Cytokines suppress adipogenesis and PPAR-γ function through the TAK1/TAB1/NIK cascade

Suzawa, Miyuki; Takada, Ichiro; Yanagisawa, Junn; Ohtake, Fumiaki; Ogawa, Shinpei; Yamauchi, Toshimasa; Kadowaki, Tomoko; Takeuchi, Yasuhiro; Shibuya, H.; Gotoh, Yukiko; Matsumoto, Kunihiro; Kato, Shigeaki

doi:10.1038/ncb942

Cited by 270 publications

(209 citation statements)

References 30 publications

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“…Recent basic studies have shown that several cytokines implicated in the pathogenesis of SpA, such as TNF␣, transforming growth factor ␤, and bone morphogenetic protein 2, inhibit adipocyte differentiation from bone marrow stem cells (33)(34)(35). In murine adipose cell lines, conditioned media from lipopolysaccharideactivated macrophages strongly suppress differentiation in preadipocytes, which continue to proliferate and exhibit a fibroblastic appearance (36).…”

Section: Discussionmentioning

confidence: 99%

Focal fat lesions at vertebral corners on magnetic resonance imaging predict the development of new syndesmophytes in ankylosing spondylitis

Chiowchanwisawakit

Lambert

Conner‐Spady

et al. 2011

Arthritis & Rheumatism

178

113

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Objective. Focal fat infiltration is frequently visible on magnetic resonance imaging (MRI) of the spine in patients with ankylosing spondylitis (AS) and likely reflects postinflammatory tissue metaplasia. To support the concept of coupling between inflammation and new bone formation, we tested the hypothesis that focal fat infiltration at a vertebral corner is more likely to evolve into a de novo syndesmophyte.Methods. MRI scans were obtained at baseline and radiographs were obtained at baseline and 2 years in 100 AS patients from 2 cohorts: a clinical trial cohort (n ‫؍‬ 38) and an observational cohort (n ‫؍‬ 62). In the clinical trial cohort, patients were randomized to receive anti-tumor necrosis factor (anti-TNF) therapy or placebo for 12-24 weeks and then open-label treatment for 2 years. In the observational cohort, patients received either standard therapy (n ‫؍‬ 36) or anti-TNF therapy (n ‫؍‬ 26) for 2 years. Vertebral corner inflammation and fat infiltration were assessed independently by pairs of readers who were blinded with regard to the radiographic findings.Results. New syndesmophytes developed significantly more frequently in vertebral corners with fat in both the clinical trial (10.2%) and the observational (6.5%) cohort as compared to those without either Conclusion. Our data lend support to the hypothesis that inflammatory lesions evolve into new bone through a process of tissue metaplasia that includes fat infiltration.A hallmark of ankylosing spondylitis (AS) is the development of new bone in the spine, which typically leads to ankylosis across the disc spaces. Bone proliferation typically starts at the vertebral rim and grows in the direction of the anulus fibrosus, parallel to the vertebral axis. Ossification may extend across the vertical length of the anulus and becomes visible on radiographs as a syndesmophyte.Until recently, it was hypothesized that ankylosis occurred in response to inflammation and following a reparative process that included cartilage metaplasia. However, data from animal models of spondylarthritis (SpA), principally ankylosing enthesitis, directly challenged this hypothesis by demonstrating that anti-tumor necrosis factor ␣ (anti-TNF␣) therapy did not prevent the development of ankylosis (1). An alternative hypothesis was then proposed whereby pathogenetic factors such as altered gene expression, biomechanical factors, and bacteria trigger the concomitant expression of inflammation and new bone formation, which then proceed

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Section: Discussionmentioning

confidence: 99%

Focal fat lesions at vertebral corners on magnetic resonance imaging predict the development of new syndesmophytes in ankylosing spondylitis

Chiowchanwisawakit

Lambert

Conner‐Spady

et al. 2011

Arthritis & Rheumatism

178

113

View full text Add to dashboard Cite

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“…38,39 The peripheral effects of leptin may also be mediated by IL-1b since both IL-1b and IL-1 receptors are expressed in human WAT and IL-1b stimulates lipolysis and suppresses lipogenesis and adipocyte differentiation in WAT in vitro. [40][41][42] The ratio of IL-1Ra to IL-1b is increased almost fivefold in WAT from obese patients, suggesting that IL-1Ra may also promote obesity by inhibiting the peripheral actions of IL-1b and leptin. 31 Accordingly, IL-1Ra blocks the inhibitory effects of IL-1 on WAT adipogenesis in vitro 42 and mice lacking the IL-1Ra gene are significantly lighter than wild-type mice, with decreased fat mass related to impaired adipogenesis and increased energy expenditure.…”

