Biology subjects

Scheidl, T.

Publications and source records attributed to Scheidl, T..

4 recordsLinked to original sources

bioRxiv2025

Hyper-proliferation of Adipose Progenitors During Developmental Adipogenesis Programs Higher Adipocyte Number and Early-onset Obesity in Offspring Born to Obese Dams

Being born to a mother who was obese during pregnancy is one of the strongest predictors of early onset obesity and metabolic syndrome. To identify the developmental mechanism linking maternal obesity to cardiometabolic disease in the offspring, a high fat/high fructose diet or low-fat control diet were introduced 4 weeks prior to mating in C57BL6 females and continued throughout pregnancy and lactation. Offspring born to obese dams had greater whole-body adiposity prior to puberty and were more susceptible to diet-induced obesity in adulthood. On postnatal day 10 (PND10) when pups born to obese dams had greater accumulation of subcutaneous adipose tissue, single cell sequencing was used to identify adipose progenitor cells (APCs) in the stromal vascular fraction. Two distinct lineages of APCs were identified that arose from a common proliferative root, terminating in committed preadipocytes and anti-adipogenic APCs. In pups born to obese dams, the proliferative root made up a greater proportion of APCs, more of these cells were in the G2M and S phases of the cell cycle and there was an enrichment in genes associated with proliferation (mKi67, Fat3, Ccn4, Gata4). On PND10, APCs isolated from the inguinal depots of pups born to obese dams were hyper-proliferative and there was a greater abundance of total APCs, whereas there were no differences in adipocyte size. After puberty, APCs in subcutaneous depots of offspring born to obese dams were more adipogenic in vitro and this group gained a greater amount of body fat in response to pharmacological stimulation of adipogenesis by rosiglitazone. Male adults born to obese dams had a lower abundance of APCs and were more susceptible to APC exhaustion due to prolonged exposure to rosiglitazone. Therefore, early onset obesity in offspring exposed to maternal obesity in utero is due to a prolongation of the proliferative phase of early life adipogenesis, leading to a higher adipocyte number.

developmental biology↗

bioRxiv2024

Redox Signaling Mediates Differentiation of Adipose Progenitors in Response to Inflammatory Cytokines in the Adipose Tissue Secretome

Adipogenesis, the terminal differentiation of adipose progenitor cells (APCs), is critical in maintaining the functional integrity of adipose depots under obesogenic conditions. It is thought that a signal arising from the adipose microenvironment triggers APC differentiation; yet the identity and source of the signal remains unknown. This study sought to uncover the signal responsible for activating adipogenesis. Redox signaling was shown to influence adipogenesis in primary murine APCs treated with pharmacologic agents to manipulate the levels of reactive oxygen species (ROS). Increased generation of superoxide (O2-) and hydrogen peroxide (H2O2) via redox cyclers amplified both early and late APC differentiation, while ROS scavengers and antioxidants blunted differentiation. The impact of specifically targeting H2O2 with the antioxidant, catalase, or a catalase inhibitor, was restricted to lipid accumulation in late adipogenesis. Protein was concentrated from conditioned media of adipose tissue explants cultured ex vivo to capture signals within the adipose secretome. Differentiation was enhanced in APCs cultured in the presence of the adipose secretome, an effect that was diminished with scavenging of ROS and amplified when the secretome was collected from mice fed a high fat diet for 8 weeks. Proteomic analysis revealed that the adipose secretome from animals on a high fat diet was enriched in pathways related to immune cell-mediated inflammation, with interleukin 6 (IL-6) as a central regulator of differentially expressed proteins. A multiplex assay to measure cytokines confirmed higher IL-6 in the adipose secretome of high fat-fed animals. Exposure of APCs to IL-6 increased adipogenesis, while treatment of APCs with an IL-6 blocking antibodies diminished the adipogenic effect of the adipose secretome. Together, these findings substantiate a role for redox signaling in the regulation of adipogenesis and identify IL-6 as a novel activator of adipogenesis that may mediate APC differentiation via generation of ROS under obesogenic conditions.

