True Cadence, Arik Anam, Lindsley Sarah, Kirigiti Melissa, Sullivan Elinor, Kievit Paul
Cardiometabolic Health Division, Oregon National Primate Research Center, Beaverton, OR, United States.
Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR, United States.
Front Endocrinol (Lausanne). 2018 Sep 10;9:508. doi: 10.3389/fendo.2018.00508. eCollection 2018.
Maternal obesity and consumption of a high-fat diet (HFD) during pregnancy has a negative impact on offspring, including an increased risk for the development of obesity in adolescence. The mechanism for this transferred metabolic risk is unclear, but many studies have focused on the brain due to its important role in appetite and body-weight regulation. Two main pathways regulate appetite in the brain; homeostatic regulation that occurs predominantly in hypothalamic circuits and hedonic regulation of feeding that occurs via dopaminergic pathways. The current proposal examined the impact of early HFD exposure on the dopaminergic control of hedonic feeding pathways in a translational nonhuman primate model. Japanese macaque offspring from mothers consuming a control (CTR) or HFD were weaned onto control or HFD at an average 8 months of age yielding four groups: maternal and post-weaning control diet (mCTRpCTR), maternal control diet and post-weaning HFD (mCTRpHFD), maternal HFD and post-weaning control diet (mHFDpCTR) and maternal and post-weaning HFD (mHFDpHFD). Brains from 13-month-old offspring were evaluated for expression of neuropeptides that regulate dopaminergic pathways including orexin, melanin-concentrating hormone (MCH) in the lateral hypothalamus (LH), and tyrosine hydroxylase expression in the ventral tegmental area (VTA). Orexin cell numbers in the LH were significantly increased in animals exposed to a post-weaning HFD, while no difference was observed for orexin mRNA content or MCH cell numbers. Orexin fiber projections to the rostral VTA were significantly reduced in mCTRpHFD, mHFDpCTR, and mHFDpHFD groups, but these differences were not significant in the caudal VTA. There was no difference in the percentage of dopamine neurons receiving close appositions from orexin fibers in either the rostral or caudal VTA, nor was there any difference between groups in the number of orexin contacts per TH cell. In conclusion, the current study finds that prolonged early exposure to HFD during the and postnatal period causes alterations at several levels in the dopaminergic circuits regulating reward.
孕期母体肥胖和高脂饮食（HFD）对后代有负面影响，包括青春期肥胖发生风险增加。这种传递性代谢风险的机制尚不清楚，但由于大脑在食欲和体重调节中起重要作用，许多研究都聚焦于大脑。大脑中有两条主要途径调节食欲；稳态调节主要发生在下丘脑回路中，而享乐性进食调节则通过多巴胺能途径发生。当前的研究在一个转化性非人灵长类动物模型中，检验了早期高脂饮食暴露对享乐性进食途径多巴胺能控制的影响。来自食用对照（CTR）或高脂饮食的母亲的日本猕猴后代，在平均8个月大时断奶，分别给予对照饮食或高脂饮食，产生四组：母体和断奶后对照饮食（mCTRpCTR）、母体对照饮食和断奶后高脂饮食（mCTRpHFD）、母体高脂饮食和断奶后对照饮食（mHFDpCTR）以及母体和断奶后高脂饮食（mHFDpHFD）。对13个月大后代的大脑进行评估，以检测调节多巴胺能途径的神经肽的表达，这些神经肽包括食欲素、下丘脑外侧区（LH）的促黑素细胞激素（MCH），以及腹侧被盖区（VTA）的酪氨酸羟化酶表达。断奶后食用高脂饮食的动物，其LH中的食欲素细胞数量显著增加，而食欲素mRNA含量或MCH细胞数量未观察到差异。mCTRpHFD、mHFDpCTR和mHFDpHFD组中，向吻侧VTA的食欲素纤维投射显著减少，但在尾侧VTA中这些差异不显著。在吻侧或尾侧VTA中，接受食欲素纤维紧密贴附的多巴胺神经元百分比没有差异，每组中每个TH细胞的食欲素接触数量也没有差异。总之，当前研究发现，在孕期和出生后早期长期暴露于高脂饮食会导致调节奖赏的多巴胺能回路在多个水平上发生改变。
