Context:
Soluble TNF-like weak inducer of apoptosis (sTWEAK) is generated by the intracellular proteolytic cleavage of full-length membrane-bound TNF-like weak inducer of apoptosis (mTWEAK). sTWEAK ...levels are reduced in diseases with an inflammatory component. Additionally, sTWEAK hampers TNFα activity in human cells.
Objectives:
The objectives of the study were as follows: 1) to determine circulating sTWEAK in severe obesity and after bariatric surgery; 2) to study m/sTWEAK and its receptor fibroblast growth factor-inducible 14 (Fn14) protein expression in sc adipose tissue (SAT) of severely obese subjects, in SAT stromal vascular fraction (SVF), and isolated adipocytes and in human monocyte-derived macrophages; and 3) to explore, on human adipocytes, the sTWEAK effect on TNFα proinflammatory activity.
Design:
sTWEAK levels were measured in cohort 1: severely obese subjects (n = 23) and a control group (n = 35); and in cohort 2: (n = 23) severely obese subjects before and after surgery. The m/sTWEAK and Fn14 expressions were determined in SAT biopsies, SVF, and isolated adipocytes from severely obese and control subjects and in human monocyte-derived macrophages. In human primary cultured adipocytes, sTWEAK pretreated and TNFα challenged, IL-6, IL-8, and adiponectin protein and gene expressions were determined and nuclear factor-κ B and MAPK signaling analyzed.
Results:
sTWEAK levels were reduced in severely obese subjects. After surgery, sTWEAK levels rose in 69% of patients. mTWEAK protein expression was increased in SAT and SVF of severely obese subjects, whereas Fn14 was up-regulated in isolated adipocytes. M2 human monocyte-derived macrophages overexpress mTWEAK. In human adipocytes, sTWEAK down-regulates TNFα cytokine production by hampering TNFα intracellular signaling events.
Conclusion:
The decrease of sTWEAK in severely obese patients may favor the proinflammatory activity elicited by TNFα.
Flavonoids are functional constituents of many fruits and vegetables. Procyanidins are flavonoids with an oligomeric structure, and it has been shown that they can improve the pathological oxidative ...state of a diabetic situation. To evaluate whether procyanidins can modulate inflammation, an event strongly associated with obesity, diabetes and insulin resistance states, we used human adipocytes (SGBS) and macrophage-like (THP-1) cell lines and administered an extract of grape-seed procyanidins (GSPE). THP-1 and SGBS cells pre-treated with GSPE showed a reduction of IL-6 and MCP-1 expression after an inflammatory stimulus. GSPE stimuli alone modulate adipokine (
APM1 and
LEP) and cytokine (
IL-6 and
MCP-1) gene expression. GSPE partially inhibited NF-κB translocation to the nucleus in both cell lines. These preliminary findings demonstrate that GSPE reduces the expression of
IL-6 and
MCP-1 and enhances the production of the anti-inflammatory adipokine adiponectin suggesting that may have a beneficial effect on low-grade inflammatory diseases such obesity and type 2 diabetes.
Objective
To analyze the reference range of thyroid‐stimulating hormone (TSH) in different BMI categories and its impact on the classification of hypothyroidism.
Methods
The study included 3,928 ...individuals free of thyroid disease (without previous thyroid disease, no interfering medications, TSH <10 µUI/mL and thyroid peroxidase antibodies TPO Abs <50 IU/mL) who participated in a national, cross‐sectional, population‐based study and were representative of the adult population of Spain. Data gathered included clinical and demographic characteristics, physical examination, and blood and urine sampling. TSH, free thyroxine, free triiodothyronine, and TPO Ab were analyzed by electrochemiluminescence (E170, Roche Diagnostics, Basel, Switzerland).
Results
The reference range (p2.5‐97.5) for TSH was estimated as 0.6 to 4.8 µUI/mL in the underweight category (BMI<20 kg/m2), 0.6 to 5.5 µUI/mL in the normal‐weight category (BMI 20‐24.9 kg/m2), 0.6 to 5.5 µUI/mL in the overweight category (BMI 25‐29.9 kg/m2), 0.5 to 5.9 µUI/mL in the obesity category (BMI 30‐39.9 kg/m2), and 0.7 to 7.5 µUI/mL in the morbid obesity category (BMI ≥40). By using the reference criteria for the normal‐weight population, the prevalence of high TSH levels increased threefold in the morbid obesity category (P < 0.01).
Conclusions
Persons with morbid obesity might be inappropriately classified if the standard ranges of normality of TSH for the normal‐weight population are applied to them.
