 13.
The association between dietary obesity and mesolimbic systems that regulate hedonic aspects of feeding is currently unresolved. In the present study, we examined differences in baseline and stimulated central dopamine levels in obesity-prone (OP) and obesity-resistant (OR) rats. OP rats were hyperphagic and showed a 20% weight gain over OR rats at wk 15 of age, when fed a standard chow diet. This phenotype was associated with a 50% reduction in basal extracellular dopamine, as measured by a microdialysis probe in the nucleus accumbens, a projection site of the mesolimbic dopamine system that has been implicated in food reward. Similar defects were also observed in younger animals (4 wk old). In electrophysiology studies, electrically evoked dopamine release in slice preparations was significantly attenuated in OP rats, not only in the nucleus accumbens but also in additional terminal sites of dopamine neurons such as the accumbens shell, dorsal striatum, and medial prefrontal cortex, suggesting that there may be a widespread dysfunction in mechanisms regulating dopamine release in this obesity model. Moreover, dopamine impairment in OP rats was apparent at birth and associated with changes in expression of several factors regulating dopamine synthesis and release: vesicular monoamine transporter-2, tyrosine hydroxylase, dopamine transporter, and dopamine receptor-2 short-form. Taken together, these results suggest that an attenuated central dopamine system would reduce the hedonic response associated with feeding and induce compensatory hyperphagia, leading to obesity.
饮食性肥胖与调节进食享乐方面的中脑边缘系统之间的关联目前尚无定论。在本研究中，我们检测了易肥胖（OP）和抗肥胖（OR）大鼠的基线及刺激后的中枢多巴胺水平差异。当给OP大鼠喂食标准饲料时，它们食量过大，在15周龄时比OR大鼠体重增加了20%。这种表型与伏隔核（中脑边缘多巴胺系统的一个投射部位，与食物奖赏有关）中通过微透析探针测得的基础细胞外多巴胺减少50%有关。在较年幼的动物（4周龄）中也观察到了类似的缺陷。在电生理学研究中，不仅在伏隔核，而且在多巴胺神经元的其他终末部位，如伏隔核壳、背侧纹状体和内侧前额叶皮质，OP大鼠切片标本中电诱发的多巴胺释放均显著减弱，这表明在该肥胖模型中，调节多巴胺释放的机制可能存在广泛的功能障碍。此外，OP大鼠的多巴胺损伤在出生时就很明显，并且与几种调节多巴胺合成和释放的因子的表达变化有关：囊泡单胺转运体-2（vesicular monoamine transporter-2）、酪氨酸羟化酶（tyrosine hydroxylase）、多巴胺转运体（dopamine transporter）和多巴胺受体-2短型（dopamine receptor-2 short-form）。综上所述，这些结果表明，中枢多巴胺系统功能减弱会降低与进食相关的享乐反应，并诱发代偿性多食，从而导致肥胖。
