Roux-en-Y gastric bypass and caloric restriction but not gut hormone-based treatments profoundly impact the hypothalamic transcriptome in obese rats

Background: The hypothalamus is an important brain region for the regulation of energy balance. Roux-en-Y gastric bypass (RYGB) surgery and gut hormone-based treatments are known to reduce body weight, but their effects on hypothalamic gene expression and signaling pathways are poorly studied. Methods: Diet-induced obese male Wistar rats were randomized into the following groups: RYGB, sham-operation, sham + body weight-matched (BWM) to the RYGB group, osmotic minipump delivering PYY3-36 (0.1mg/kg/day), liraglutide s.c. (0.4mg/kg/day), PYY3-36+liraglutide and saline. All groups (except BWM) were kept on a free choice of high- and low-fat diets. Four weeks after interventions, hypothalami were collected for RNA-sequencing. Results: While rats in the RYGB, BWM and PYY3-36+liraglutide groups had comparable reductions in body weight, only RYGB and BWM treatment had a major impact on hypothalamic gene expression. In these groups, hypothalamic leptin receptor expression as well as the JAK–STAT, PI3K-Akt and AMPK signaling pathways were upregulated. No significant changes could be detected in PYY3-36+liraglutide, liraglutide and PYY treated groups. Conclusions: Despite causing similar body weight changes compared to RYGB and BWM, PYY3-36+liraglutide treatment does not impact hypothalamic gene expression. Whether this striking difference is favorable or unfavorable to metabolic health in the long term requires further investigation.背景：下丘脑（hypothalamus）是调控机体能量平衡的关键脑区。鲁比诺-恩胃转流（Roux-en-Y gastric bypass, RYGB）手术以及基于肠道激素的治疗手段已被证实可有效减轻体重，但二者对下丘脑基因表达与信号通路的影响却鲜有研究。 方法：将饮食诱导肥胖的雄性Wistar大鼠随机分为以下组别：RYGB组、假手术组、体重匹配（body weight-matched, BWM）假手术组、输注PYY3-36的渗透微泵组（给药剂量0.1mg/kg/天）、皮下注射利拉鲁肽组（给药剂量0.4mg/kg/天）、PYY3-36联合利拉鲁肽组以及生理盐水对照组。除BWM组外，其余各组均自由选择高脂与低脂饲料。干预4周后，采集大鼠下丘脑组织进行RNA测序（RNA-sequencing）。 结果：RYGB组、BWM组与PYY3-36联合利拉鲁肽组的大鼠体重减轻程度相近，但仅RYGB与BWM处理对下丘脑基因表达产生显著影响。在这两组中，下丘脑瘦素受体（leptin receptor）的表达水平以及JAK-STAT、PI3K-Akt与AMPK信号通路均被显著上调。PYY3-36联合利拉鲁肽组、利拉鲁肽组及PYY处理组未检测到显著基因表达变化。 结论：尽管PYY3-36联合利拉鲁肽治疗带来的体重变化与RYGB及BWM组相似，但其并未对下丘脑基因表达产生影响。这种显著差异是否有利于长期代谢健康，仍需进一步深入研究。