Sex Steroid-Induced Changes in Circulating Monocyte Chemoattractant Protein-1 Levels May Contribute to Metabolic Dysfunction in Obese Men

Ruige, Johannes; Bekaert, Marlies; Lapauw, Bruno; Fiers, Tom; Lehr, Stefan; Hartwig, Sonja; Wiza, Daniella Herzfeld de; Schiller, Martina; Paßlack, Waltraud; Nieuwenhove, Yves Van; Pattyn, Piet; Cuvelier, Claude; Taes, Youri; Sell, Henrike; Eckel, Jürgen; Kaufman, Jean‐Marc; Ouwens, D. Margriet

doi:10.1210/jc.2011-3069

Cited by 18 publications

(15 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the latter reports were based on elderly men in whom the association between low testosterone and increased levels of inflammatory markers might be confounded by already manifest CVD and hence the direction of causality difficult to disentangle. A recent publication showed that transient elevation of estradiol levels with coincident lowering of testosterone affect several pro-inflammatory markers including MIP1a in young men [26]. The results are in agreement with our present findings regarding testosterone, but in contrast we did not find any link between estradiol and markers of LGSI.…”

Section: Discussionsupporting

confidence: 92%

Negative Association between Testosterone Concentration and Inflammatory Markers in Young Men: A Nested Cross-Sectional Study

et al. 2013

View full text Add to dashboard Cite

ObjectiveLow grade systemic inflammation (LGSI) as well as androgen deficiency has in older men been associated with several pathologies, including cardiovascular disease (CVD). We wanted to investigate whether low testosterone levels are linked to biomarkers of LGSI already in young age, before any concurrent manifestations of CVD or other systemic diseases.DesignNested cross-sectional study.MethodsForty subfertile biochemically hypogonadal (n = 20) or eugonadal (n = 20) men (mean age 37 years, SD = 4.3) and 20 age-matched controls were randomly selected from an ongoing study on male subfertility. Subjects comprised male partners in infertile couples in whom also subnormal sperm concentration was present. Blood sampling, interviews, and anthropometric measures were undertaken. Serum levels of testosterone, LH, estradiol, SHBG, and 21 LGSI-markers were assessed.ResultsAmong 21 inflammatory markers, macrophage inflammatory protein 1-alpha (MIP1a) (ß = −0.025; p = 0.028), 1-beta (MIP1B) (ß = −0.015; p = 0.049) and tumor necrosis factor alpha (TNFa) (ß = −0.015; p = 0.040) showed negative association to total testosterone (TT) levels. MIP1a (ß = −1.95; p = 0.001) and TNFa (ß = −0.95; p = 0.014) showed negative association to calculated free testosterone (cFT) levels. Compared to men with normal TT and cFT levels, TNFa levels were higher in men with subnormal levels of TT (mean ratio 1.61; p = 0.006) and cFT (mean ratio 1.58; p = 0.007). Also, MIP1a levels were higher in men with subnormal levels of TT (mean ratio 1.84; p = 0.030).ConclusionsSubnormal testosterone may already in young age associate to LGSI, which might be a part of the mechanism underlying adverse health outcomes of male hypogonadism.

show abstract

Section: Discussionsupporting

confidence: 92%

Negative Association between Testosterone Concentration and Inflammatory Markers in Young Men: A Nested Cross-Sectional Study

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Several previous studies have also reported a similar negative correlation between serum IL-6 and testosterone [16, 23, 29, 30], with the majority of these investigators suggesting that the observed increase in IL-6/inflammation with obesity was due to a withdrawal of testosterone’s immunosuppressive effect [13–15, 29, 30]. However, we believe that IL-6 may be directly inhibiting testicular function, thereby leading to a reduction in testosterone and AMH levels.…”

Section: Discussionsupporting

confidence: 64%

“…Secondly, while we have reported very significant positive correlations between LBP and IL-6, and negative correlations between IL-6 and testosterone levels, the purely observational nature of our study does not enable us to draw definitive cause-effect relationships. However, given previous reports linking IL-6 exposure to impaired testosterone production [16, 23, 29, 30], we do believe that metabolic endotoxaemia related increase in IL-6 production is likely to play some role in impairing testicular function in obese men. We also acknowledge that LBP is only an indirect measure of endotoxaemia and the passage of gut bacteria derived endotoxin into the circulation.…”

Section: Discussionmentioning

confidence: 66%

Metabolic endotoxaemia related inflammation is associated with hypogonadism in overweight men

Tremellen

McPhee

Pearce

2017

Basic Clin. Androl.

