Cheong Lenny Yi Tong, Saipuljumri Eka Norfaishanty, Loi Gavin Wen Zhao, Zeng Jialiu, Lo Chih Hung
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 308232, Singapore.
Program in Neuroscience & Cognitive Science, University of Arizona, Tucson, AZ, 85721, USA.
Curr Obes Rep. 2025 May 14;14(1):43. doi: 10.1007/s13679-025-00638-8.
PURPOSE OF REVIEW: Obesity is a global health crisis affecting individuals across all age groups, significantly increasing the risk of metabolic disorders such as type 2 diabetes (T2D), metabolic dysfunction-associated fatty liver disease (MAFLD), and cardiovascular diseases. The World Health Organization reported in 2022 that 2.5 billion adults were overweight, with 890 million classified as obese, emphasizing the urgent need for effective interventions. A critical aspect of obesity's pathophysiology is meta-inflammation-a chronic, systemic low-grade inflammatory state driven by excess adipose tissue, which disrupts metabolic homeostasis. This review examines the role of autolysosomal dysfunction in obesity-related metabolic disorders, exploring its impact across multiple metabolic organs and evaluating potential therapeutic strategies that target autophagy and lysosomal function. RECENT FINDINGS: Emerging research highlights the importance of autophagy in maintaining cellular homeostasis and metabolic balance. Obesity-induced lysosomal dysfunction impairs the autophagic degradation process, contributing to the accumulation of damaged organelles and toxic aggregates, exacerbating insulin resistance, lipotoxicity, and chronic inflammation. Studies have identified autophagic defects in key metabolic tissues, including adipose tissue, skeletal muscle, liver, pancreas, kidney, heart, and brain, linking autophagy dysregulation to the progression of metabolic diseases. Preclinical investigations suggest that pharmacological and nutritional interventions-such as AMPK activation, caloric restriction mimetics, and lysosomal-targeting compounds-can restore autophagic function and improve metabolic outcomes in obesity models. Autolysosomal dysfunction is a pivotal contributor to obesity-associated metabolic disorders , influencing systemic inflammation and metabolic dysfunction. Restoring autophagy and lysosomal function holds promise as a therapeutic strategy to mitigate obesity-driven pathologies. Future research should focus on translating these findings into clinical applications, optimizing targeted interventions to improve metabolic health and reduce obesity-associated complications.
综述目的:肥胖是一场全球性的健康危机,影响着所有年龄组的人群,显著增加了2型糖尿病(T2D)、代谢功能障碍相关脂肪性肝病(MAFLD)和心血管疾病等代谢紊乱的风险。世界卫生组织在2022年报告称,25亿成年人超重,其中8.9亿人被归类为肥胖,这凸显了有效干预措施的迫切需求。肥胖病理生理学的一个关键方面是元炎症——一种由过多脂肪组织驱动的慢性、全身性低度炎症状态,它会破坏代谢稳态。本综述探讨了自溶酶体功能障碍在肥胖相关代谢紊乱中的作用,研究其在多个代谢器官中的影响,并评估针对自噬和溶酶体功能的潜在治疗策略。 最新发现:新出现的研究强调了自噬在维持细胞内稳态和代谢平衡中的重要性。肥胖诱导的溶酶体功能障碍会损害自噬降解过程,导致受损细胞器和有毒聚集体的积累,加剧胰岛素抵抗、脂毒性和慢性炎症。研究已经确定了关键代谢组织中的自噬缺陷,包括脂肪组织、骨骼肌、肝脏、胰腺、肾脏、心脏和大脑,将自噬失调与代谢疾病的进展联系起来。临床前研究表明,药理学和营养干预措施,如激活AMPK、热量限制模拟物和靶向溶酶体的化合物,可以恢复自噬功能,并改善肥胖模型中的代谢结果。自溶酶体功能障碍是肥胖相关代谢紊乱的关键促成因素,影响全身炎症和代谢功能障碍。恢复自噬和溶酶体功能有望成为减轻肥胖驱动的病理状况的治疗策略。未来的研究应专注于将这些发现转化为临床应用,优化靶向干预措施,以改善代谢健康并减少肥胖相关并发症。
Curr Obes Rep. 2025-5-14
Arch Ital Urol Androl. 2025-6-30
Int J Mol Sci. 2024-12-14
Cochrane Database Syst Rev. 2018-2-6
Cochrane Database Syst Rev. 2023-3-27
Prostaglandins Other Lipid Mediat. 2025-4-1
Clin Exp Nephrol. 2025-3-25
Front Endocrinol (Lausanne). 2025-2-11
Front Endocrinol (Lausanne). 2025-1-17
Biochim Biophys Acta Biomembr. 2025-1