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dc.contributor.advisorMichael Czech, PhD
dc.contributor.authorGuo, Chang-An
dc.date2022-08-11T08:08:44.000
dc.date.accessioned2022-08-23T16:06:17Z
dc.date.available2022-08-23T16:06:17Z
dc.date.issued2013-04-23
dc.date.submitted2013-12-23
dc.identifier.doi10.13028/M2VW2M
dc.identifier.urihttp://hdl.handle.net/20.500.14038/32032
dc.description.abstractThe past two decades have seen an explosive increase of obesity rates worldwide, with more than one billion adults overweight and 300 million of them obese. Obesity and its associated complications have become leading causes of morbidity and mortality in the United States and major contributing factors to the rising costs of national health care. The pathophysiology of obesity and type 2 diabetes in rodents and humans is characterized by low-grade inflammation and chronic activation of immune pathways in adipose tissue and liver. The CD40 receptor and its ligand, CD40L, initiate immune cell signaling promoting inflammation, but conflicting data on CD40L-null mice confound its role in obesity-associated insulin resistance. A clear understanding of how CD40 and its ligand communicate to regulate and sustain the inflammatory environment of obesity is lacking. Here we demonstrate that CD40 receptor deficient mice on a high-fat diet display the expected decrease in hepatic cytokine levels, but paradoxically exhibit liver steatosis, insulin resistance and glucose intolerance compared with their age-matched wild-type controls. Hyperinsulinemic-euglycemic clamp studies also demonstrated insulin resistance in glucose utilization by the CD40-null mice compared with wild-type mice. In contrast to liver, visceral adipose tissue in CD40 deficient animals harbors elevated cytokine levels and infiltration of inflammatory cells, particularly macrophages and CD8+ effector T cells. In addition, ex vivo explants of epididymal adipose tissue from CD40-null mice display elevated basal and isoproterenol-stimulated lipolysis, suggesting a potential increase of lipid efflux from visceral fat to the liver. These findings reveal that 1) CD40-null mice represent an unusual model of hepatic steatosis with reduced hepatic inflammation, and 2) CD40 unexpectedly functions in adipose tissue to attenuate the chronic inflammation associated with obesity, thereby protecting against hepatic steatosis.
dc.language.isoen_US
dc.rightsCopyright is held by the author, with all rights reserved.
dc.subjectDissertations, UMMS
dc.subjectAdipose Tissue
dc.subjectAntigens, CD40
dc.subjectObesity
dc.subjectFatty Liver
dc.subjectInsulin Resistance
dc.subjectInflammation
dc.subjectAdipose tissue inflammation
dc.subjectCD40
dc.subjectCD8+ T cell
dc.subjecthepatic steatosis
dc.subjectinsulin resistance
dc.subjectBiochemistry
dc.subjectCellular and Molecular Physiology
dc.subjectEndocrinology
dc.subjectImmunopathology
dc.subjectMolecular Genetics
dc.titleGenetic Deficiency of CD40 in Mice Exacerbates Metabolic Manifestations of Diet-induced Obesity: A Dissertation
dc.typeDoctoral Dissertation
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1680&context=gsbs_diss&unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_diss/678
dc.legacy.embargo2014-08-27T00:00:00-07:00
dc.identifier.contextkey4943389
refterms.dateFOA2022-08-26T03:58:00Z
html.description.abstract<p>The past two decades have seen an explosive increase of obesity rates worldwide, with more than one billion adults overweight and 300 million of them obese. Obesity and its associated complications have become leading causes of morbidity and mortality in the United States and major contributing factors to the rising costs of national health care.</p> <p>The pathophysiology of obesity and type 2 diabetes in rodents and humans is characterized by low-grade inflammation and chronic activation of immune pathways in adipose tissue and liver. The CD40 receptor and its ligand, CD40L, initiate immune cell signaling promoting inflammation, but conflicting data on CD40L-null mice confound its role in obesity-associated insulin resistance. A clear understanding of how CD40 and its ligand communicate to regulate and sustain the inflammatory environment of obesity is lacking. Here we demonstrate that CD40 receptor deficient mice on a high-fat diet display the expected decrease in hepatic cytokine levels, but paradoxically exhibit liver steatosis, insulin resistance and glucose intolerance compared with their age-matched wild-type controls. Hyperinsulinemic-euglycemic clamp studies also demonstrated insulin resistance in glucose utilization by the CD40-null mice compared with wild-type mice. In contrast to liver, visceral adipose tissue in CD40 deficient animals harbors elevated cytokine levels and infiltration of inflammatory cells, particularly macrophages and CD8+ effector T cells. In addition, <em>ex vivo</em> explants of epididymal adipose tissue from CD40-null mice display elevated basal and isoproterenol-stimulated lipolysis, suggesting a potential increase of lipid efflux from visceral fat to the liver.</p> <p>These findings reveal that 1) CD40-null mice represent an unusual model of hepatic steatosis with reduced hepatic inflammation, and 2) CD40 unexpectedly functions in adipose tissue to attenuate the chronic inflammation associated with obesity, thereby protecting against hepatic steatosis.</p>
dc.identifier.submissionpathgsbs_diss/678
dc.contributor.departmentProgram in Molecular Medicine
dc.description.thesisprogramInterdisciplinary Graduate Program


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