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Subclinical hypothyroidism is known to be associated with increased serum cholesterol. Since thyroid-stimulating hormone (TSH) exerts an inductor effect on cholesterol biosynthesis, we aimed to investigate the relationship between TSH mRNA and cholesterol metabolism in human adipose tissue (AT). Cross-sectionally, AT TSH-β (TSHB) mRNA was evaluated in 4 independent cohorts in association with serum total and LDL cholesterol, and AT lipidomics. Longitudinally, the effects of statins and of diet and exercise on AT TSHB mRNA were also examined. The bidirectional relationship between cholesterol and TSHB were studied in isolated human adipocytes. TSHB mRNA was consistently detected in AT from euthyroid subjects, and positively associated with serum total- and LDL-cholesterol, and with AT-specific cholesterol metabolism-associated lipids [arachidonoyl cholesteryl ester, C8-dihydroceramide, N-stearoyl-d-sphingosine, and GlcCer(18:0, 24:1)]. Reduction of cholesterol with statins and with diet and exercise interventions led to decreased TSHB mRNA in human AT, whereas excess cholesterol up-regulated TSHB mRNA in human adipocytes. In addition, recombinant human TSH α/β administration resulted in increased HMGCR mRNA levels in human adipocytes. In mice, subcutaneous AT Tshb expression levels correlated directly with circulating cholesterol levels. In summary, current results provide novel evidence of TSHB as a paracrine factor that is modulated in parallel with cholesterol metabolism in human AT.—Moreno-Navarrete, J. M., Moreno, M., Ortega, F., Xifra, G., Hong, S., Asara, J. M., Serrano, J. C. E., Jové, M., Pissios, P., Blüher, M., Ricart, W., Portero-Otin, M., Fernández-Real, J. M. TSHB mRNA is linked to cholesterol metabolism in adipose tissue.

Scope: Changes in genetic variations affecting the taste receptor, type 2, member 38 (TAS2R38) may identify the interacting mechanism leading to obesity and potential associations with proteins partaking in innate immunity, such as surfactant protein D (SPD) and mannan-binding lectin (MBL). Methods and results: We evaluated haplotypes of the bitter-taste receptor TAS2R38 in an identification sample of 210 women in different weight conditions, including anorexia nervosa and obesity. The association with SPD and MBL was tested in an independent sample picturing general population (n = 534). The relationship with obesity was validated in an extended final sample of 1319 participants. In the sample comprised of women in extreme weight conditions, increased obesity was identified in AVI/AVI subjects (OR = 2.5 [1.06–6.11], p = 0.035). In the sample picturing general population, increased SPD and MBL concentrations were found in nonsmoking AVI carriers. In this cohort, smoking and obesity blunted associations between TAS2R38 haplotypes and SPD and MBL. In the extended sample, the association of AVI/AVI haplotypes with increased obesity was also identified (OR = 1.4 [0.99/1.85], p = 0.049), being more robust in subjects aged

Background Adipose tissue of obese subjects is known to exhibit increased inflammatory activity linked to altered expression of factors involved in glucose and lipid metabolism. The surgical procedure constitutes an injury per se, evoking a systemic inflammatory response. Objective To evaluate changes in the expression of key-genes in adipose tissue after common surgical procedures performed in obese patients. Setting A tertiary hospital. Methods Paired subcutaneous (SAT) and visceral (VAT) adipose tissue samples were collected at the beginning and the end of surgery in 33 obese patients that underwent laparoscopic Roux-en-Y gastric bypass (RYGB, n=17) or laparoscopic vertical sleeve gastrectomy (SG, n=16). The expression of genes involved in inflammation, glucose and lipid metabolism was assessed. Results The surgical procedure led to increased expression of interleukin 6, interleukin 8 ( P P = .001 in SAT), and lipopolysaccharide binding protein ( P = .0004 in VAT). Surgery also induced concomitant decreased expression of GLUT4, IRS1 ( P = .046 in VAT), and adiponectin, whereas the messenger RNA of lipogenic genes [fatty acid synthase ( P = .024); sterol regulatory element binding transcription factor 1 ( P = .011) and aquaporin 9 ( P P = .018) and solute carrier family 27 (fatty acid transporter), member 2 ( P = .028) in VAT] increased in parallel to inflammation. Changes in gene expression during surgery were enhanced in patients following RYGB, when compared with SG. Conclusions Bariatric surgery acutely changes the expression of inflammatory and lipogenic genes in adipose tissue. This information should be considered cautiously when designing studies to assess adipose tissue gene expression in morbidly obese patients. The same timing of sampling is mandatory.

Scope Very few studies have evaluated serum hepcidin in patients with type 2 diabetes and they have reported conflicting results. In addition, the effect of antidiabetic drugs on circulating hepcidin has not been explored so far. The aims of the study were to evaluate hepcidin concentrations and hepcidin/ferritin ratio in type 2 diabetes subjects and healthy non-diabetic controls and to evaluate the effect of metformin on hepcidin concentrations. Methods and results Study 1: Cross-sectional multivariate study of 239 non-diabetic individuals and 65 people with type 2 diabetes. The multivariate analysis included covariates of chronic inflammation, BMI, pharmacological treatment, menopausal status and insulin resistance. Study 2: Randomized, double-blinded, placebo-controlled 4-month trial metformin compared to placebo among 36 type 2 diabetic patients. In both groups diet was controlled by maintaining a hypocaloric intake across the trial. Hepcidin levels were significantly lower in patients with type 2 diabetes than in non-diabetic individuals either in crude or adjusted regression models (P

