間歇性禁食、運動與飲食調整：影響代謝穩態的獨特基因表現模式

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本研究探討了間歇性禁食（IF）、運動（EX）與飲食調整（DR）對肥胖小鼠多組織基因表現的影響。結果顯示，這三種減重干預方法在減輕體重方面效果相似，但對脂肪、肌肉與肝臟的代謝狀態及基因表現有顯著不同的影響。運動與禁食顯著改善全身炎症、葡萄糖與脂質代謝，而飲食調整未能顯著改善代謝健康。此外，研究識別出一組可預測體重反彈的基因，對長期減重管理具有重要臨床意涵。

Intermittent fasting, exercise, and dietary modification induce unique transcriptomic signatures of multiple tissues governing metabolic homeostasis during weight loss and rebound weight gain

間歇性斷食、運動與飲食調整在體重減輕與復胖期間誘導多組織特異性轉錄組特徵，調控代謝平衡

Liu T, Liu Y, Yan T, et al. Intermittent fasting, exercise, and dietary modification induce unique transcriptomic signatures of multiple tissues governing metabolic homeostasis during weight loss and rebound weight gain. J Nutr Biochem. 2024;130:109649. doi:10.1016/j.jnutbio.2024.109649

https://pubmed.ncbi.nlm.nih.gov/38642842/

Abstract

Obesity and its related metabolic diseases bring great challenges to public health. In-depth understanding on the efficacy of weight-loss interventions is critical for long-term weight control. Our study demonstrated the comparable efficacy of exercise (EX), intermittent fasting (IF), or the change of daily diet from an unhealthy to a normal chow (DR) for weight reduction, but largely divergently affected metabolic status and transcriptome of subcutaneous fat, scapular brown fat, skeletal muscles and liver in high-fat-high-fructose diet (HFHF) induced obese mice. EX and IF reduced systematic inflammation, improved glucose and lipid metabolism in liver and muscle, and amino acid metabolism and thermogenesis in adipose tissues. EX exhibited broad regulatory effects on TCA cycle, carbon metabolism, thermogenesis, propanoate-, fatty acid and amino acid metabolism across multiple tissues. IF prominently affected genes involved in mitophagy and autophagy in adipose tissues and core genes involved in butanoate metabolism in liver. DR, however, failed to improve metabolic homeostasis and biological dysfunctions in obese mice. Notably, by exploring potential inter-organ communication, we identified an obesity-resistant-like gene profile that were strongly correlated with HFHF induced metabolic derangements and could predict the degree of weight regain induced by the follow-up HFHF diet. Among them, 12 genes (e.g., Gdf15, Tfrc, Cdv3, Map2k4, and Nqo1) were causally associated with human metabolic traits, i.e., BMI, body fat mass, HbA1C, fasting glucose, and cholesterol. Our findings provide critical groundwork for improved understanding of the impacts of weight-loss interventions on host metabolism. The identified genes predicting weight regain may be considered regulatory targets for improving long-term weight control.

摘要

肥胖及其相關的代謝性疾病對公共衛生構成重大挑戰。深入了解減重介入措施的效果，對於長期體重控制至關重要。本研究顯示，運動（EX）、間歇性斷食（IF）及將日常飲食從不健康飲食改為正常飼料（DR）在減重方面具有相當的效果，但對於由高脂高果糖飲食（HFHF）誘導肥胖小鼠的代謝狀態及皮下脂肪、肩胛棕色脂肪、骨骼肌和肝臟的轉錄組影響各異。EX 和 IF 能夠降低全身性炎症，改善肝臟與肌肉的葡萄糖及脂質代謝，並提升脂肪組織的胺基酸代謝與生熱作用。EX 在三羧酸循環（TCA cycle）、碳代謝、生熱作用、丙酸代謝、脂肪酸及胺基酸代謝等多種組織中展現廣泛的調控作用。IF 主要影響脂肪組織中參與粒線體自噬及細胞自噬的基因，並顯著調控肝臟中核心的丁酸代謝相關基因。相較之下，DR 未能改善肥胖小鼠的代謝穩態與生理功能障礙。值得注意的是，透過探索潛在的器官間訊息傳遞，我們識別出一組類抗肥胖基因譜，這些基因與 HFHF 誘導的代謝失調高度相關，並可預測隨後 HFHF 飲食誘導的體重回升程度。其中 12 個基因（如 Gdf15、Tfrc、Cdv3、Map2k4 和 Nqo1）與人體的代謝特徵（如 BMI、體脂肪量、糖化血紅素（HbA1C）、空腹血糖及膽固醇）具有因果關聯。我們的研究為理解減重介入措施對宿主代謝的影響提供了關鍵基礎，並指出可用於預測體重回升的基因，這些基因或可作為改善長期體重控制的潛在調控目標。

