Cell子刊：毕艳/李靓合作发现中枢瘦素抵抗新机制，开辟肥胖治疗全新路径

Core Viewpoint - Obesity is a complex disease that significantly contributes to metabolic disorders and poses a heavy burden on healthcare systems. Current interventions have limited long-term efficacy, highlighting the need for a deeper understanding of the mechanisms behind obesity development [2]. Group 1: Mechanisms of Obesity - The primary cause of obesity is energy imbalance, where energy intake exceeds energy expenditure over time. The energy homeostasis is regulated by the brain-peripheral organ interaction, particularly through the gut-brain axis and the fat-brain axis [2]. - Research on the gut-brain axis has made significant progress, especially in targeting incretin pathways, while the core mechanisms of the fat-brain axis remain to be fully understood [2]. Group 2: Leptin Resistance - Leptin, a key feedback signal from adipose tissue, regulates energy balance by inhibiting food intake and promoting energy expenditure. However, obesity often leads to leptin resistance, disrupting the communication between adipose tissue and the brain [3][4]. - A recent study published in Cell Metabolism reveals a new mechanism driving central leptin resistance, identifying extracellular vesicles (EVs) derived from adipose tissue as crucial regulators of central leptin sensitivity [4][10]. Group 3: Role of Extracellular Vesicles - The study demonstrates that inhibiting adipose EV production in animal models leads to significant weight gain and increased body fat due to increased food intake and decreased energy expenditure [5]. - Only EVs from healthy mice effectively reduced weight and improved energy imbalance in obese mice, indicating the importance of healthy adipose EVs in maintaining energy homeostasis [5][6]. Group 4: Mechanisms of Action - The weight loss effect of adipose EVs relies on an intact leptin signaling pathway, as they do not induce weight loss in leptin-deficient mice [6]. - Adipose EVs can cross the blood-brain barrier and specifically target neurons expressing leptin receptors, enhancing central leptin sensitivity and maintaining energy balance [6][8]. Group 5: miRNA and Targeting Mechanisms - miRNA within adipose EVs are identified as key components mediating the effects on central leptin sensitivity. The study categorizes miRNAs into leptin-sensitizing and leptin-desensitizing types, with the former being crucial for preventing central leptin resistance [7][10]. - The research also identifies specific membrane proteins on adipose EVs that facilitate brain targeting, leading to the development of engineered EVs for delivering leptin-sensitizing miRNAs to the brain [8][10]. Group 6: Implications for Treatment - This research shifts the paradigm of leptin resistance from a central brain-focused approach to an inter-organ communication framework, opening new avenues for innovative obesity therapies targeting the fat-brain axis [10][11].