TY - JOUR A1 - Hauffe, Robert A1 - Rath, Michaela A1 - Agyapong, Wilson A1 - Jonas, Wenke A1 - Vogel, Heike A1 - Schulz, Tim Julius A1 - Schwarz, Maria A1 - Kipp, Anna Patricia A1 - Blüher, Matthias A1 - Kleinridders, André T1 - Obesity Hinders the Protective Effect of Selenite Supplementation on Insulin Signaling JF - Antioxidants N2 - The intake of high-fat diets (HFDs) containing large amounts of saturated long-chain fatty acids leads to obesity, oxidative stress, inflammation, and insulin resistance. The trace element selenium, as a crucial part of antioxidative selenoproteins, can protect against the development of diet-induced insulin resistance in white adipose tissue (WAT) by increasing glutathione peroxidase 3 (GPx3) and insulin receptor (IR) expression. Whether selenite (Se) can attenuate insulin resistance in established lipotoxic and obese conditions is unclear. We confirm that GPX3 mRNA expression in adipose tissue correlates with BMI in humans. Cultivating 3T3-L1 pre-adipocytes in palmitate-containing medium followed by Se treatment attenuates insulin resistance with enhanced GPx3 and IR expression and adipocyte differentiation. However, feeding obese mice a selenium-enriched high-fat diet (SRHFD) only resulted in a modest increase in overall selenoprotein gene expression in WAT in mice with unaltered body weight development, glucose tolerance, and insulin resistance. While Se supplementation improved adipocyte morphology, it did not alter WAT insulin sensitivity. However, mice fed a SRHFD exhibited increased insulin content in the pancreas. Overall, while selenite protects against palmitate-induced insulin resistance in vitro, obesity impedes the effect of selenite on insulin action and adipose tissue metabolism in vivo. KW - selenite KW - insulin KW - adipose tissue KW - obesity KW - insulin resistance Y1 - 2022 U6 - https://doi.org/10.3390/antiox11050862 SN - 2076-3921 VL - 11 SP - 1 EP - 16 PB - MDPI CY - Basel, Schweiz ET - 5 ER - TY - JOUR A1 - Busse, David A1 - Simon, Philipp A1 - Petroff, David A1 - El-Najjar, Nahed A1 - Schmitt, Lisa A1 - Bindellini, Davide A1 - Dietrich, Arne A1 - Zeitlinger, Markus A1 - Huisinga, Wilhelm A1 - Michelet, Robin A1 - Wrigge, Hermann A1 - Kloft, Charlotte T1 - High-dosage fosfomycin results in adequate plasma and target-site exposure in morbidly obese and nonobese nonhyperfiltration patients JF - Antimicrobial agents and chemotherapy N2 - The objectives of this study were the identification in (morbidly) obese and nonobese patients of (i) the most appropriate body size descriptor for fosfomycin dose adjustments and (ii) adequacy of the currently employed dosing regimens. Plasma and target site (interstitial fluid of subcutaneous adipose tissue) concentrations after fosfomycin administration (8 g) to 30 surgery patients (15 obese/15 nonobese) were obtained from a prospective clinical trial. After characterization of plasma and microdialysis-derived target site pharmacokinetics via population analysis, short-term infusions of fosfomycin 3 to 4 times daily were simulated. The adequacy of therapy was assessed by probability of pharmacokinetic/pharmacodynamic target attainment (PTA) analysis based on the unbound drug-related targets of an %fT(>= MIC) (the fraction of time that unbound fosfomycin concentrations exceed the MIC during 24 h) of 70 and an fAUC(0-24h)/MIC (the area under the concentration-time curve from 0 to 24 h for the unbound fraction of fosfomycin relative to the MIC) of 40.8 to 83.3. Lean body weight, fat mass, and creatinine clearance calculated via adjusted body weight (ABW) (CLCRCG_ABW) of all patients (body mass index [BMI] = 20.1 to 52.0 kg/m(2)) explained a considerable proportion of between-patient pharmacokinetic variability (up to 31.0% relative reduction). The steady-state unbound target site/plasma concentration ratio was 26.3% lower in (morbidly) obese than nonobese patients. For infections with fosfomycin-susceptible pathogens (MIC <= 16 mg/L), intermittent "high-dosage" intravenous (i.v.) fosfomycin (8 g, three times daily) was sufficient to treat patients with a CLCRCG_ABW