Qiu Yifu, Nguyen Khoa D, Odegaard Justin I, Cui Xiaojin, Tian Xiaoyu, Locksley Richard M, Palmiter Richard D, Chawla Ajay
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158-9001, USA.
Departments of Medicine and Microbiology and Immunology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158-9001, USA; Howard Hughes Medical Institute, Department of Biochemistry, University of Washington, Seattle, WA 98195-7350, USA.
Cell. 2014 Jun 5;157(6):1292-1308. doi: 10.1016/j.cell.2014.03.066.
Beige fat, which expresses the thermogenic protein UCP1, provides a defense against cold and obesity. Although a cold environment is the physiologic stimulus for inducing beige fat in mice and humans, the events that lead from the sensing of cold to the development of beige fat remain poorly understood. Here, we identify the efferent beige fat thermogenic circuit, consisting of eosinophils, type 2 cytokines interleukin (IL)-4/13, and alternatively activated macrophages. Genetic loss of eosinophils or IL-4/13 signaling impairs cold-induced biogenesis of beige fat. Mechanistically, macrophages recruited to cold-stressed subcutaneous white adipose tissue (scWAT) undergo alternative activation to induce tyrosine hydroxylase expression and catecholamine production, factors required for browning of scWAT. Conversely, administration of IL-4 to thermoneutral mice increases beige fat mass and thermogenic capacity to ameliorate pre-established obesity. Together, our findings have uncovered the efferent circuit controlling biogenesis of beige fat and provide support for its targeting to treat obesity.
米色脂肪表达产热蛋白UCP1，可抵御寒冷和肥胖。尽管寒冷环境是诱导小鼠和人类产生米色脂肪的生理刺激因素，但从感知寒冷到米色脂肪发育的过程仍知之甚少。在此，我们确定了传出性米色脂肪产热回路，该回路由嗜酸性粒细胞、2型细胞因子白细胞介素（IL）-4/13和替代性活化巨噬细胞组成。嗜酸性粒细胞或IL-4/13信号的基因缺失会损害寒冷诱导的米色脂肪生成。从机制上讲，招募到冷应激皮下白色脂肪组织（scWAT）的巨噬细胞会发生替代性活化，以诱导酪氨酸羟化酶表达和儿茶酚胺生成，这些是scWAT褐变所需的因素。相反，向处于热中性状态的小鼠注射IL-4可增加米色脂肪量和产热能力，以改善已有的肥胖状况。总之，我们的研究结果揭示了控制米色脂肪生成的传出回路，并为将其作为治疗肥胖症的靶点提供了支持。
