Local Macrophage Proliferation in Adipose Tissue Is a Characteristic of Obesity-Associated Inflammation: A Dissertation

Obesity and diabetes are major public health problems facing the world today. Extending our understanding of adipose tissue biology, and how it changes in obesity, will hopefully better equip our society in dealing with the obesity epidemic. Macrophages and other immune cells accumulate in the adipose tissue in obesity and secrete cytokines that can promote insulin resistance. Adipose tissue macrophages (ATMs) are thought to originate from bone marrow-derived monocytes, which infiltrate the tissue from the circulation. Much work has been done to demonstrate that inhibition of monocyte recruitment to the adipose tissue can ameliorate insulin resistance. While monocytes can enter the adipose tissue, we have shown here that local macrophage proliferation may be the predominant mechanism by which macrophages self-renew in the adipose tissue. We demonstrated that two cell proliferation markers, Ki67 and EdU, can be readily detected in macrophages isolated from adipose tissue of both lean and obese mice. These analyses revealed that 2-4% of ATMs in lean and 10-20% of ATMs in obese mice express the proliferation marker Ki67. Importantly, Ki67+ macrophages were identified within the adipose tissue in crown-like structures. Similarly, a 3-hour in vivo pulse with the thymidine analog EdU showed that nearly 5% of macrophages in epididymal adipose tissue of ob/ob mice were in the S-phase of cell division. Interestingly, obesity increased the rate of macrophage proliferation in adipose tissue but did not affect macrophage proliferation in other tissues. We also used clodronate liposomes to deplete circulating monocytes in obese mice. Surprisingly, monocyte depletion for a total of at least 80 hours did not cause a decrease in ATM content in adipose tissue. Prolonged exposure of mice to