Inflammation and altered glucose metabolism are two pathways implicated in the pathophysiology of major depressive disorder (MDD). We have previously shown that high inflammation as measured by C-reactive protein (CRP) in MDD patients is associated with symptoms of anhedonia, a core symptom of MDD, along with deficits in dopaminergic reward circuitry. Increased inflammation can shift metabolic demand and reprogram cellular energy sources, which may collectively impact the brain and reward processing to contribute to symptoms of anhedonia. To determine whether immunometabolic gene signatures were enriched in immune cells of depressed patients with increased inflammation and anhedonia, we examined whole-blood gene expression microarray (Illumina HumanHT-12) data from unmedicated, medically-stable patients with MDD (n=93). Patients were considered to have increased inflammation based on High (>3mg/L) versus Low (≤3mg/L) plasma CRP, and further classified as having a self-reported phenotype of High (n=30, 33rd percentile) versus Low (n=32, 67th percentile) Anhedonia. Functional enrichment of gene pathways was assessed by Gene Set Enrichment Analysis (GSEA) using the KEGG pathway database. Pathways related to glucose metabolism (insulin signaling, insulin resistance, HIF-1, PI3K/AKT signaling), cancer (e.g., genes related to insulin and PI3K/AKT signaling), and inflammation (B cell, T cell and Fc receptor signaling) were specifically enriched in patients with both High CRP and High Anhedonia (all FDR q<0.25). Within patients with High CRP in GSEA, the insulin signaling pathway was the top enriched pathway in patients with High versus Low Anhedonia (n=10 and 9 respectively), which was driven by genes expressed predominantly in monocytes (z=2.95, p<0.01). Conversely, within patients with High Anhedonia, in addition to enrichment of immunometabolic pathways, the tyrosine metabolism pathway was also reduced in patients with High versus Low CRP (n=20 and 10 respectively). Of note, enrichment of immunometabolic pathways was confirmed in complementary linear regression analyses examining pathways associated with a CRP-by-Anhedonia interaction term while controlling for clinical covariates in all patients (n=93). These results indicate that increased glucose and low tyrosine metabolism define a subset of depressed patients with high inflammation and anhedonia. Enrichment of cancer-related pathways driven by metabolic genes also suggests a shift in immune cell metabolism from oxidative phosphorylation to glycolysis. Together these data suggest that anhedonia in MDD with high CRP involves both immunometabolic shifts and reduced dopamine precursor availability.

中文翻译：

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与胰岛素抵抗和低酪氨酸代谢相关的外周血免疫细胞中的基因特征定义了具有高 CRP 和快感缺乏症的抑郁症亚型

炎症和葡萄糖代谢改变是与重度抑郁症 (MDD) 病理生理学相关的两条途径。我们之前已经表明，MDD 患者中通过 C 反应蛋白 (CRP) 测量的高度炎症与快感缺乏症（MDD 的核心症状）的症状以及多巴胺能奖赏回路的缺陷有关。炎症增加会改变代谢需求并重新编程细胞能量来源，这可能会共同影响大脑和奖励处理，从而导致快感缺乏症的症状。为了确定免疫代谢基因特征是否在炎症增加和快感缺乏的抑郁症患者的免疫细胞中富集，我们检查了来自未接受药物治疗、医学上稳定的 MDD 患者（n=93）的全血基因表达微阵列（Illumina HumanHT-12）数据。根据高 (>3mg/L) 与低 (≤3mg/L) 血浆 CRP，患者被认为炎症增加，并进一步分类为具有高（n=30，第 33 个百分位）与低（ n=32，第 67 个百分位数）快感缺失。使用 KEGG 通路数据库通过基因集富集分析 (GSEA) 评估基因通路的功能富集。与葡萄糖代谢（胰岛素信号、胰岛素抵抗、HIF-1、PI3K/AKT 信号）、癌症（例如，与胰岛素和 PI3K/AKT 信号相关的基因）和炎症（B 细胞、T 细胞和 Fc 受体信号）相关的通路在同时具有高 CRP 和高快感缺乏症的患者中特别富集（所有 FDR q<0.25）。在 GSEA 中具有高 CRP 的患者中，胰岛素信号通路是高与低快感缺失患者（分别为 n = 10 和 9）中最富集的通路，其由主要在单核细胞中表达的基因驱动（z = 2.95，p < 0.01）。相反，在高快感缺失患者中，除了免疫代谢途径富集外，高与低 CRP 患者的酪氨酸代谢途径也减少（分别为 n=20 和 10）。值得注意的是，在检查与 CRP-by-Anhedonia 相互作用项相关的通路的互补线性回归分析中证实了免疫代谢通路的富集，同时控制了所有患者 (n=93) 的临床协变量。这些结果表明，增加的葡萄糖和低酪氨酸代谢定义了具有高度炎症和快感缺乏症的抑郁症患者的子集。由代谢基因驱动的癌症相关通路的富集也表明免疫细胞代谢从氧化磷酸化转变为糖酵解。这些数据一起表明，具有高 CRP 的 MDD 中的快感缺乏涉及免疫代谢变化和多巴胺前体可用性降低。