Nitric Oxide Produced by Macrophages Inhibits Adipocyte Differentiation and Promotes Profibrogenic Responses in Preadipocytes to Induce Adipose Tissue Fibrosis

• Published in: Diabetes (New York, N.Y.) Vol. 65; no. 9; pp. 2516 - 2528
• Main Authors: Jang, Jung Eun, Ko, Myoung Seok, Yun, Ji-Young, Kim, Mi-Ok, Kim, Jin Hee, Park, Hye Sun, Kim, Ah-Ram, Kim, Hyuk-Joong, Kim, Bum Joong, Ahn, Young Eun, Oh, Jin Sun, Lee, Woo Je, Harris, Robert A, Koh, Eun Hee, Lee, Ki-Up
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01-09-2016
• Subjects: Adipocytes; Adipocytes - cytology; Adipocytes - drug effects; Adipocytes - metabolism; Animals; Cell Differentiation - drug effects; Cells, Cultured; Diet; Enzyme Inhibitors - pharmacology; Fibrosis - etiology; Fibrosis - metabolism; Fluorescent Antibody Technique; Glucose Tolerance Test; Insulin resistance; Isothiuronium - analogs & derivatives; Isothiuronium - pharmacology; Macrophages - drug effects; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - antagonists & inhibitors; Nitric Oxide Synthase Type II - metabolism; Nitrites - metabolism; Oils & fats; RAW 264.7 Cells; Rodents; Tissues
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db15-1624

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.