Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance.
OBJECTIVE
Increased activity of the innate immune system has been implicated in the pathogenesis of the dyslipidemia and insulin resistance associated with obesity and type 2 diabetes. In this study, we addressed the potential role of Kupffer cells (liver-specific macrophages, KCs) in these metabolic abnormalities.


METHODS
Rats were depleted of KCs by administration of gadolinium chloride, after which all animals were exposed to a 2-week high-fat or high-sucrose diet. Subsequently, the effects of these interventions on the development of hepatic insulin resistance and steatosis were assessed. In further studies, the effects of M1-polarized KCs on hepatocyte lipid metabolism and insulin sensitivity were addressed.


RESULTS
As expected, a high-fat or high-sucrose diet induced steatosis and hepatic insulin resistance. However, these metabolic abnormalities were prevented when liver was depleted of KCs. In vitro, KCs recapitulated the in vivo effects of diet by increasing hepatocyte triglyceride accumulation and fatty acid esterification, and decreasing fatty acid oxidation and insulin responsiveness. To address the mechanisms(s) of KC action, we inhibited a panel of cytokines using neutralizing antibodies. Only neutralizing antibodies against tumor necrosis factor-alpha (TNFalpha) attenuated KC-induced alterations in hepatocyte fatty acid oxidation, triglyceride accumulation, and insulin responsiveness. Importantly, KC TNFalpha levels were increased by diet in vivo and in isolated M1-polarized KCs in vitro.


CONCLUSIONS
These data demonstrate a role for liver macrophages in diet-induced alterations in hepatic lipid metabolism and insulin sensitivity, and suggest a role for these cells in the etiology of the metabolic abnormalities of obesity/type 2 diabetes.
Huang
Wan
W
Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Metlakunta
Anantha
A
Dedousis
Nikolaos
N
Zhang
Pili
P
Sipula
Ian
I
Dube
John J
JJ
Scott
Donald K
DK
O'Doherty
Robert M
RM
D000273:Adipose Tissue / Q000473:pathology; D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D000943:Antigens, Differentiation / Q000235:genetics; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics; D004041:Dietary Fats / Q000494:pharmacology; D002149:Energy Intake; D005234:Fatty Liver / Q000517:prevention & control*; D005682:Gadolinium / Q000494:pharmacology; D015309:Glucose Clamp Technique; D022781:Hepatocytes / Q000166:cytology / Q000473:pathology; D007150:Immunohistochemistry; D007333:Insulin Resistance / Q000502:physiology*; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D008099:Liver / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D013395:Sucrose / Q000494:pharmacology; D000097382:CD68 Molecule
D015703:Antigens, CD; D000943:Antigens, Differentiation; D015214:Antigens, Differentiation, Myelomonocytic; D004041:Dietary Fats; D005682:Gadolinium; D008562:Membrane Glycoproteins; D013395:Sucrose; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C036763:monocyte-macrophage differentiation antigen; C038958:gadolinium chloride