Macrophage phenotype and function in adipose tissue

描述（由申请人提供）：脂肪细胞是脂肪组织中主要和最独特的细胞群，被认为是肥胖最显著改变的细胞。然而，脂肪组织库含有非脂肪细胞群，包括内皮细胞、成纤维细胞、脂肪祖细胞和常驻巨噬细胞。这些非脂肪细胞在正常生理学中的功能以及它们因肥胖和衰老而发生的改变在很大程度上仍未被探索。我们实验室最近的工作表明，脂肪组织巨噬细胞（ATM）显着改变肥胖，并可能在脂肪细胞组织生理学中发挥重要作用。在小鼠中，内脏脂肪组织的表达谱揭示了巨噬细胞转录物与体重和脂肪细胞大小的强正相关性。组织学检查证实，随着肥胖的增加，性腺周围、网膜和肾周围的ATM数量也在增加。值得注意的是，在严重肥胖（B6.V Lepop/op）小鼠中，内脏脂肪库中近50%的细胞是巨噬细胞。肥胖也改变ATM的形态，导致多核巨细胞的出现，使人想起在慢性炎症性疾病如结节病和韦格纳肉芽肿病中看到的那些。ATM数量和形态的这些改变与先前报道的肥胖内脏脂肪组织产生促炎细胞因子和因子相关。在皮下贮库中观察到ATM数量和形态的显著但不太显著的变化。巨噬细胞缺陷型（B6 C3 Fe Csflop/op）小鼠在皮下贮库中显示出脂肪量的优先积累。因此，我们假设肥胖改变ATM的数量和激活状态，进而调节脂肪细胞发育和代谢功能，并可能是代谢综合征患者中注意到的促炎表型的原因。本研究的目的是：（1）从瘦小鼠和肥胖小鼠的内脏和皮下脂肪组织中，对脂肪组织巨噬细胞进行表型表征;（2）开发体外系统以测定脂肪组织巨噬细胞对脂肪细胞的代谢和发育影响，和（3）表征改变的脂肪组织巨噬细胞数量和功能对脂肪细胞肥大和增生的体内影响，和全身胰岛素敏感性。

DESCRIPTION (provided by applicant): Adipocytes are the primary and most distinctive cell population within adipose tissue and are thought to be the cells most significantly altered by obesity. However, adipose tissue depots contain non-adipocyte populations, including endothelial cells, fibroblasts, adipocyte progenitors and resident macrophages. The function of these non-adipocytes in normal physiology and their alteration by obesity and aging remain largely unexplored. Recent work in our laboratory has revealed that adipose tissue macrophages (ATM's) are dramatically altered by obesity and may play an essential role in adipocyte tissue physiology. In mice, expression profiles of visceral adipose tissue reveal a strong positive correlation of macrophage transcripts with body mass and adipocyte size. Histological examination confirms increasing numbers of ATM's in perigonadal, omental and perirenal depots with increasing obesity. Remarkably, in severely obese (B6.V Lepop/op) mice, nearly 50 percent of cells within visceral adipose depots are macrophages. Obesity also alters the morphology of ATM's, leading to the appearance of multinucleated giant cells, reminiscent of those seen in chronic inflammatory conditions such as sarcoidosis and Wegner's granulomatosis. These alterations in ATM number and morphology correlate with previously reported production of pro-inflammatory cytokines and factors by obese visceral adipose tissue. Significant but less dramatic changes in ATM number and morphology are noted in subcutaneous depots. Macrophage deficient (B6C3Fe Csflop/op) mice show preferential accumulation of adipose mass in subcutaneous depots. We therefore hypothesize that obesity alters the number and activation state of ATM's that in turn modulate adipocyte development and metabolic function and may be responsible for the pro-inflammatory phenotype noted in patients with the metabolic syndrome. The aims of this proposal are to: (1) Phenotypically characterize adipose tissue macrophages from visceral and subcutaneous adipose tissue in lean and obese mice; (2) Develop in vitro systems to assay the metabolic and developmental effects of adipose tissue macrophages on adipocytes and (3) Characterize the in vivo effects of altered adipose tissue macrophage number and function on the hypertrophy and hyperplasia of adipocytes, and on systemic insulin sensitivity.