systems biology↗

bioRxiv2023

High Maternal Adiposity During Pregnancy Programs an Imbalance in the Lipidome and Predisposes to Diet-induced Hepatosteatosis in the Offspring

BackgroundExposure to high maternal adiposity in utero is a significant risk factor for the later-life development of metabolic syndrome (MetS), including non-alcoholic fatty liver disease (NAFLD). We have previously shown that high pre-pregnancy adiposity programs adipose tissue dysfunction in the offspring, leading to spillover of fatty acids into the circulation, a key pathogenic event in obesity-associated MetS. Herein, we hypothesized that programming of adipose tissue dysfunction in offspring born to overweight dams increases the risk for developing NAFLD. ResultsFemales heterozygous for leptin receptor deficiency (Hetdb) were used as a model of high pre-pregnancy adiposity. Wild-type (Wt) offspring born to Hetdb pregnancies gained significantly more body fat following high fat/fructose diet (HFFD) compared to Wt offspring born to Wt dams. HFFD increased circulating free fatty acids (FFA) in male offspring of control dams, while FFA levels were similar in HFFD-fed offspring from Wt dams compared to CD or HFFD-Wt offspring from Hetdb dams. Despite female-specific protection from diet-induced FFA spillover, both male and female offspring from Hetdb. dams were more susceptible to diet-induced hepatosteatosis. Lipidomic analysis revealed that CD-offspring of overweight dams had decreased hepatic PUFA levels compared to control offspring. Changes to saturated fatty acids (SFA) and the de novo lipogenic (DNL) index were diet driven; however, there was a significant effect of the intrauterine environment on FA elongation and {Delta}9 desaturase activity. ConclusionHigh maternal adiposity during pregnancy programs a susceptibility to diet-induced hepatosteatosis.

developmental biology↗

bioRxiv2022

Exploring oxidative stress and endothelial dysfunction as a mechanism linking bisphenol S exposure to vascular disease in human umbilical vein endothelial cells and a mouse model of postnatal exposure.

BackgroundStructural analogues used to replace bisphenol A (BPA) since the introduction of new regulatory restrictions are considered emerging environmental toxicants and remain understudied with respect to their biological actions and health effects. Studies reveal a link between BPA exposure and vascular disease in human populations, whereas the vascular effects of BPA substitutes remain largely unknown. ObjectivesTo determine the effect of BPS, a commonly used BPA substitute, on redox balance, nitric oxide (NO) availability and microvascular NO-dependent dilation. MethodsIn human umbilical vein endothelial cells (HUVEC), production of reactive oxygen species (ROS) and NO after exposure to BPS was measured using fluorescent probes for DCFDA and DAF-FM diacetate, respectively. The contribution of endothelial NO synthase (eNOS) uncoupling to ROS generation was determined by measuring ROS in the presence or absence of an eNOS inhibitor (L-NAME) or eNOS co-factor, BH4, while the contribution of mitochondria-derived ROS was determined by treating cells with mitochondria-specific antioxidants prior to BPS exposure. Bioenergetic profiles were assessed using Seahorse extracellular flux analysis and mitochondria membrane polarization was measured with TMRE and JC-1 assays. In a mouse model of low dose BPS exposure, NO-mediated endothelial function was assessed in pressurized microvessels by inducing endothelium-dependent dilation in the presence or absence of L-NAME. ResultsBPS exposure ([≥] 25 nM) reduced NO and increased ROS production in HUVEC, the latter corrected by treating cells with L-NAME or BH4. BPS exposure led to a loss of mitochondria membrane potential but had no impact on bioenergetic parameters except for a decrease in the spare respiratory capacity. Treatment of HUVEC with mitochondria-specific antioxidants abolished the effect of BPS on NO and ROS. NO-mediated vasodilation was impaired in male mice exposed to BPS. DiscussionExposure to BPS may promote cardiovascular disease by perturbing NO-mediated vascular homeostasis through the induction of oxidative stress.

physiology↗