肥胖是一種以脂質累積及能量代謝失衡為特徵的代謝性疾病。近年研究指出，肥胖相關代謝壓力會影響下視丘神經功能，其中弓狀核（arcuate nucleus, ARC）的POMC神經元在維持能量平衡中扮演重要角色。然而，脂質過載如何影響POMC神經元之粒線體功能、能量代謝及神經結構完整性仍未完全釐清。本研究利用棕櫚酸（palmitic acid, PA）誘導之細胞模型及高脂飲食（high-fat diet, HFD）小鼠模型，探討脂質壓力對POMC神經元代謝適應及神經功能之影響。
體外實驗顯示，PA處理可誘導POMC神經元脂質累積、活性氧化物增加及內質網壓力反應，但不影響細胞存活率。PA亦誘導粒線體適應性重塑反應，包括粒線體融合及生合成相關標誌增加。然而，此適應性反應仍不足以維持細胞能量恆定，PA處理造成ATP生成下降，主要來自糖解作用ATP產生減少。此外，PA處理導致神經突延伸減少及MAP2免疫反應性降低，顯示神經結構完整性受損；但基礎及胰島素刺激後之c-fos表現皆未受到顯著影響。
在動物實驗中，HFD餵食9週造成小鼠體重增加、葡萄糖耐受性下降及血脂異常，其中總膽固醇於多個時間點持續升高，而三酸甘油酯僅於第7週呈現短暫增加。然而，空腹血糖及胰島素耐受性未見顯著改變。下視丘免疫組織化學分析顯示，HFD小鼠之βIII-tubulin及MAP2免疫反應性降低，顯示慢性脂質壓力造成下視丘神經結構受損。
綜合而言，本研究證實脂質過載可誘導POMC神經元產生代謝壓力及粒線體適應性重塑，但此反應不足以避免能量代謝失衡與神經結構改變。此研究結果提供肥胖相關下視丘功能異常之細胞機制新見解。

Obesity is a major metabolic disorder characterized by excessive lipid accumulation and impaired energy homeostasis. Increasing evidence indicates that obesity-associated metabolic stress affects hypothalamic neuronal function, particularly in pro-opiomelanocortin (POMC) neurons, which play a critical role in regulating energy balance. However, how lipid overload influences mitochondrial function and neuronal integrity in POMC neurons remains unclear. This study investigated the effects of palmitic acid (PA)-induced lipid stress and high-fat diet (HFD)-induced metabolic dysfunction on mitochondrial adaptation, energy metabolism, and neuronal alterations in POMC neurons.
In vitro, PA treatment induced lipid accumulation, reactive oxygen species production, and endoplasmic reticulum stress responses in POMC neurons without affecting cell viability. PA exposure triggered mitochondrial remodeling responses, characterized by increased expression of mitochondrial fusion and biogenesis-related markers, including OPA1, PGC1α, and ND-1. However, these adaptive responses were insufficient to maintain cellular energy homeostasis, as PA treatment resulted in reduced ATP production, mainly through decreased glycolytic ATP generation. Furthermore, PA exposure caused neuronal structural alterations, including reduced neurite length and decreased MAP2 immunoreactivity. Despite these metabolic and structural changes, basal and insulin-stimulated c-fos expression remained unchanged.
In vivo, mice fed a HFD for 9 weeks exhibited increased body weight gain, impaired glucose tolerance, and altered serum lipid profiles, including sustained elevation of total cholesterol and a transient increase in triglyceride levels at week 7. However, fasting blood glucose levels and insulin tolerance were not significantly affected. Immunohistochemical analysis of the hypothalamus revealed reduced βIII-tubulin and MAP2 immunoreactivity in HFD-fed mice, indicating impaired neuronal structural integrity.
Collectively, this study demonstrates that lipid overload induces metabolic stress and mitochondrial adaptive remodeling in POMC neurons. Although mitochondrial adaptation responses are activated, they are insufficient to prevent energy imbalance and neuronal structural alterations. These findings provide insights into the cellular mechanisms underlying obesity-associated hypothalamic dysfunction.

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