Biology subjects

Wager, J. L.

Publications and source records attributed to Wager, J. L..

3 recordsLinked to original sources

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↗

bioRxiv2024

Diet-induced hyperplastic expansion in subcutaneous adipose tissue and protection against adipose progenitor exhaustion in female mice are lost with ovariectomy.

BackgroundThe protection of females against cardiometabolic disease is in part attributable to a tendency for fat accumulation in subcutaneous depots, which promote lipid homeostasis by serving as a metabolic sink. At menopause this protection is lost, and body fat distribution resembles the male-like pattern of visceral adiposity. Adipose progenitor cells (APCs) can be recruited to support adipose expansion in the setting of obesity. Sex differences in diet-induced APC responses may in part explain sexual dimorphism in risk for obesity-associated insulin resistance; however, the role of sex and estrogen in governing APC function remains unclear. MethodsFour groups of C57BL/6 mice were assessed: intact males vs. females, and sham vs. ovariectomized (ovx) with or without 17{beta}-estradiol (E2). Adipogenesis was stimulated by rosiglitazone (rosi), while obesity was induced by high fat/fructose diet (HHFD). Flow cytometry quantified the total number of APCs and identify committed preadipocytes by the loss of CD24 expression. Body composition was measured by NMR, while adipose function assessed by measuring circulating adipokines and free fatty acids and lipolysis in adipose explants. ResultsDespite greater accumulation of fat mass in response to rosi, females were protected against the depletion in subcutaneous APCs and preadipocytes that was observed in rosi-treated males. Similar to intact males, APC and preadipocytes in subcutaneous depots of ovx females were reduced after rosi treatment. The protection of obese females against the development of insulin resistance and adipose dysfunction was lost with ovx, and E2 re-supplementation rescued HFFD- induced APC exhaustion. Exposure to HFFD after discontinuation of rosi exacerbated glucose intolerance in males only. ConclusionsEstrogen-mediated hyperplastic expansion in subcutaneous depots permits renewal of the APC pool and preservation of adipose function. PLAIN ENGLISH SUMMARYDespite well-established sex differences in the risk for type 2 diabetes that vary across the lifespan, very little is known regarding sex-specific mechanisms in its pathophysiology. In the setting of obesity, stem cells resident in fat tissue can be recruited for the generation of new fat cells, an important mechanism that maintains metabolic health. It is thought that a reduced availability or dysfunction in fat-residing stem cells is an important pathophysiological event that triggers the onset of obesity-associated type 2 diabetes. Herein, we aimed to determine how sex and estrogen influence stem cell availability and function. Our data show that the ability of fat- residing stem cells to respond to an obesogenic environment is greater in females in an estrogen- dependent manner. Estrogen-dependent stem cell responses to an obesogenic environment may contribute to the protection of females against obesity-induced type 2 diabetes and loss of this protection after menopause. HIGHLIGHTSSexual dimorphism in activation of adipogenesis by rosiglitazone is mediated by estrogen. Exhaustion of the APC pool occurs in subcutaneous depots of male mice, while estrogen mediates protection of females against APC exhaustion. Preservation of subcutaneous adipose expansion capacity due to renewal of the progenitor pool may contribute to protection of females against obesity-associated insulin resistance.

physiology↗

bioRxiv2022

Potentiation of Adipogenesis by Reactive Oxygen Species is a Unifying Mechanism in the Pro-adipogenic Properties of Bisphenol A and its New Structural Analogues.

AimsStructural analogues of bisphenol A (BPA), including BPS and BPF, are emerging environmental toxicants as their presence in the environment is rising since new regulatory restrictions were placed on BPA-containing infant products. The adipogenesis-enhancing effect of bisphenols may explain the link between human exposure and metabolic disease; however, underlying molecular pathways remain unresolved. ResultsExposure to BPS, BPF, BPA or ROS generators enhanced lipid droplet formation and expression of adipogenic markers after induction of differentiation in adipose-derived progenitors isolated from mice. RNAseq analysis in BPS-exposed progenitors revealed modulation in pathways regulating adipogenesis and responses to oxidative stress. ROS was higher in bisphenol-exposed cells, while co-treatment with antioxidants attenuated adipogenesis and abolished the effect of BPS. There was a loss of mitochondria membrane potential in BPS-exposed cells and mitochondria-derived ROS contributed to potentiation of adipogenesis by BPS and its analogues. Male mice exposed to BPS during gestation had higher whole-body adiposity, as measured by TD-NMR, while postnatal exposure had no impact on adiposity in either sex. InnovationThese findings support existing evidence showing a role for ROS in regulating adipocyte differentiation and are the first to highlight ROS as a unifying mechanism that explains the pro-adipogenic properties of BPA and its structural analogues. ConclusionROS act as signaling molecules in the regulation of adipocyte differentiation and mediate bisphenol-induced potentiation of adipogenesis.

molecular biology↗