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- Title
Myeloid Sirtuin 6 Deficiency Causes Insulin Resistance in High-Fat Diet-Fed Mice by Eliciting Macrophage Polarization Toward an M1 Phenotype.
- Authors
Youngyi Lee; Sun-O Ka; Hye-Na Cha; Yu-Na Chae; Mi-Kyung Kim; So-Young Park; Eun Ju Bae; Byung-Hyun Park; Lee, Youngyi; Ka, Sun-O; Cha, Hye-Na; Chae, Yu-Na; Kim, Mi-Kyung; Park, So-Young; Bae, Eun Ju; Park, Byung-Hyun
- Abstract
Obesity-related insulin resistance is closely associated with macrophage accumulation and subsequent cytokine release in local tissues. Sirtuin 6 (Sirt6) is known to exert an anti-inflammatory function, but its role in macrophages in the context of obesity has not been investigated. We generated myeloid-specific Sirt6 knockout (mS6KO) mice and investigated the metabolic characteristics after high-fat diet (HFD) feeding for 16 weeks. Compared with their wild-type littermates, HFD-fed mS6KO mice exhibited greater increases in body weight, fasting blood glucose and insulin levels, hepatic steatosis, glucose intolerance, and insulin resistance. Gene expression, histology, and flow cytometric analyses demonstrated that liver and adipose tissue inflammation were elevated in HFD-fed mS6KO mice relative to wild type, with a greater accumulation of F4/80+CD11b+CD11c+ adipose tissue macrophages. Myeloid Sirt6 deletion facilitated proinflammatory M1 polarization of bone marrow macrophages and augmented the migration potential of macrophages toward adipose-derived chemoattractants. Mechanistically, Sirt6 deletion in macrophages promoted the activation of nuclear factor-κB (NF-κB) and endogenous production of interleukin-6, which led to STAT3 activation and the positive feedback circuits for NF-κB stimulation; this cross talk expedited an M1 polarization. We conclude that Sirt6 in macrophages is required for the prevention of obesity-associated tissue inflammation and insulin resistance.
- Subjects
SIRTUINS; INSULIN resistance; OBESITY complications; HIGH-fat diet; OBESITY; ADIPOSE tissues; ANIMAL experimentation; CARRIER proteins; CELL lines; CELL physiology; CELLS; DIET; INFLAMMATION; INTERLEUKINS; LIVER; MACROPHAGES; MICE; POLYMERASE chain reaction; WESTERN immunoblotting; DNA-binding proteins; REVERSE transcriptase polymerase chain reaction; GLUCOSE intolerance
- Publication
Diabetes, 2017, Vol 66, Issue 10, p2659
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db16-1446