Yang Yan, Moghadam Alexander A, Cordner Zachary A, Liang Nu-Chu, Moran Timothy H
Department of Endocrinology (Y.Y.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Department of Psychiatry and Behavioral Sciences (Y.Y., A.A.M., Z.A.C., T.H.M.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; and Department of Psychology (N.C.L.), University of Illinois-Urbana Champaign, Champaign, Illinois 61820.
Endocrinology. 2014 Sep;155(9):3473-83. doi: 10.1210/en.2014-1052. Epub 2014 Jun 20.
Repeated administration of the long-acting glucagon-like peptide 1 receptor agonist exendin-4 (EX-4) has been shown to reduce food intake and body weight and do so without a rebound increase in food intake after treatment termination. The current study examines the neural mechanisms underlying these actions. After 6 weeks of maintenance on a standard chow or a high-fat (HF) diet, male Sprague Dawley rats were treated with EX-4 (3.2 μg/kg, i.p., twice a day) or vehicle for 9 consecutive days. Food intake and body weight (BW) were monitored daily. Expression of the genes for the hypothalamic arcuate nucleus (ARC) peptides proopiomelanocortin (POMC), neuropeptide Y (NPY), and agouti gene-related protein was determined. Expression of the dopamine precursor tyrosine hydroxylase (TH) gene in the ventral tegmental area and genes for dopamine receptors 1 (D1R) and dopamine receptor 2 in the nucleus accumbens were also determined. Pair-fed groups were included to control for the effects of reduced food intake and BW. Treatment with EX-4 significantly decreased food intake and BW over the 9-day period in both the standard chow and HF groups. HF feeding decreased POMC without changing NPY/agouti gene-related protein gene expression in the ARC. Treatment with EX-4 increased POMC and decreased NPY expression independent of the reduction of food intake and BW. Mesolimbic TH and D1R gene expression were decreased significantly in chronic HF diet-fed rats, and these changes were reversed in both EX-4 and pair-fed conditions. These results suggest a role for increased POMC and decreased NPY expression in the ARC in the effects of EX-4 on food intake and BW. Our findings also suggest that EX-4 induced the recovery of mesolimbic TH and D1R expression in HF diet-fed rats may be secondary to HF intake reduction and/or weight loss.
长期重复给予长效胰高血糖素样肽-1受体激动剂艾塞那肽-4（EX-4）已被证明可减少食物摄入量和体重，且在治疗终止后不会出现食物摄入量的反弹性增加。本研究探讨了这些作用背后的神经机制。在标准饲料或高脂（HF）饮食维持6周后，雄性Sprague Dawley大鼠连续9天接受EX-4（3.2μg/kg，腹腔注射，每日两次）或赋形剂治疗。每天监测食物摄入量和体重（BW）。测定下丘脑弓状核（ARC）肽前阿黑皮素原（POMC）、神经肽Y（NPY）和刺鼠基因相关蛋白的基因表达。还测定了腹侧被盖区多巴胺前体酪氨酸羟化酶（TH）基因以及伏隔核中多巴胺受体1（D1R）和多巴胺受体2的基因表达。纳入配对喂养组以控制食物摄入量和体重降低的影响。在标准饲料组和HF组中，EX-4治疗在9天期间均显著降低了食物摄入量和体重。HF喂养降低了ARC中的POMC，但未改变NPY/刺鼠基因相关蛋白基因表达。EX-4治疗增加了POMC并降低了NPY表达，且与食物摄入量和体重的降低无关。慢性HF饮食喂养的大鼠中脑边缘TH和D1R基因表达显著降低，而在EX-4和配对喂养条件下这些变化均得到逆转。这些结果表明，ARC中POMC增加和NPY表达降低在EX-4对食物摄入量和体重的影响中起作用。我们的研究结果还表明，EX-4诱导HF饮食喂养大鼠中脑边缘TH和D1R表达的恢复可能继发于HF摄入量的减少和/或体重减轻。
