Next-generation sequencing facilitates quantitative analysis of T1-T4 sympathetic ganglia transcriptomes from TRKC+/-, AdNTF3-Tg and their respective wild type control mice after 1 day cold exposure at 5℃

Activation of brown fat thermogenesis increases energy expenditure and alleviates obesity. Sympathetic nervous system (SNS) is important in brown/beige adipocyte thermogenesis. Here we discover a novel fat-derived “adipokine” neurotrophic factor neurotrophin 3 (NTF3) and its receptor Tropomyosin receptor kinase C (TRKC) as key regulators of SNS growth and innervation in adipose tissue. NTF3 is highly expressed in brown/beige adipocytes, and potently stimulates sympathetic neuron neurite growth. NTF3/TRKC regulates a plethora of pathways in neuronal axonal growth and elongation. Adipose tissue sympathetic innervation is significantly increased in mice with adipocyte-specific NTF3 overexpression, but profoundly reduced in mice with TRKC haploinsufficiency (TRKC+/-). Increasing NTF3 via pharmacological or genetic approach promotes beige adipocyte development, enhances cold-induced thermogenesis and protects against diet-induced obesity (DIO); whereas TRKC+/- mice or SNS TRKC deficient mice are cold intolerant and prone to DIO. Thus, NTF3 is an important fat-derived neurotrophic factor regulating SNS innervation, energy metabolism and obesity. T1-T4 sympathetic ganglia (which innervate into iBAT) mRNA profiles of 12-week-old WT and TrkC+/- as well as WT and AdNTF3-Tg mice after 1 day cold exposure at 5℃

棕色脂肪产热激活可提升能量消耗并缓解肥胖。交感神经系统（sympathetic nervous system，简称SNS）在棕色/米色脂肪细胞产热过程中发挥关键调控作用。本研究发现了一种全新的脂肪源性脂肪因子神经营养素3（neurotrophin 3，简称NTF3）及其受体原肌球蛋白受体激酶C（Tropomyosin receptor kinase C，简称TRKC），二者是脂肪组织交感神经生长与支配的核心调控因子。NTF3在棕色/米色脂肪细胞中呈高表达状态，可强效刺激交感神经元的神经突生长；NTF3/TRKC信号通路调控神经元轴突生长与延伸的多条生物学通路。脂肪细胞特异性NTF3过表达小鼠的脂肪组织交感神经支配水平显著升高，而TRKC单倍体功能不足（TRKC+/-）小鼠的该指标则显著降低。通过药理学或遗传学手段上调NTF3水平，可促进米色脂肪细胞生成、增强冷诱导产热，并对饮食诱导肥胖（diet-induced obesity，简称DIO）起到防护作用；反之，TRKC+/-小鼠或交感神经TRKC缺陷小鼠则表现出耐寒能力受损，且更易罹患饮食诱导肥胖。综上，NTF3是一类重要的脂肪源性神经营养因子，可调控交感神经支配、能量代谢与肥胖发生。本研究采集了5℃冷暴露1天后的12周龄野生型（WT）、TRKC+/-小鼠以及野生型、脂肪细胞特异性NTF3转基因（AdNTF3-Tg）小鼠的T1-T4交感神经节（该神经节支配肩胛间棕色脂肪组织iBAT）的mRNA表达谱。