Objective:
The aim was to compare the effects of a traditional therapy (an oral estroprogestagen) to those of a novel treatment (a low-dose combination of generics) in adolescent girls with androgen ...excess.
Study Design and Methods:
In an open-label trial over 1 yr, 34 adolescents (age, 16 yr; body mass index, 23 kg/m2) with hyperinsulinemic androgen excess and without pregnancy risk were randomized to receive daily ethinyl estradiol-cyproterone acetate (EE-CA; Diane 35 Diario) or a low-dose combination of pioglitazone 7.5 mg/d, flutamide 62.5 mg/d, and metformin 850 mg/d (PioFluMet). Markers of androgen excess, C-reactive protein, high molecular weight adiponectin, lipids, carotid intima media thickness, body composition (absorptiometry), abdominal fat partitioning (magnetic resonance imaging), and gene expression in longitudinal biopsies of sc adipose tissue at the abdominal level (RT-PCR) were assessed at baseline and after 1 yr.
Results:
EE-CA and low-dose PioFluMet reduced androgen excess comparably, but had divergent effects on C-reactive protein, high molecular weight adiponectin, lipids, carotid intima media thickness, lean mass, abdominal and visceral fat, and on the expression of CD163, leptin, TNF-like weak inducer of apoptosis receptor, and angiopoietin-like protein 4, respectively, related to macrophage activation, fat accretion, inflammation, and lipoprotein metabolism in adipose tissue. All these divergences pointed to a healthier condition on low-dose PioFluMet.
Conclusion:
EE-CA and PioFluMet are similarly effective in reversing androgen excess over 1 yr, but low-dose PioFluMet is superior in reversing inflammatory, metabolic, and cardiovascular anomalies that are often associated with androgen excess.
Context and Objective:
Because serum concentrations of soluble forms of TNF-like weak inducer of apoptosis (sTWEAK) and scavenger receptor CD163 (sCD163) have been associated with insulin resistance ...and type 2 diabetes mellitus (T2D), we tested the associations of sTWEAK and sCD163 with the future development of T2D in elderly subjects at high cardiovascular risk.
Design, Setting, and Participants:
A prospective, matched case-control study of 153 cases of newly diagnosed diabetic subjects and 306 individually matched controls who did not develop diabetes during a mean 5-year follow-up was conducted using data from the PREDIMED study. Conditional logistic regression was used to estimate the matched odds ratio (OR) for incident T2D according to categories of baseline sTWEAK and sCD163 concentrations measured by ELISA.
Results:
Baseline sTWEAK concentrations were lower in cases than controls. There were no case-control differences in sCD163 concentrations. In the conditional logistic model that took into account the matching factors, the ORs for T2D incidence in the highest vs the lowest quartile of sTWEAK and the sCD163/sTWEAK ratio were 0.49 (95% confidence interval CI, 0.31–0.76; P for trend <.01) and 1.67 (95% CI, 1.06–2.63; P for trend = .05), respectively. Further adjustment for potential lifestyle confounding factors had little impact on these estimates, whereas adjustment for metabolic syndrome components and fasting insulin levels attenuated the magnitude of associations and only the sTWEAK remained statistically significant (OR = 0.63; 95% CI, 0.40–0.98; P for trend = .05).
Conclusion:
These findings indicate that in a population at high cardiovascular risk, reduced circulating levels of sTWEAK are associated with an increased risk of diabetes incidence.
Visceral fat is strongly associated with insulin resistance. Obesity-associated adipose tissue inflammation and inflammatory cytokine production are considered key mediators of insulin signaling ...inhibition. TWEAK is a relatively new member of the TNF cytokine superfamily, which can exist as full length membrane-associated (mTWEAK) and soluble (sTWEAK) isoforms. Although TWEAK has been shown to have important functions in chronic inflammatory diseases its physiological role in adipose tissue remains unresolved. In this study, we explore the molecular mechanisms involved in the modulation of TNF-α-induced effects on insulin sensitivity by sTWEAK in a human visceral adipose cell line and also in primary human adipocytes obtained from visceral fat depots. Our data reveal that sTWEAK ameliorates TNF-α-induced insulin resistance on glucose uptake, GLUT4 translocation and insulin signaling without affecting other metabolic effects of TNF-α such as lipolysis or apoptotis. Co-immunoprecipitation experiments in adipose cells revealed that pretreatment with sTWEAK specifically inhibits TRAF2 association with TNFR1, but not with TNFR2, which mediates insulin resistance. However, sTWEAK does not affect other downstream molecules activated by TNF-α, such as TAK1. Rather, sTWEAK abolishes the stimulatory effect of TNF-α on JNK1/2, which is directly involved in the development of insulin resistance. This is associated with an increase in PP2A activity upon sTWEAK treatment. Silencing of the PP2A catalytic subunit gene overcomes the dephosphorylation effect of sTWEAK on JNK1/2, pointing to PP2A as a relevant mediator of sTWEAK-induced JNK inactivation. Overall, our data reveal a protective role of TWEAK in glucose homeostasis and identify PP2A as a new driver in the modulation of TNF-α signaling by sTWEAK.
