Biology subjects

Hasty, A.

Publications and source records attributed to Hasty, A..

3 recordsLinked to original sources

bioRxiv2024

Deficiency of the hemoglobin-haptoglobin receptor, CD163, worsens insulin sensitivity in obese male mice

Excessive iron accumulation in metabolic organs such as the adipose tissue, liver, and skeletal muscle is associated with increased diabetes risk. Tissue-resident macrophages serve multiple roles including managing inflammatory tone and regulating parachymal iron homeostasis; thus protecting against metabolic dysfunction upon iron overload. The scavenger receptor CD163 is uniquely present on tissue-resident macrophages, and plays a significant role in iron homeostasis by clearing extracellular hemoglobin-haptoglobin complexes, thereby limiting oxidative damage caused by free hemoglobin in metabolic tissues. We show that the absence of CD163 exacerbates glucose intolerance and insulin resistance in male mice with obesity. Additionally, loss of CD163 reduced the expression of iron regulatory genes (Tfr1, Cisd1, Slc40a1) in adipose tissue macrophages and anti-inflammatory (M2-like) bone marrow-derived macrophages (BMDMs). Further, CD163 deficiency mediated a pro-inflammatory shift and limited hemoglobin scavenging specifically in M2-like BMDMs. To this end, iron buffering was diminished in inguinal white adipose tissue (iWAT) macrophages in vivo, which culminated in iron spillover into adipocytes and CD45+CD11B- non-myeloid immune cells in iWAT. These findings show that CD163 on tissue-resident macrophages is critical for their anti-inflammatory and hemoglobin scavenging roles, and its absence results in impaired systemic insulin action in an obese setting. Article HighlightsO_LILoss of CD163 mediates a phenotypic switch in M2-like macrophages towards a pro-inflammatory state. C_LIO_LICD163 is involved in free hemoglobin uptake and catabolism as well as oxidative metabolism, specifically in M2-like macrophages. C_LIO_LIIn inguinal white adipose tissue (iWAT) of CD163 defficient mice, macrophage iron is reduced; while concomitantly, adipocyte and other immune cell iron content is increased. C_LIO_LILoss of CD163 provokes glucose intolerance and insulin resistance in obese male mice. C_LI

physiology↗

bioRxiv2023

Single cell RNA-sequencing suggests a novel lipid associated mast cell population following weight cycling

We previously demonstrated that weight cycled mice have increased adipose mast cells compared to obese mice by single cell RNA-sequencing. Here, we aimed to confirm and elucidate these changes. Interestingly, we did not detect an increase in total mast cell numbers in weight cycled mice by Toluidine blue or flow cytometry, however, further subcluster analysis of our dataset showed that our initial mast cell cluster consisted of two unique populations. One population had very high expression of classical mast cell markers and another had elevated lipid handling and antigen presentation genes with a concomitant reduction in classical mast cell genes. This new "lipid-associated" mast cell cluster accounted for most of the mast cells in the weight cycled group. We induced a similar phenotype in vitro using repeated exposure to adipose tissue conditioned media to mimic weight gain and weight regain. Upon repeated exposure to adipose tissue conditioned media, bone marrow-derived mast cells had increased lipid droplets and reduced expression of cKit and Fc{varepsilon}R1 compared to control cells. Moreover, we analyzed mast cells in a pilot study of subcutaneous adipose tissue from four obese, prediabetic women. We found two mast cell populations that appear similar to the murine populations detected by sequencing. The population with reduced cKit and Fc{varepsilon}R1 was significantly correlated with weight variance. Together, these data suggest that weight cycling may induce a unique population of mast cells similar to lipid-associated macrophages, which have been shown to play a role in diverse diseases from obesity and atherosclerosis to Alzheimers disease. Future studies will focus on isolation of these cells from mice and humans to better determine their lineage, differentiation, and functional roles.

immunology↗

bioRxiv2019

Palmitate induces apoptotic cell death and inflammasome activation in human placental macrophages

IntroductionThere is an increasing prevalence of non-communicable diseases worldwide. Metabolic diseases such as obesity and gestational diabetes mellitus (GDM) increasingly affect women during pregnancy, which can harm pregnancy outcomes and the long-term health and wellbeing of exposed offspring. Both obesity and GDM have been associated with proinflammatory effects within the placenta, the critical organ governing fetal development.\n\nMethodsThe purpose of these studies was to model, in vitro, the effects of metabolic stress (high levels of glucose, insulin and saturated lipids) on placental macrophage biology, since these cells are the primary innate immune phagocyte within the placenta with roles in governing maternofetal immune tolerance and antimicrobial host defense. Macrophages were isolated from the villous core of term, human placentae delivered through nonlaboring, elective Cesarean sections and exposed to combinations of elevated glucose (30 mM), insulin (10 nM) and the saturated lipid palmitic acid (palmitate, 0.4 mM).\n\nResultsWe found that palmitate alone induced the activation of the nucleotide-binding oligomerization domain-like receptor (NLR) Family Pyrin Domain Containing 3 (NLRP3) inflammasome in placental macrophages, which was associated with increased interleukin 1 beta release and an increase in apoptotic cell death. Glucose and insulin neither provoked these effects nor augmented the impact of palmitate itself.\n\nDiscussionOur findings confirm an impact of saturated fat on placental macrophage immune activation and could be relevant to the impact of metabolic stress in vivo.

immunology↗