引言

肥胖流行已成為全球嚴重的公共衛生問題 [1]，大幅提升非傳染性疾病的風險，並導致罹病率與死亡率上升 [2][3][4]。肥胖是一種複雜且異質性的疾病 [5]。人類與動物研究均顯示，肥胖與多個器官的功能障礙密切相關，包括脂肪組織、肝臟與骨骼肌 [6][7][8]。高糖高脂的飲食被廣泛認為是導致全球肥胖盛行的主要因素 [9][10][11]，然而，僅有少數研究探討飲食誘導的肥胖如何在基因層面同時影響多個器官。

為對抗肥胖，科學界投入大量研究並提出多種減重策略 [12][13]。運動（EX）、間歇性斷食（IF）與改善飲食習慣（從不健康飲食轉換為健康飲食）均被證實可預防肥胖及其相關的代謝疾病 [14][15][16]。儘管過去已有研究探討減重策略的成效及其潛在機制 [17][18][19]，但至今尚無研究揭示這些策略如何在多個器官中系統性地影響基因表達。

值得注意的是，減重後的體重回升是肥胖者普遍面臨的問題，也是長期管理體重與健康的核心挑戰 [20][21][22][23]。一項針對 29 項人類試驗的統合分析顯示，在低熱量飲食（無論是否搭配運動）進行長期追蹤後，約一半的減重成果在兩年內回升，而五年內回升比例超過 75% [24]。除了減重介入措施的依從性問題外，骨骼肌與脂肪組織的調控涉及多種生理機制，遠超過單純的飲食與運動影響。因此，全面解析多組織的轉錄組，並識別與體重回升相關的潛在標的，對於制定有效的肥胖管理策略至關重要。然而，迄今尚無研究對此進行完整的特徵描繪。

本研究運用高通量轉錄組技術，解析飲食誘導的肥胖對小鼠四種不同組織的影響，包括肩胛棕色脂肪組織（BAT）、腹股溝白色脂肪組織（iWAT）、肝臟與股四頭肌（QFM）。我們透過深入分析，探討運動（EX）、間歇性斷食（IF）與飲食替換（DR）如何分別影響組織特異性基因，進而協調複雜的代謝穩態。此外，我們進一步研究體重回升對曾經肥胖的小鼠代謝參數的影響，並探討減重後基因表達變化與體重回升的關聯程度。本研究提供了創新且有力的證據，揭示不同減重策略對代謝狀態、多組織基因表達的影響，以及調控體重回升的關鍵基因，這些發現具有深遠的臨床意義。

本研究選用健康的雄性 C57BL/6 小鼠（體重 15–18 g），購自中國西安的陝西師範大學動物實驗中心。小鼠飼養於標準化實驗室環境，12 小時明暗循環，室溫控制在 22 ± 2 ℃，濕度維持在 60%。經過一週適應性餵養後，隨機分為正常對照組（NC，n = 15）及高脂高果糖飲食組（HFHF，n = 60），後者餵食高脂飼料並提供含 20% 果糖的自來水，共持續八週。

肥胖已成為全球主要健康問題，並與多種健康狀況密切相關 [1][3][4]。以高脂與高果糖為特徵的西方飲食風行全球，導致肥胖及其相關代謝疾病的高發生率 [30][31]。本研究發現，HFHF 飲食顯著增加小鼠體重（圖 1A）、腹股溝白色脂肪（iWAT）及肝臟重量（圖 1B），並伴隨空腹血糖上升、葡萄糖耐受性降低及胰島素敏感性下降（圖略）。

肥胖及其相關代謝性疾病對公共衛生構成重大挑戰。深入了解減重介入措施的影響，對長期體重管理至關重要。本研究證實，HFHF 飲食對脂肪組織、骨骼肌與肝臟的代謝穩態及炎症反應產生不良影響。短期運動（EX）、間歇性斷食（IF）或將每日飲食從 HFHF 轉換為正常飼料（NC）能有效逆轉飲食誘導的肥胖，但其對代謝的影響存在顯著差異。

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