Lipid-Associated Macrophages Reshape BAT Cell Identity in Obesity [DBDB_singlecell]. Lipid-Associated Macrophages Reshape BAT Cell Identity in Obesity [DBDB_singlecell]

Obesity and type 2 diabetes cause a loss in brown adipose tissue (BAT) activity in mice and human, but the molecular mechanisms that drive BAT cell remodeling remain largely. Using a multilayered approach, we comprehensively map a deep reorganization in the BAT cells. We uncovered a subset of macrophages as the lipid-associated macrophages (LAM), which were massively increased in genetic and dietary model of BAT expansion. LAM participate in this scenario by capturing extracellular vesicles carrying damaged lipids and mitochondria released from metabolically-stressed brown adipocytes. CD36 scavenger receptor drives LAM phenotype and through * in vitro* and *in vivo* models, we demonstrated that CD36-deficient LAM increased brown fat genes. LAM release Tgfb1 that reduces brown adipocytes identity through Aldh1a1 induction. This study provides the first description of cell dynamics in BAT of obese models identifying LAM as responder to tissue-level metabolic stress and key driver to loss of BAT cell identity. Overall design: Brown adipose tissue samples from 8-weeks and 16-weeks old WT, db/db and HFD mice with at least three biological replicates were used for expression profiling.

肥胖与2型糖尿病会导致小鼠及人类的棕色脂肪组织（brown adipose tissue, BAT）活性丧失，但驱动BAT细胞重塑的分子机制仍未完全阐明。本研究采用多层组学策略，全面绘制了BAT细胞的深度重编程图谱。我们发现一类巨噬细胞亚群为脂质相关巨噬细胞（lipid-associated macrophages, LAM），该类细胞在BAT扩张的遗传模型与饮食诱导模型中丰度显著升高。LAM通过捕获来自代谢应激状态下棕色脂肪细胞释放的、携带受损脂质与线粒体的细胞外囊泡，参与这一过程。CD36清道夫受体调控LAM表型；通过体外（in vitro）与体内（in vivo）实验模型，我们证实CD36缺陷型LAM会上调棕色脂肪相关基因的表达。LAM可分泌Tgfb1，通过诱导Aldh1a1的表达降低棕色脂肪细胞的细胞特性。本研究首次阐明了肥胖模型中BAT的细胞动态变化，确定LAM是组织水平代谢应激的响应细胞，同时是BAT细胞特性丧失的关键调控因子。实验设计：选取8周龄与16周龄的野生型（wild type, WT）、db/db小鼠及高脂饮食（high-fat diet, HFD）小鼠的棕色脂肪组织样本，每组至少设置3次生物学重复，用于表达谱分析。