Manceau Romane, Anthony Pinçon, Hryhorczuk Cécile, Labbé Pauline, Thorin-Trescases Nathalie, Fulton Stephanie, Thorin Éric
Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CR-CHUM), Montréal, QC, Canada.
Department of Neurosciences, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.
Int J Obes (Lond). 2025 Mar 26. doi: 10.1038/s41366-025-01754-0.
Adipokines regulate body weight and metabolism by targeting the hypothalamus, influencing feeding, energy expenditure (EE) and insulin sensitivity. Angiopoietin-like 2 (Angptl2) is a pro-inflammatory adipokine linking obesity to insulin resistance. Both Angptl2 and its receptor are expressed in the central nervous system. Yet, the contribution of Angptl2 to the regulation of energy metabolism and relevant hypothalamic neuropeptides in male and female mice is unknown. We aim at determining the impact of Angptl2 knockdown (KD) on energy balance, nutrient partitioning and hypothalamic responses to a standard (STD) or high-fat diet (HFD) in mice.
Three-month-old male and female Angptl2-KD mice and wildtype (WT) littermates were fed 16 weeks either a STD or a HFD. Body weight, food consumption and insulin sensitivity were assessed along with measurements of EE, respiratory exchange ratio (RER) and locomotor activity. We quantified the expression of Angptl2 and its receptors itga5, mag and pirb in the medio-basal hypothalamus (MBH) of WT mice, and MBH neuropeptide Y (NPY), agouti-related neuropeptide (AgRP) and proopiomelanocortin (POMC) gene expression in both KD and control fasting mice.
Lack of Angptl2 reduced food intake in males on both diets, and in females on HFD. In KD males, this anorexigenic effect was associated with lower body weight, increased EE, improved insulin sensitivity and lower hypothalamic orexigenic NPY expression compared to controls. Female Angptl2-KD mice however, exhibited unaltered body weight, EE and insulin sensitivity, and elevated NPY, AgRP and MC4R expression compared to controls. Fasting caused an increase in the MBH of mag expression in males and females but Angptl2 expression only in female mice.
Angptl2 KD improved diet-induced obesity and associated metabolic dysfunction in male mice. The lack of similar changes in female mice and divergent MBH neuropeptide profile suggest that sex-dependent mechanisms underly the anabolic effects of this proinflammatory adipokine.
脂肪因子通过作用于下丘脑来调节体重和新陈代谢，影响进食、能量消耗（EE）和胰岛素敏感性。血管生成素样蛋白2（Angptl2）是一种促炎性脂肪因子，将肥胖与胰岛素抵抗联系起来。Angptl2及其受体均在中枢神经系统中表达。然而，Angptl2对雄性和雌性小鼠能量代谢调节及相关下丘脑神经肽的作用尚不清楚。我们旨在确定敲低（KD）Angptl2对小鼠能量平衡、营养分配以及下丘脑对标准（STD）或高脂饮食（HFD）的反应的影响。
对3个月大的雄性和雌性Angptl2-KD小鼠及野生型（WT）同窝小鼠喂食16周STD或HFD。评估体重、食物摄入量和胰岛素敏感性，并测量EE、呼吸交换率（RER）和运动活性。我们定量了WT小鼠中脑-基底下丘脑（MBH）中Angptl2及其受体itga5、mag和pirb的表达，以及KD和对照禁食小鼠中MBH神经肽Y（NPY）、刺鼠相关神经肽（AgRP）和阿黑皮素原（POMC）基因的表达。
缺乏Angptl2可降低两种饮食条件下雄性小鼠的食物摄入量，以及HFD条件下雌性小鼠的食物摄入量。与对照组相比，在KD雄性小鼠中，这种厌食作用与体重降低、EE增加、胰岛素敏感性改善以及下丘脑促食欲NPY表达降低有关。然而，雌性Angptl2-KD小鼠的体重、EE和胰岛素敏感性未改变，与对照组相比，NPY、AgRP和MC4R表达升高。禁食导致雄性和雌性小鼠MBH中mag表达增加，但仅在雌性小鼠中Angptl2表达增加。
敲低Angptl2可改善雄性小鼠饮食诱导的肥胖及相关代谢功能障碍。雌性小鼠缺乏类似变化以及MBH神经肽谱不同，表明性别依赖性机制是这种促炎性脂肪因子合成代谢作用的基础。