View full text Add to dashboard Cite

BackgroundObesity is associated with both impaired testosterone production and a chronic state of low grade inflammation. Previously it was believed that this inflammation was mediated by a decline in the immunosuppressive action of testosterone. However, more recently an alternative hypothesis (GELDING theory) has suggested that inflammation originating from the passage of intestinal bacteria into the circulation (metabolic endotoxaemia) may actually be the cause of impaired testicular function in obese men. The aim of this study is to investigate if metabolic endotoxaemia, as quantified by serum Lipopolysaccharide Binding Protein (LBP), is associated with impaired testicular endocrine function.MethodsA total of 50 men aged between 21 and 50 years (mean 35.1 ± 6.8 years) were assessed for adiposity (BMI, waist circumference and % body fat using bio-impedance), inflammatory status (serum CRP, IL-1β, IL-6, TNFα and LBP) and testicular endocrine function (serum testosterone, estradiol, AMH, LH and FSH). Statistical analysis was performed using Pearson correlation analysis, with log transformation of data where appropriate, and multi-variate regression.ResultsOverall increasing adiposity (% body fat) was positively associated with metabolic endotoxaemia (LBP, r = 0.366, p = 0.009) and inflammation (CRP r = 0.531, p < 0.001; IL-6 r = 0.463, p = 0.001), while also being negatively correlated with serum testosterone (r = −0.403, p = 0.004). Serum testosterone levels were significantly negatively correlated with inflammation (CRP r = −0.471, p = 0.001; IL-6 r = −0.516, p < 0.001) and endotoxaemia (LBP) after adjusting for serum LH levels (p = −0.317, p = 0.03). Furthermore, serum IL-6 was negatively associated with AMH levels (r = −0.324, p = 0.023), with a negative trend between LBP and AMH also approaching significance (r = −0.267, p = 0.064).ConclusionsObesity and its associated metabolic endotoxaemia helps initiate a pro-inflammatory state characterised by raised serum IL-6 levels, which in turn is correlated with impairment of both Leydig (testosterone) and Sertoli cell function (AMH). These results open up the potential for new treatments of obesity related male hypogonadism that focus on preventing the endotoxaemia associated chronic inflammatory state.

show abstract

“…35,36 In general, hormones, interleukins and chemokines may trigger a response even if their circulating amount is low. 37,38 Hypoxia induced by treatment with 1% O 2 has been shown to elevate VEGFA mRNA stability; 27 however, in our current model, the halflife of the VEGFA mRNA was not affected by the chemical inducer CoCl 2 , while transcription was moderately increased (Fig. 2), perhaps through a CoCl 2 -elicited increase in HIF1a expression levels.…”

Section: Discussionmentioning

confidence: 53%

Induction of VEGFA mRNA translation by CoCl₂ mediated by HuR

et al. 2015

View full text Add to dashboard Cite

These authors equally contributed to the work.Keywords: biotin pulldown, mass spectrometry, post-transcriptional gene regulation, polysome profiling, ribonucleoprotein complex, RNA-binding proteins Vascular endothelial growth factor (VEGF) A is a master regulator of neovascularization and angiogenesis. VEGFA is potently induced by hypoxia and by pathological conditions including diabetic retinopathy and tumorigenesis. Finetuning of VEGFA expression by different stimuli is important for maintaining tissue vascularization and organ homeostasis. Here, we tested the effect of the hypoxia mimetic cobalt chloride (CoCl 2 ) on VEGFA expression in human cervical carcinoma HeLa cells. We found that CoCl 2 increased the levels of VEGFA mRNA and VEGFA protein without affecting VEGFA mRNA stability. Biotin pulldown analysis to capture the RNA-binding proteins (RBPs) bound to VEGFA mRNA followed by mass spectrometry analysis revealed that the RBP HuR [human antigen R, a member of the embryonic lethal abnormal vision (ELAV) family of proteins], interacts with VEGFA mRNA. VEGFA mRNA-tagging experiments showed that exposure to CoCl 2 increases the interaction of HuR with VEGFA mRNA and promoted the colocalization of HuR and the distal part of the VEGFA 3 0 -untranslated region (UTR) in the cytoplasm. We propose that under hypoxia-like conditions, HuR enhances VEGFA mRNA translation.

show abstract

Sex Steroid-Induced Changes in Circulating Monocyte Chemoattractant Protein-1 Levels May Contribute to Metabolic Dysfunction in Obese Men

Cited by 18 publications

References 20 publications

Negative Association between Testosterone Concentration and Inflammatory Markers in Young Men: A Nested Cross-Sectional Study

Negative Association between Testosterone Concentration and Inflammatory Markers in Young Men: A Nested Cross-Sectional Study

Metabolic endotoxaemia related inflammation is associated with hypogonadism in overweight men

Induction of VEGFA mRNA translation by CoCl₂ mediated by HuR

Contact Info

Product

Resources

About

Sex Steroid-Induced Changes in Circulating Monocyte Chemoattractant Protein-1 Levels May Contribute to Metabolic Dysfunction in Obese Men

Cited by 18 publications

References 20 publications

Negative Association between Testosterone Concentration and Inflammatory Markers in Young Men: A Nested Cross-Sectional Study

Negative Association between Testosterone Concentration and Inflammatory Markers in Young Men: A Nested Cross-Sectional Study

Metabolic endotoxaemia related inflammation is associated with hypogonadism in overweight men

Induction of VEGFA mRNA translation by CoCl2 mediated by HuR

Contact Info

Product

Resources

About

Induction of VEGFA mRNA translation by CoCl₂ mediated by HuR