of,130 mL/min, irrespective of the pharmacokinetic/pharmacodynamic indices considered. For infections by Pseudomonas aeruginosa with a MIC of 32 mg/L, when the index fAUC0-24h/MIC is applied, fosfomycin might represent a promising treatment option in obese and nonobese patients, especially in combination therapy to complement beta-lactams, in which carbapenem-resistant P. aeruginosa is critical. In conclusion, fosfomycin showed excellent target site penetration in obese and nonobese patients. Dosing should be guided by renal function rather than obesity status. KW - population pharmacokinetics KW - pharmacodynamics KW - fosfomycin KW - obesity KW - adipose tissue KW - interstitial space fluid KW - microdialysis KW - anti-infective KW - probability of target attainment Y1 - 2022 U6 - https://doi.org/10.1128/aac.02302-21 SN - 0066-4804 SN - 1098-6596 VL - 66 IS - 6 PB - American Society for Microbiology CY - Washington ER - TY - JOUR A1 - Gohlke, Sabrina A1 - Mancini, Carola A1 - Garcia-Carrizo, Francisco A1 - Schulz, Tim J. T1 - Loss of the ciliary gene Bbs4 results in defective thermogenesis due to metabolic inefficiency and impaired lipid metabolism JF - The FASEB journal : the official journal of the Federation of American Societies for Experimental Biology N2 - Adipose tissue is central to the regulation of energy balance. While white adipose tissue (WAT) is responsible for triglyceride storage, brown adipose tissue specializes in energy expenditure. Deterioration of brown adipocyte function contributes to the development of metabolic complications like obesity and diabetes. These disorders are also leading symptoms of the Bardet-Biedl syndrome (BBS), a hereditary disorder in humans which is caused by dysfunctions of the primary cilium and which therefore belongs to the group of ciliopathies. The cilium is a hair-like organelle involved in cellular signal transduction. The BBSome, a supercomplex of several Bbs gene products, localizes to the basal body of cilia and is thought to be involved in protein sorting to and from the ciliary membrane. The effects of a functional BBSome on energy metabolism and lipid mobilization in brown and white adipocytes were tested in whole-body Bbs4 knockout mice that were subjected to metabolic challenges. Chronic cold exposure reveals cold-intolerance of knockout mice but also ameliorates the markers of metabolic pathology detected in knockouts prior to cold. Hepatic triglyceride content is markedly reduced in knockout mice while circulating lipids are elevated, altogether suggesting that defective lipid metabolism in adipose tissue creates increased demand for systemic lipid mobilization to meet energetic demands of reduced body temperatures. These findings taken together suggest that Bbs4 is essential for the regulation of adipose tissue lipid metabolism, representing a potential target to treat metabolic disorders. KW - adipose tissue KW - Bbs4 KW - BBsome KW - browning KW - cilium KW - lipid metabolism Y1 - 2021 U6 - https://doi.org/10.1096/fj.202100772RR SN - 1530-6860 VL - 35 IS - 11 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Graja, Antonia A1 - Garcia-Carrizo, Francisco A1 - Jank, Anne-Marie A1 - Gohlke, Sabrina A1 - Ambrosi, Thomas H. A1 - Jonas, Wenke A1 - Ussar, Siegfried A1 - Kern, Matthias A1 - Schürmann, Annette A1 - Aleksandrova, Krasimira A1 - Bluher, Matthias A1 - Schulz, Tim Julius T1 - Loss of periostin occurs in aging adipose tissue of mice and its genetic ablation impairs adipose tissue lipid metabolism JF - Aging Cell N2 - Remodeling of the extracellular matrix is a key component of the metabolic adaptations of adipose tissue in response to dietary and physiological challenges. Disruption of its integrity is a well-known aspect of adipose tissue dysfunction, for instance, during aging and obesity. Adipocyte regeneration from a tissue-resident pool of mesenchymal stem cells is part of normal tissue homeostasis. Among the pathophysiological consequences of adipogenic stem cell aging, characteristic changes in the secretory phenotype, which includes matrix-modifying proteins, have been