We studied whether PPARβ/δ deficiency modifies the effects of high fructose intake (30% fructose in drinking water) on glucose tolerance and adipose tissue dysfunction, focusing on the CD36-dependent ...pathway that enhances adipose tissue inflammation and impairs insulin signaling. Fructose intake for 8weeks significantly increased body and liver weight, and hepatic triglyceride accumulation in PPARβ/δ-deficient mice but not in wild-type mice. Feeding PPARβ/δ-deficient mice with fructose exacerbated glucose intolerance and led to macrophage infiltration, inflammation, enhanced mRNA and protein levels of CD36, and activation of the JNK pathway in white adipose tissue compared to those of water-fed PPARβ/δ-deficient mice. Cultured adipocytes exposed to fructose also exhibited increased CD36 protein levels and this increase was prevented by the PPARβ/δ activator GW501516. Interestingly, the levels of the nuclear factor E2-related factor 2 (Nrf2), a transcription factor reported to up-regulate Cd36 expression and to impair insulin signaling, were increased in fructose-exposed adipocytes whereas co-incubation with GW501516 abolished this increase. In agreement with Nrf2 playing a role in the fructose-induced CD36 protein level increases, the Nrf2 inhibitor trigonelline prevented the increase and the reduction in insulin-stimulated AKT phosphorylation caused by fructose in adipocytes. Protein levels of the well-known Nrf2 target gene NAD(P)H:quinone oxidoreductase 1 (Nqo1) were increased in water-fed PPARβ/δ-null mice, suggesting that PPARβ/δ deficiency increases Nrf2 activity; and this increase was exacerbated in fructose-fed PPARβ/δ-deficient mice. These findings indicate that the combination of high fructose intake and PPARβ/δ deficiency increases CD36 protein levels via Nrf2, a process that promotes chronic inflammation and insulin resistance in adipose tissue.
•Fructose supplementation exacerbates glucose intolerance and causes adipose tissue inflammation in PPARβ/δ-deficient mice.•Fructose amplifies the oxLDL-CD36-JNK pathway in PPARβ/δ-deficient mice adipose tissue.•Adipocytes exposed to fructose showed increased nuclear protein levels of Nrf2.•Activation of PPARβ/δ prevents Nrf2 activation and the reduction in insulin sensitivity caused by fructose in adipocytes.
OBJECTIVE: Our goal was to test any association between human plasma circulating levels of monocyte chemoattractant protein-1 (cMCP-1) and insulin resistance and to compare monocyte chemoattractant ...protein-1 (MCP-1) adipose tissue gene expression and cMCP-1 in relation with inflammatory markers. RESEARCH METHODS AND PROCEDURES: cMCP-1 was measured in n = 116 consecutive control male subjects to whom an insulin sensitivity (Si) test was performed. Circulating levels of soluble CD14, soluble tumor necrosis factor receptor type 2 (sTNFR2), soluble interleukin-6 (sIL-6), and adiponectin also were measured. Subcutaneous adipose tissue samples were obtained from n = 107 non-diabetic and type 2 diabetic subjects with different degrees of obesity. Real-time polymerase chain reaction was used to measure gene expression of MCP-1, CD68, tumor necrosis factor-α (TNF-α), and its receptor TNFR2. RESULTS: In the Si study, no independent effect of cMCP-1 levels on insulin sensitivity was observed. In the expression study, in non-diabetic subjects, MCP-1 mRNA had a positive correlation with BMI (r = 0.407, p = 0.003), TNF-α mRNA (r = 0.419, p = 0.002), and TNFR2 mRNA (r = 0.410, p = 0.003). In these subjects, cMCP-1 was found to correlate with waist-to-hip ratio (r = 0.322, p = 0.048). In patients with type 2 diabetes, MCP-1 mRNA was up-regulated compared with non-diabetic subjects. TNF-α mRNA was found to independently contribute to MCP-1 mRNA expression. In this group, CD68 mRNA was found to correlate with BMI (r = 0.455, p = 0.001). DISCUSSION: cMCP-1 is not associated with insulin sensitivity in apparently healthy men. TNF-α is the inflammatory cytokine associated with MCP-1 expression in subcutaneous adipose tissue.
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