OBJECTIVE Circulating markers of iron overload are associated with insulin resistance. Less is known about the impact of iron overload on adipose tissue (AT). We hypothesized that gene expression markers of iron metabolism in AT could be associated with insulin action. RESEARCH DESIGN AND METHODS The AT expression of ferroportin (SLC40A1), transferrin (TF), TF receptor (TFRC), ferritin (FT) heavy polypeptide 1 (FTH1), and FT light polypeptide (FTL) was analyzed cross-sectionally in three independent cohorts and also after weight loss–induced changes in insulin sensitivity (clamp M value) in an independent fourth cohort. RESULTS In human AT, TF mRNA and protein levels were decreased with obesity and insulin resistance in the three cohorts and were positively associated with adipogenic mRNAs and insulin action. Otherwise, FTL mRNA and protein and SLC40A1 transcripts were positively associated with BMI and negatively linked to adipogenic genes and insulin action. Bariatric surgery–induced weight loss led to increased TF and decreased TFRC, FTH1, FTL, and SLC40A1 in subcutaneous AT in parallel to improved insulin action. CONCLUSIONS These results suggest that iron overload impacts on AT in association with insulin resistance.

OBJECTIVE The linkage among the tissue iron stores, insulin resistance (IR), and cognition remains unclear in the obese population. We aimed to identify the factors that contribute to increased hepatic iron concentration (HIC) and brain iron overload (BIO), as evaluated by MRI, and to evaluate their impact on cognitive performance in obese and nonobese subjects. RESEARCH DESIGN AND METHODS We prospectively recruited 23 middle-aged obese subjects without diabetes (13 women; age 50.4 ± 7.7 years; BMI 43.7 ± 4.48 kg/m2) and 20 healthy nonobese volunteers (10 women; age 48.8 ± 9.5 years; BMI 24.3 ± 3.54 kg/m2) in whom iron load was assessed in white and gray matter and the liver by MRI. IR was measured from HOMA-IR and an oral glucose tolerance test. A battery of neuropsychological tests was used to evaluate the cognitive performance. Multivariate regression analysis was used to identify the independent associations of BIO and cognitive performance. RESULTS A significant increase in iron load was detected at the caudate nucleus (P < 0.001), lenticular nucleus (P = 0.004), hypothalamus (P = 0.002), hippocampus (P < 0.001), and liver (P < 0.001) in obese subjects. There was a positive correlation between HIC and BIO at caudate (r = 0.517, P < 0.001), hypothalamus (r = 0.396, P = 0.009), and hippocampus (r = 0.347, P < 0.023). The area under the curve of insulin was independently associated with BIO at the caudate (P = 0.001), hippocampus (P = 0.028), and HIC (P = 0.025). BIOs at the caudate (P = 0.028), hypothalamus (P = 0.006), and lenticular nucleus (P = 0.012) were independently associated with worse cognitive performance. CONCLUSIONS Obesity and IR may contribute to increased HIC and BIO being associated with worse cognitive performance. BIO could be a potentially useful MRI biomarker for IR and obesity-associated cognitive dysfunction.

Recently, serum lipopolysaccharide-binding protein (LBP) has been closely associated with coronary artery disease. Here, we aimed to investigate the possible relationship between serum LBP and markers of atherosclerosis.Serum LBP and carotid intima media thickness (C-IMT) were measured in 332 subjects (101 men and 231 women) who were recruited from an ongoing multicenter project.Serum LBP was significantly associated with obesity [BMI, fat mass and waist circumference (r 0.38, p 0.0001)], HOMA (r = 0.36, p 0.0001) and high sensitivity CRP (hsCRP) (r = 0.50, p 0.0001). Circulating LBP was also positively associated with C-IMT (r = 0.27, p 0.0001). Circulating LBP (β = 0.16; p = 0.001) contributed independently to C-IMT variance, after controlling for the effects of age, gender, BMI and hsCRP. Of note, circulating LBP was found to be increased in the population with carotid plaque (n = 50; 32.7 ± 12.5 vs 28.7 ± 10.7; p = 0.021).The consistent association between serum LBP and the carotid intima media thickness, a widely used atherosclerosis marker, reveals serum LBP as a putative factor related to atherosclerosis.

Obesity is an important determinant of increased cardiovascular risk. Increased fat mass has been assumed to constitute the main prominent contributor to changes in carotid intima-media thickness (c-IMT).In 421 consecutive subjects (301 women), c-IMT was evaluated ultrasonographically in 6 independent territories and body composition was assessed by dual-energy X-ray absorptiometry.c-IMT was positively associated with lean body mass in both men (r = 0.328, p = 0.0001) and women (r = 0.268 p = 0.0001) and increased across lean mass quartiles (p = 0.0001 for linear-trend ANOVA). Stepwise linear regression analysis showed that age and lean mass (but not fat mass or traditional cardiovascular risk factors) contributed to 46.2% of c-IMT variance in men (p = 0.0001). Even within obese men, lean mass was an independent contributor to c-IMT variance. Among women, age, lean mass and ultrasensitive CRP levels contributed independently to 47.7% of c-IMT variance (p 0.0001).Lean mass, and not fat mass, might contribute to increase c-IMT in obese patients independently of classical atherosclerotic risk factors. These data reinforce the concept that the increase in metabolically fat-free mass that accompanies the body weight enlargement is closely related to the raise in blood pressure.