Macrophage VLDLR mediates obesity-induced insulin resistance with adipose tissue inflammation

Kyung Cheul Shin, Injae Hwang, Sung Sik Choe, Jeu Park, Yul Ji, Jong In Kim, Gha Young Lee, Sung Hee Choi, Jianhong Ching, Jean-Paul Kovalik and Jae Bum Kim ()
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Kyung Cheul Shin: National Creative Research Initiatives Center for Adipose Tissue Remodeling, Institute of Molecular Biology and Genetics, Seoul National University
Injae Hwang: National Creative Research Initiatives Center for Adipose Tissue Remodeling, Institute of Molecular Biology and Genetics, Seoul National University
Sung Sik Choe: National Creative Research Initiatives Center for Adipose Tissue Remodeling, Institute of Molecular Biology and Genetics, Seoul National University
Jeu Park: National Creative Research Initiatives Center for Adipose Tissue Remodeling, Institute of Molecular Biology and Genetics, Seoul National University
Yul Ji: National Creative Research Initiatives Center for Adipose Tissue Remodeling, Institute of Molecular Biology and Genetics, Seoul National University
Jong In Kim: National Creative Research Initiatives Center for Adipose Tissue Remodeling, Institute of Molecular Biology and Genetics, Seoul National University
Gha Young Lee: Seoul National University College of Medicine and Seoul National University Bundang Hospital
Sung Hee Choi: Seoul National University College of Medicine and Seoul National University Bundang Hospital
Jianhong Ching: Cardiovascular and Metabolic Disorders, Duke-NUS Medical School
Jean-Paul Kovalik: Cardiovascular and Metabolic Disorders, Duke-NUS Medical School
Jae Bum Kim: National Creative Research Initiatives Center for Adipose Tissue Remodeling, Institute of Molecular Biology and Genetics, Seoul National University

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract Obesity is closely associated with increased adipose tissue macrophages (ATMs), which contribute to systemic insulin resistance and altered lipid metabolism by creating a pro-inflammatory environment. Very low-density lipoprotein receptor (VLDLR) is involved in lipoprotein uptake and storage. However, whether lipid uptake via VLDLR in macrophages affects obesity-induced inflammatory responses and insulin resistance is not well understood. Here we show that elevated VLDLR expression in ATMs promotes adipose tissue inflammation and glucose intolerance in obese mice. In macrophages, VLDL treatment upregulates intracellular levels of C16:0 ceramides in a VLDLR-dependent manner, which potentiates pro-inflammatory responses and promotes M1-like macrophage polarization. Adoptive transfer of VLDLR knockout bone marrow to wild-type mice relieves adipose tissue inflammation and improves insulin resistance in diet-induced obese mice. These findings suggest that increased VLDL-VLDLR signaling in ATMs aggravates adipose tissue inflammation and insulin resistance in obesity.

Date: 2017
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DOI: 10.1038/s41467-017-01232-w

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