Mutran Thais A J, Pedroso Amanda P, de Souza Adriana P, Boldarine Valter T, Neto Antonio M M, Angeli Claudia B, Oyama Lila M, Palmisiano Giuseppe, Ribeiro Eliane B, Telles Monica M
Department of Physiology, Universidade Federal de São Paulo, São Paulo, Brazil.
Department of Parasitology, Universidade de São Paulo, São Paulo, Brazil.
Metab Brain Dis. 2025 Aug 29;40(7):250. doi: 10.1007/s11011-025-01675-x.
We have previously demonstrated that 4-month-old IUGR male rats had obesity, hyperglycemia, and increased hypothalamic glucose levels, indicative of disruption of hypothalamic glucose metabolism. To evaluate, by proteomic analysis, the hypothalamic response to a systemic glucose load before the development of IUGR-induced obesity. Wistar rats were fed either ad libitum (Control group, C) or received 50% of C intake throughout pregnancy (Restricted group, R), and fed ad libitum during lactation. The male C and R offspring were fed ad libitum from weaning to 3-months-old. They were injected intraperitoneally with either saline (CS and RS) or 2 g/kg glucose (CG and RG) (n = 4 each), euthanized after 45 min., and had their hypothalami harvested. Pathway search was conducted with significantly modulated proteins (Student's t-test, p < 0.05). When comparing CS and RS, the tricarboxylic acids cycle and the respiratory chain pathways had multiple down-regulated proteins. Comparing CG and RG, while these pathways were also affected, only pyruvate dehydrogenase complex (PDH) (Fold change (FC) 0.63) was down-regulated while citrate synthase (FC 1.43) and respiratory chain complex I (FC 1.63) were up-regulated. This could represent a compensatory response aimed at overcoming the down-regulation of the respiratory chain induced by IUGR. These seemingly beneficial responses may, however, induce increased reactive oxidative species, insulin resistance and obesity. The results suggest that, even before the establishment of obesity and hyperglycemia, IUGR may have impacted metabolic pathways and the hypothalamic response to a systemic glucose load, that in the long term, could have a negative impact on energy homeostasis.
我们之前已经证明，4个月大的宫内生长受限（IUGR）雄性大鼠存在肥胖、高血糖以及下丘脑葡萄糖水平升高的情况，这表明下丘脑葡萄糖代谢受到了破坏。为了通过蛋白质组学分析评估在IUGR诱导的肥胖发生之前，下丘脑对全身葡萄糖负荷的反应。将Wistar大鼠分为两组，一组自由进食（对照组，C），另一组在整个孕期给予C组摄入量50%的食物（限制组，R），哺乳期自由进食。雄性C组和R组后代从断奶到3个月大时自由进食。它们腹腔注射生理盐水（CS组和RS组）或2 g/kg葡萄糖（CG组和RG组）（每组n = 4），45分钟后安乐死，并采集下丘脑。对显著调节的蛋白质进行通路搜索（Student's t检验，p < 0.05）。比较CS组和RS组时，三羧酸循环和呼吸链通路有多个下调的蛋白质。比较CG组和RG组时，虽然这些通路也受到影响，但只有丙酮酸脱氢酶复合体（PDH）（倍数变化（FC）0.63）下调，而柠檬酸合酶（FC 1.43）和呼吸链复合体I（FC 1.63）上调。这可能代表一种旨在克服IUGR诱导的呼吸链下调的代偿反应。然而，这些看似有益的反应可能会导致活性氧化物质增加、胰岛素抵抗和肥胖。结果表明，即使在肥胖和高血糖确立之前，IUGR可能已经影响了代谢通路以及下丘脑对全身葡萄糖负荷的反应，从长远来看，这可能会对能量稳态产生负面影响。
