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dc.contributor.advisorMichael Czech, PhD
dc.contributor.authorAmano, Shinya U.
dc.date2022-08-11T08:08:44.000
dc.date.accessioned2022-08-23T16:06:05Z
dc.date.available2022-08-23T16:06:05Z
dc.date.issued2013-03-27
dc.date.submitted2013-06-15
dc.identifier.doi10.13028/M2BW2Z
dc.identifier.urihttp://hdl.handle.net/20.500.14038/32004
dc.description.abstractObesity 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 EdU in drinking water revealed that approximately half of the ATMs in the epididymal fat pads of ob/ob mice had proliferated locally within 80 hours. Amazingly, these rates were the same with or without monocyte depletion, meaning that the proliferating cells were not freshly recruited monocytes. Overall, these results suggest that local proliferation unexpectedly makes a major contribution to maintaining the large population of macrophages present in the obese adipose tissue in the steady state. This suggests that increased rates of local macrophage proliferation may also be partly responsible for the massive increase in ATM content that occurs in obesity. This information could have implications for future therapeutic strategies in the management of diabetes.
dc.language.isoen_US
dc.rightsCopyright is held by the author, with all rights reserved.
dc.subjectDissertations, UMMS
dc.subjectAdipose Tissue
dc.subjectMacrophages
dc.subjectObesity
dc.subjectInflammation
dc.subjectDiabetes Mellitus
dc.subjectInsulin Resistance
dc.subjectAdipose Tissue
dc.subjectMacrophages
dc.subjectObesity
dc.subjectInflammation
dc.subjectDiabetes Mellitus
dc.subjectInsulin Resistance
dc.subjectCellular and Molecular Physiology
dc.subjectEndocrinology
dc.subjectNutritional and Metabolic Diseases
dc.subjectPhysiology
dc.titleLocal Macrophage Proliferation in Adipose Tissue Is a Characteristic of Obesity-Associated Inflammation: A Dissertation
dc.typeDoctoral Dissertation
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1652&context=gsbs_diss&unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_diss/652
dc.legacy.embargo2014-04-18T00:00:00-07:00
dc.identifier.contextkey4228074
refterms.dateFOA2022-08-25T05:27:31Z
html.description.abstract<p>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.</p> <p>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 <em> in vivo </em> pulse with the thymidine analog EdU showed that nearly 5% of macrophages in epididymal adipose tissue of <em> ob/ob </em> 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 EdU in drinking water revealed that approximately half of the ATMs in the epididymal fat pads of <em> ob/ob </em> mice had proliferated locally within 80 hours. Amazingly, these rates were the same with or without monocyte depletion, meaning that the proliferating cells were not freshly recruited monocytes.</p> <p>Overall, these results suggest that local proliferation unexpectedly makes a major contribution to maintaining the large population of macrophages present in the obese adipose tissue in the steady state. This suggests that increased rates of local macrophage proliferation may also be partly responsible for the massive increase in ATM content that occurs in obesity. This information could have implications for future therapeutic strategies in the management of diabetes.</p>
dc.identifier.submissionpathgsbs_diss/652
dc.contributor.departmentProgram in Molecular Medicine
dc.description.thesisprogramMD/PhD


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