C-C chemokine receptor 2 (CCR2) regulates the hepatic recruitment of myeloid cells that promote obesity-induced hepatic steatosis.
OBJECTIVE
Obesity induces a program of systemic inflammation that is implicated in the development of many of its clinical sequelae. Hepatic inflammation is a feature of obesity-induced liver disease, and our previous studies demonstrated reduced hepatic steatosis in obese mice deficient in the C-C chemokine receptor 2 (CCR2) that regulates myeloid cell recruitment. This suggests that a myeloid cell population is recruited to the liver in obesity and contributes to nonalcoholic fatty liver disease.


METHODS
We used fluorescence-activated cell sorting to measure hepatic leukocyte populations in genetic and diet forms of murine obesity. We characterized in vivo models that increase and decrease an obesity-regulated CCR2-expressing population of hepatic leukocytes. Finally, using an in vitro co-culture system, we measured the ability of these cells to modulate a hepatocyte program of lipid metabolism.


RESULTS
We demonstrate that obesity activates hepatocyte expression of C-C chemokine ligand 2 (CCL2/MCP-1) leading to hepatic recruitment of CCR2(+) myeloid cells that promote hepatosteatosis. The quantity of these cells correlates with body mass and in obese mice represents the second largest immune cell population in the liver. Hepatic expression of CCL2 increases their recruitment and in the presence of dietary fat induces hepatosteatosis. These cells activate hepatic transcription of genes responsible for fatty acid esterification and steatosis.


CONCLUSIONS
Obesity induces hepatic recruitment of a myeloid cell population that promotes hepatocyte lipid storage. These findings demonstrate that recruitment of myeloid cells to metabolic tissues is a common feature of obesity, not limited to adipose tissue.
Obstfeld
Amrom E
AE
Department of Medicine, Columbia University, New York, New York, USA.
Sugaru
Eiji
E
Thearle
Marie
M
Francisco
Anne-Marie
AM
Gayet
Constance
C
Ginsberg
Henry N
HN
Ables
Eleanore V
EV
Ferrante
Anthony W
AW
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001786:Blood Glucose / Q000032:analysis; D016026:Bone Marrow Transplantation; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics; D004041:Dietary Fats / Q000494:pharmacology; D005234:Fatty Liver / Q000235:genetics / Q000503:physiopathology; D005260:Female; D005784:Gene Amplification; D006801:Humans; D007328:Insulin / Q000097:blood; D007668:Kidney / Q000196:embryology; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000502:physiology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000502:physiology; D009765:Obesity / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D054390:Receptors, CCR2 / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D001786:Blood Glucose; C111835:CCL2 protein, human; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D004041:Dietary Fats; D007328:Insulin; D054390:Receptors, CCR2; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase