Biology subjects

Breznik, J. A.

Publications and source records attributed to Breznik, J. A..

3 recordsLinked to original sources

bioRxiv2023

Maternal adaptations in mouse lactation are vulnerable to diet-induced excess adiposity

Lifetime maternal risk of obesity is increased by excess gestational weight gain, which alters maternal metabolic adaptations in pregnancy, but the effects of excess weight retention/adiposity in the early postpartum period have not been extensively studied. The pathophysiology of excess adiposity and its accompanying immunometabolic dysregulation are associated with impaired intestinal barrier function in both non-pregnant and pregnant contexts. Using a mouse model, we investigated effects of diet-induced excess adiposity on maternal physiological adaptations during lactation. We report that in lactation, excess adiposity altered maternal intestinal morphology, influenced local immune cell composition and phenotype, increased intestinal permeability, and altered whole-body glucose metabolism as well as peripheral inflammation and immune cell composition. Many of these effects persisted two months post-lactation in mice with excess adiposity. Our findings have important implications for the development of interventions for periconceptual/perinatal excess adiposity and emphasize that further studies are needed to better understand effects of excess adiposity on maternal postpartum health.

developmental biology↗

bioRxiv2022

Diet-induced obesity alters intestinal monocyte-derived and tissue-resident macrophages in female mice independent of TNF

Macrophages are essential for homeostatic maintenance of the anti-inflammatory and tolerogenic intestinal environment, yet monocyte-derived macrophages can promote local inflammation. Pro-inflammatory macrophage accumulation within the intestines may contribute to the development of systemic chronic inflammation and immunometabolic dysfunction in obesity. Using a model of high fat diet-induced obesity in C57BL/6J female mice, we assessed intestinal permeability by in vitro and in vivo assays, and quantitated intestinal macrophages in ileum and colon tissues by multicolour flow cytometry after short (6 weeks), intermediate (12 weeks), and prolonged (18 weeks) diet allocation. We characterized monocyte-derived CD4-TIM4- and CD4+TIM4- macrophages, as well as tissue-resident CD4+TIM4+ macrophages. Diet-induced obesity had tissue and time-dependent effects on intestinal permeability, as well as monocyte and macrophage numbers, surface phenotype, and intracellular production of the cytokines IL-10 and TNF. We found that obese mice had increased paracellular permeability, in particular within the ileum, but this did not elicit recruitment of monocytes, nor a local pro-inflammatory response by monocyte-derived or tissue-resident macrophages, in either the ileum or colon. Proliferation of monocyte-derived and tissue-resident macrophages was also unchanged. Wildtype and TNF-/- littermate mice had similar intestinal permeability and macrophage population characteristics in response to diet-induced obesity. These data are unique from reported effects of diet-induced obesity on macrophages in metabolic tissues, as well as outcomes of acute inflammation within the intestines, and collectively indicate that TNF does not mediate effects of diet-induced obesity on intestinal monocyte-derived and tissue-resident intestinal macrophages in young female mice. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/509732v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@140a3c8org.highwire.dtl.DTLVardef@c0d887org.highwire.dtl.DTLVardef@c7c70dorg.highwire.dtl.DTLVardef@1dd5404_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

Intestinal permeability and peripheral immune cell composition are altered by pregnancy and adiposity at mid- and late-gestation in the mouse

It is clear that the gastrointestinal tract influences metabolism and immune function. Most studies to date have used male test subjects, with a focus on effects of obesity and dietary challenges. Despite significant physiological adaptations that occur across gestation, relatively few studies have examined pregnancy-related gut function. In this study, we investigated the impacts of pregnancy and adiposity on maternal intestinal epithelium morphology, in vivo intestinal permeability, and peripheral blood immunophenotype, using control (CTL) and high-fat (HF) fed non-pregnant female mice and pregnant mice at mid-(embryonic day (E)14.5) and late (E18.5) gestation. We found that small intestine length increased between non-pregnant mice and dams at late-gestation, but ileum villus length, and ileum and colon crypt depths and goblet cell numbers remained similar. Compared to CTL-fed mice, HF-fed mice had reduced small intestine length, ileum crypt depth and villus length. Goblet cell numbers were only consistently reduced in HF-fed non-pregnant mice. Pregnancy increased in vivo gut permeability, with a greater effect at mid-versus late-gestation. Non-pregnant HF-fed mice had greater gut permeability, and permeability was also increased in HF-fed pregnant dams at mid but not late-gestation. The impaired maternal gut barrier in HF-fed dams at mid-gestation coincided with changes in maternal blood and bone marrow immune cell composition, including an expansion of circulating inflammatory Ly6Chigh monocytes. In summary, pregnancy has temporal effects on maternal intestinal structure and barrier function, and on peripheral immunophenotype, which are further modified by HF diet-induced maternal adiposity.

developmental biology↗