described. Here, we show that the expression of the matricellular protein periostin, a component of the extracellular matrix produced and secreted by adipose tissue-resident interstitial cells, is markedly decreased in aged brown and white adipose tissue depots. Using a mouse model, we demonstrate that the adaptation of adipose tissue to adrenergic stimulation and high-fat diet feeding is impaired in animals with systemic ablation of the gene encoding for periostin. Our data suggest that loss of periostin attenuates lipid metabolism in adipose tissue, thus recapitulating one aspect of age-related metabolic dysfunction. In human white adipose tissue, periostin expression showed an unexpected positive correlation with age of study participants. This correlation, however, was no longer evident after adjusting for BMI or plasma lipid and liver function biomarkers. These findings taken together suggest that age-related alterations of the adipose tissue extracellular matrix may contribute to the development of metabolic disease by negatively affecting nutrient homeostasis. KW - adipogenic progenitor cells KW - adipose tissue KW - aging KW - extracellular matrix KW - fatty acid metabolism KW - periostin Y1 - 2018 U6 - https://doi.org/10.1111/acel.12810 SN - 1474-9718 SN - 1474-9726 VL - 17 IS - 5 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Musalek, Martin A1 - Kokstejn, Jakub A1 - Papez, Pavel A1 - Scheffler, Christiane A1 - Mumm, Rebekka A1 - Czernitzki, Anna-Franziska A1 - Koziel, Slawomir T1 - Impact of normal weight obesity on fundamental motor skills in pre-school children aged 3 to 6 years JF - Journal of biological and clinical anthropology : Anthropologischer Anzeiger ; Mitteilungsorgan der Gesellschaft für Anthropologie N2 - Normal weight obesity is defined as having excessive body fat, but normal BMI. Even though previous research revealed that excessive body fat in children inhibited their physical activity and decreased motor performance, there has been only little evidence about motor performance of normal weight obese children. This study aims to establish whether normal weight obese pre-school children aged 3-6 years will have a significantly worse level of fundamental motor skills compared to normal weight non-obese counterparts. The research sample consisted of 152 pre-schoolers selected from a specific district of Prague, the Czech Republic. According to values from four skinfolds: triceps, subscapula, suprailiaca, calf, and BMI three categories of children aged 3-6 years were determined: A) normal weight obese n = 51; B) normal weight non-obese n = 52; C) overweight and obese n = 49. The Movement Assessment Battery for Children (MABC-2) was used for the assessment of fundamental motor skills. Normal weight obese children had significantly higher amount of adipose tissue p < 0.001 than normal weight non-obese children but the same average BMI. Moreover, normal weight obese children did not have significantly less amount of subcutaneous fat on triceps and calf compared to their overweight and obese peers. In majority of MABC-2 tests, normal weight obese pre-schoolers showed the poorest performance. Moreover, normal weight obese children had significantly worse total standard score = 38.82 compared to normal weight non-obese peers = 52.27; p < 0.05. In addition, normal weight obese children had a more than three times higher frequency OR = 3.69 CI95% (1.10; 12.35) of severe motor deficit performance <= 5th centile of the MABC-2 norm. These findings are strongly alarming since indices like BMI are not able to identify normal weight obese individual. We recommend verifying real portion of normal weight obese children as they are probably in higher risk of health and motor problems than overweight and obese population due to their low lean mass. KW - normal weight obesity KW - fundamental motor skills KW - MABC-2 KW - performance KW - pre-school children KW - skinfolds KW - adipose tissue KW - lean mass Y1 - 2017 U6 - https://doi.org/10.1127/anthranz/2017/0752 SN - 0003-5548 VL - 74 SP - 203 EP - 212 PB - Schweizerbart CY - Stuttgart ER -