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Publication
CD40 deficiency in mice exacerbates obesity-induced adipose tissue inflammation,
hepatic steatosis, and insulin resistance.
Authors Guo CA, Kogan S, Amano SU, Wang M, Dagdeviren S, Friedline RH, Aouadi M, Kim JK,
Czech MP
Submitted By Michael Czech on 10/29/2013
Status Published
Journal American journal of physiology. Endocrinology and metabolism
Year 2013
Date Published
Volume : Pages 304 : E951 - E963
PubMed Reference 23482447
Abstract The pathophysiology of obesity and type 2 diabetes in rodents and humans is
characterized by low-grade inflammation 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. 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, 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(-/-) 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
its inflammation in obesity, thereby protecting against hepatic steatosis.




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