title: Nitric Oxide Produced by Macrophages Inhibits Adipocyte Differentiation and Promotes Profibrogenic Responses in Preadipocytes to Induce Adipose Tissue Fibrosis.
abstract: Fibrosis of adipose tissue induces ectopic fat accumulation and insulin resistance by inhibiting adipose tissue expandability. Mechanisms responsible for the induction of adipose tissue fibrosis may provide therapeutic targets but are poorly understood. In this study, high-fat diet (HFD)-fed wild-type (WT) and iNOS(-/-) mice were used to examine the relationship between nitric oxide (NO) produced by macrophages and adipose tissue fibrosis. In contrast to WT mice, iNOS(-/-) mice fed an HFD were protected from infiltration of proinflammatory macrophages and adipose tissue fibrosis. Hypoxia-inducible factor 1α (HIF-1α) protein level was increased in adipose tissue of HFD-fed WT mice, but not iNOS(-/-) mice. In contrast, the expression of mitochondrial biogenesis factors was decreased in HFD-fed WT mice, but not iNOS(-/-) mice. In studies with cultured cells, macrophage-derived NO decreased the expression of mitochondrial biogenesis factors, and increased HIF-1α protein level, DNA damage, and phosphorylated p53 in preadipocytes. By activating p53 signaling, NO suppressed peroxisome proliferator-activated receptor γ coactivator 1α expression, which induced mitochondrial dysfunction and inhibited preadipocyte differentiation in adipocytes. The effects of NO were blocked by rosiglitazone. The findings suggest that NO produced by macrophages induces mitochondrial dysfunction in preadipocytes by activating p53 signaling, which in turn increases HIF-1α protein level and promotes a profibrogenic response in preadipocytes that results in adipose tissue fibrosis.
authors.affiliation: Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea Metabolism Research Unit, Asan Institute for Life Sciences, Seoul, Republic of Korea.
authors.forename: Jung Eun
authors.initials: JE
authors.lastname: Jang
authors.affiliation: Metabolism Research Unit, Asan Institute for Life Sciences, Seoul, Republic of Korea.
authors.forename: Myoung Seok
authors.initials: MS
authors.lastname: Ko
authors.affiliation: Metabolism Research Unit, Asan Institute for Life Sciences, Seoul, Republic of Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Yun
authors.affiliation: Metabolism Research Unit, Asan Institute for Life Sciences, Seoul, Republic of Korea.
authors.forename: Mi-Ok
authors.initials: MO
authors.lastname: Kim
authors.affiliation: Metabolism Research Unit, Asan Institute for Life Sciences, Seoul, Republic of Korea.
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Metabolism Research Unit, Asan Institute for Life Sciences, Seoul, Republic of Korea.
authors.forename: Hye Sun
authors.initials: HS
authors.lastname: Park
authors.affiliation: Metabolism Research Unit, Asan Institute for Life Sciences, Seoul, Republic of Korea.
authors.forename: Ah-Ram
authors.initials: AR
authors.lastname: Kim
authors.affiliation: Metabolism Research Unit, Asan Institute for Life Sciences, Seoul, Republic of Korea.
authors.forename: Hyuk-Joong
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Metabolism Research Unit, Asan Institute for Life Sciences, Seoul, Republic of Korea.
authors.forename: Bum Joong
authors.initials: BJ
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea Metabolism Research Unit, Asan Institute for Life Sciences, Seoul, Republic of Korea.
authors.forename: Young Eun
authors.initials: YE
authors.lastname: Ahn
authors.affiliation: Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea Metabolism Research Unit, Asan Institute for Life Sciences, Seoul, Republic of Korea.
authors.forename: Jin Sun
authors.initials: JS
authors.lastname: Oh
authors.affiliation: Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea Metabolism Research Unit, Asan Institute for Life Sciences, Seoul, Republic of Korea.
authors.forename: Woo Je
authors.initials: WJ
authors.lastname: Lee
authors.affiliation: Richard L. Roudebush VA Medical Center and the Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harris
authors.affiliation: Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea Metabolism Research Unit, Asan Institute for Life Sciences, Seoul, Republic of Korea ehk@amc.seoul.kr kulee@amc.seoul.kr.
authors.forename: Eun Hee
authors.initials: EH
authors.lastname: Koh
authors.affiliation: Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea Metabolism Research Unit, Asan Institute for Life Sciences, Seoul, Republic of Korea ehk@amc.seoul.kr kulee@amc.seoul.kr.
authors.forename: Ki-Up
authors.initials: KU
authors.lastname: Lee
mesh_terms: D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005355:Fibrosis / Q000209:etiology / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D005951:Glucose Tolerance Test; D007550:Isothiuronium / Q000031:analogs & derivatives / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism*; D000067996:RAW 264.7 Cells
chemical_list: D004791:Enzyme Inhibitors; D009573:Nitrites; D007550:Isothiuronium; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C027744:S-methylisothiopseudouronium