Kupffer cells facilitate the acute effects of leptin on hepatic lipid metabolism.
Leptin has potent effects on lipid metabolism in a number of peripheral tissues. In liver, an acute leptin infusion (~120 min) stimulates hepatic fatty acid oxidation (~30%) and reduces triglycerides (TG, ~40%), effects that are dependent on phosphoinositol-3-kinase (PI3K) activity. In the current study we addressed the hypothesis that leptin actions on liver-resident immune cells are required for these metabolic effects. Myeloid cell-specific deletion of the leptin receptor (ObR) in mice or depletion of liver Kupffer cells (KC) in rats in vivo prevented the acute effects of leptin on liver lipid metabolism, while the metabolic effects of leptin were maintained in mice lacking ObR in hepatocytes. Notably, liver TG were elevated in both lean and obese myeloid cell ObR, but the degree of obesity and insulin resistance induced by a high-fat diet was similar to control mice. In isolated primary hepatocytes (HEP), leptin had no effects on HEP lipid metabolism and only weakly stimulated PI3K. However, the coculture of KC with HEP restored leptin action on HEP fatty acid metabolism and stimulation of HEP PI3K. Notably, leptin stimulated the release from KC of a number of cytokines. However, the exposure of HEP to these cytokines individually [granulocyte macrophage colony-stimulating factor, IL-1α, IL-1β, IL-6, IL-10, and IL-18] or in combination had no effects on HEP lipid metabolism. Together, these data demonstrate a role for liver mononuclear cells in the regulation of liver lipid metabolism by leptin.
Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, Pennsylvania; and.
Anantha
A
Metlakunta
Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, Pennsylvania; and.
Wan
W
Huang
Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, Pennsylvania; and.
Maja
M
Stefanovic-Racic
Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, Pennsylvania; and.
Nikolaos
N
Dedousis
Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, Pennsylvania; and.
Ian
I
Sipula
Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, Pennsylvania; and rmo1@pitt.edu.|Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania.
Robert M
RM
O'Doherty
D000818:Animals; D016207:Cytokines / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology; D022781:Hepatocytes / Q000378:metabolism*; D016753:Interleukin-10 / Q000276:immunology; D020382:Interleukin-18 / Q000276:immunology; D053582:Interleukin-1alpha / Q000276:immunology; D053583:Interleukin-1beta / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D007728:Kupffer Cells / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D020738:Leptin / Q000378:metabolism*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D022423:Myeloid Cells / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D054411:Receptors, Leptin / Q000235:genetics; D014280:Triglycerides / Q000378:metabolism*
D016207:Cytokines; D020382:Interleukin-18; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D015850:Interleukin-6; D020738:Leptin; D054411:Receptors, Leptin; D014280:Triglycerides; D016753:Interleukin-10; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D058539:Phosphatidylinositol 3-Kinase
Kupffer cells; inflammation; leptin; lipids; steatosis