Obesity, the cessation of ovarian steroids with menopause, and age are risk factors for mood disorders, dementia, and Alzheimer’s disease (AD). However, immediate hormone therapy (HT) after menopause may have beneficial effects in different brain regions involved in memory and cognition. To more closely replicate the age, endocrine, and metabolic environment of obese postmenopausal women, either on or off HT, middle-aged female rhesus macaques were ovariectomized/hysterectomized (OvH) and maintained on a high-fat, high-sugar, obesogenic Western-style diet (WSD) for 30 months; half of the animals received HT immediately after OvH and half served as placebo controls. RNAseq of the occipital (OC) and prefrontal cortex (PFC), hippocampus (HIP), and amygdala (AMG) identified 293, 379, 505, and 4993 differentially expressed genes (DEGs), respectively. Pathway enrichment analysis identified an activation of neuroinflammation in OC and HIP, but an inhibition in the AMG with HT. Synaptogenesis, circadian rhythm, mitochondrial dysfunction, mTOR, glutamate, serotonin, GABA, dopamine, epinephrine/norepinephrine, glucocorticoid receptor signaling, neuronal NOS, and amyloid processing were exclusively enriched in AMG. As compared to the placebo control group, most of these signaling pathways are downregulated after HT, suggesting a protective effect of HT in OvH females under a WSD. Overall, our results suggest that a chronic obesogenic diet may induce a wide range of alterations in multiple signaling pathways that are linked to age-associated brain pathology and dementia. In these individuals, HT seems to have a protective effect against neuroinflammation, amyloid beta depositions, and tau tangle formation.

肥胖、绝经后停用卵巢类固醇和年龄是情绪障碍、痴呆和阿尔茨海默病 (AD) 的危险因素。然而，绝经后立即进行激素治疗 (HT) 可能对涉及记忆和认知的不同大脑区域产生有益影响。为了更准确地复制绝经后肥胖女性的年龄、内分泌和代谢环境，无论是在 HT 上还是在 HT 之外，中年雌性恒河猴都被切除卵巢/子宫 (OvH) 并维持在高脂肪、高糖、致肥胖的西方30个月的风格饮食（WSD）；一半的动物在 OvH 后立即接受 HT，一半作为安慰剂对照。枕叶 (OC) 和前额叶皮层 (PFC)、海马 (HIP) 和杏仁核 (AMG) 的 RNAseq 分别鉴定了 293、379、505 和 4993 个差异表达基因 (DEG)。通路富集分析确定了 OC 和 HIP 中神经炎症的激活，但 HT 对 AMG 的抑制。突触发生、昼夜节律、线粒体功能障碍、mTOR、谷氨酸、5-羟色胺、GABA、多巴胺、肾上腺素/去甲肾上腺素、糖皮质激素受体信号、神经元 NOS 和淀粉样蛋白加工在 AMG 中完全富集。与安慰剂对照组相比，这些信号通路中的大多数在 HT 后下调，表明 HT 在 WSD 下的 OvH 女性中具有保护作用。总体而言，我们的研究结果表明，慢性肥胖饮食可能会导致多种信号通路发生广泛变化，这些信号通路与年龄相关的脑病理和痴呆有关。在这些个体中，HT 似乎对神经炎症、β 淀粉样蛋白沉积、