Section: Discussionmentioning

confidence: 99%

Stress-induced cytokine responses and central adiposity in young women

et al. 2007

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Background: Evidence suggests that people who are more responsive to psychological stress are at an increased risk of developing obesity. However, the biological mechanisms underlying this phenomenon are poorly understood. The cytokines leptin, interleukin-1 receptor antagonist (IL-1Ra) and interleukin-6 (IL-6) play a key role in fat metabolism and abnormal circulating levels of these proteins have been reported in obese people and in individuals subject to stress. Objective: This study investigated whether cytokine responses to acute mental stress are associated with adiposity in healthy young women. Design and Subjects: A laboratory study of 67 women, aged 18-25 years, recruited from University College London. Measurements: Height, weight and waist circumference were measured and body fat mass was estimated by bioelectrical impedance body composition analysis. Laboratory mental stress testing was carried out and blood pressure and heart rate were recorded at baseline, during two moderately challenging tasks (Stroop and speech) and during recovery 40-45 min post-stress. Blood samples taken at baseline, immediately post-stress and 45 min post-stress, were used for assessment of circulating cytokines. Saliva samples taken throughout the session were assessed for cortisol. Results: Women who had larger cytokine responses to stress were more abdominally obese than women with smaller cytokine stress responses. Specifically, there was a positive correlation between waist circumference and stress-induced increases in plasma levels of leptin (r ¼ 0.35, Po0.05) and IL-1Ra responses (r ¼ 0.29, Po0.05). There was also a significant positive correlation between prolonged diastolic blood pressure responses to stress and measures of total and abdominal obesity (r ¼ 0.28-0.33, Po0.05). Conclusion: Increased cytokine production could be a mechanism linking stress and abdominal obesity.

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“…suppresses PPARγ function, which is important for determining stem cells to the adipocyte lineage and therefore prevents hypertrophy (72) .…”

Section: Adipogenesismentioning

confidence: 99%

Adipose tissue dysregulation and metabolic consequences in childhood and adolescent obesity: potential impact of dietary fat quality

et al. 2014

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Evidence suggests that at a population level, childhood and adolescent obesity increase the long-term risk of chronic diseases such as type 2 diabetes and CVD. At an individual level, however, the metabolic consequences of obesity in youth vary immensely. Despite comparable BMI, some adolescents develop impaired glucose tolerance while others maintain normal glucose homeostasis. It has been proposed that the variation in the capacity to store lipid in the subcutaneous adipose tissue (SAT) may partially discriminate metabolically healthy from unhealthy obesity. In positive energy balance, a decreased capacity to expand SAT may drive lipid accumulation to visceral adipose tissue, liver and skeletal muscle. This state of lipotoxicity is associated with chronic low-grade inflammation, insulin resistance and dyslipidaemia. The present review examines the differential adipose tissue development and function in children and adolescents who exhibit metabolic dysregulation compared with those who are protected. Additionally, the role of manipulating dietary fat quality to potentially prevent and treat metabolic dysfunction in obesity will be discussed. The findings of the present review highlight the need for further randomised controlled trials to establish the effect of dietary n-3 PUFA on the metabolic phenotype of obese children and adolescents. Furthermore, using a personalised nutrition approach to target interventions to those at risk of, or those with established metabolic dysregulation may optimise the efficacy of modifying dietary fat quality.

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Cytokines suppress adipogenesis and PPAR-γ function through the TAK1/TAB1/NIK cascade

Cited by 270 publications

References 30 publications

Focal fat lesions at vertebral corners on magnetic resonance imaging predict the development of new syndesmophytes in ankylosing spondylitis

Focal fat lesions at vertebral corners on magnetic resonance imaging predict the development of new syndesmophytes in ankylosing spondylitis

Stress-induced cytokine responses and central adiposity in young women

Adipose tissue dysregulation and metabolic consequences in childhood and adolescent obesity: potential impact of dietary fat quality

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