Linking the FTO obesity rs1421085 variant circuitry to cellular, metabolic, and organismal phenotypes in vivo.

Variants in FTO have the strongest association with obesity; however, it is still unclear how those noncoding variants mechanistically affect whole-body physiology. We engineered a deletion of the rs1421085 conserved cis-regulatory module (CRM) in mice and confirmed in vivo that the CRM modulates Irx3 and Irx5 gene expression and mitochondrial function in adipocytes. The CRM affects molecular and cellular phenotypes in an adipose depot-dependent manner and affects organismal phenotypes that are relevant for obesity, including decreased high-fat diet-induced weight gain, decreased whole-body fat mass, and decreased skin fat thickness. Last, we connected the CRM to a genetically determined effect on steroid patterns in males that was dependent on nutritional challenge and conserved across mice and humans. Together, our data establish cross-species conservation of the rs1421085 regulatory circuitry at the molecular, cellular, metabolic, and organismal level, revealing previously unknown contextual dependence of the variant's action.

Extensive monitoring of the natural menstrual cycle using the serum biomarkers estradiol, luteinizing hormone and progesterone.

Expected values for estradiol (E2), luteinizing hormone (LH), and progesterone determined in serum allow accurate assessment of menstrual cycle phase. Automated immunoassays demonstrate variable degrees of bias, emphasizing the need to establish method-specific reference values. We therefore established method-specific reference intervals for the Elecsys® LH assay and new generation Elecsys Estradiol III and Progesterone III assays (cobas e 801 analyzer) in 85 apparently healthy women aged 22-37 (US)/18-37 (EU) years over one natural menstrual cycle. Cycle length and day of ovulation were standardized; phases were defined by LH surge and/or progesterone/E2 levels. Median (5th-95th percentile) concentrations (follicular/ovulation/luteal) were E2: 198 â€‹pmol/L (114-332), 757 â€‹pmol/L (222-1959) and 412 â€‹pmol/L (222-854); LH: 7.14 IU/L (4.78-13.2), 22.6 IU/L (8.11-72.7) and 6.24 IU/L (2.73-13.1); progesterone: 0.212 â€‹nmol/L (0.159-0.616), 1.81 â€‹nmol/L (0.175-13.2) and 28.8 â€‹nmol/L (13.1-46.3). Sub-phase (early/intermediate/late) reference values were also determined for follicular and luteal phases. This multicenter study established reliable, method-specific E2, LH and progesterone reference values that could assist clinical decision-making in women with fertility disorders and monitoring of natural cycles in assisted reproductive treatment.

Associations Between C-Reactive Protein, Insulin Sensitivity, and Resting Metabolic Rate in Adults: A Mediator Analysis.

Objective: Long-term positive energy balance promotes the development of obesity, a main risk factor for type 2 diabetes mellitus (T2DM). While an association between increased resting metabolic rate (RMR) and insulin sensitivity (IS) was shown previously, the underlying mechanisms remain unclear. Aim of the mediator analysis was to investigate the role of inflammation within the association between RMR and IS. Methods: Anthropometric, clinical, and lifestyle data were collected according to standard operating procedures. RMR was measured using indirect calorimetry. Homeostasis model assessment for insulin resistance (HOMA-IR) was used as an IS parameter and C-reactive protein (CRP) was measured to represent the inflammatory status. Statistical analyses were performed using SPSS. Results: The analysis included 782 adults (517 females) with a mean age of 32.4 ± 12.0 years and a mean body mass index (BMI) of 24.6 ± 5.2 kg/m2. Regression analysis indicated a significant evidence for associations between RMR and HOMA-IR (ß = 39.3 ± 7.3 kcal/d; p ≤ 0.001) and CRP and HOMA-IR (ß = 0.5 ± 0.1; p ≤ 0.001) after adjustment for fat-free mass, sex, age, and study site. Results of the mediator analysis did not support the hypothesis that CRP is a mediator for the association between RMR and HOMA-IR. These results did not change after participant stratification according to sex or BMI. Conclusion: A significant evidence for an association between RMR and IS was shown in a large cohort. However, the inflammatory status, determined via CRP levels, was not a mediator within this association.

Determinants of urolithiasis in patients with intestinal fat malabsorption.

OBJECTIVE: To investigate the determinants of urinary stone formation in patients with fat malabsorption, because, although the prevalence of urolithiasis is greater in patients with intestinal diseases, the pathogenetic mechanisms and risk factors associated with urolithiasis in this population remain partially unsolved. MATERIALS AND METHODS: The present study retrospectively analyzed the determinants of urolithiasis in 51 patients with fat malabsorption due to different intestinal diseases. Anthropometric, clinical, blood, 24-hour urinary parameters, and dietary intake were assessed. RESULTS: The resection rate (ie, pancreatic and/or bowel resection) differed significantly between stone formers (SF; n=10) and nonstone formers (NSF; n=41; 70% vs 29%; P=.027). Urinary citrate was lower (1.606±1.824 vs 3.156±1.968 mmol/24 h; P=.027), while oxalate excretion (0.659±0.292 vs 0.378±0.168 mmol/24 h; P=.002) and the relative supersaturation of calcium oxalate were greater in SF than NSF (8.16±4.61 vs 3.94±2.93; P=.003). Total cholesterol and low-density lipoprotein cholesterol, but also high-density lipoprotein cholesterol, plasma ß-carotene, and vitamin E concentrations, were significantly diminished, whereas serum aspartate aminotransferase activity was significantly greater in SF compared with NSF. Binary logistic regression analysis revealed resection status as a major extrarenal risk factor for stone formation (odds ratio 5.639). CONCLUSION: Increased urinary oxalate and decreased citrate excretion, probably resulting from pancreatic and/or bowel resection with mainly preserved colon, were identified as the most crucial urinary risk factors for stone formation in patients with fat malabsorption. The findings suggest that hyperoxaluria predominantly results from increased colonic permeability for oxalate due to disturbed bile acid metabolism. The impaired status of fat-soluble antioxidants ß-carotene and vitamin E indicates severe malabsorptive states associated with an enhanced stone-forming propensity.