Professional Experiences and Career Trajectories of Mid- to Senior-Career Women Clinician-Scientists: A Qualitative Study.

Importance: Despite increasing evidence and recognition of persistent gender disparities in academic medicine, qualitative data detailing the association of gender-based experiences with career progression remain sparse, particularly at the mid- to senior-career stage. Objective: To investigate the role gender has played in everyday professional experiences of mid- to senior-career women clinician-scientists and their perceptions of gender-related barriers experienced across their careers. Design, Setting, and Participants: In this qualitative study, a total of 60 of 159 invited clinician-scientists who received National Institutes of Health K08 or K23 awards between 2006 and 2009 and responded to a survey in 2021 agreed to participate. Invitees were selected using random, purposive sampling to support sample heterogeneity. Semistructured in-depth interviews were conducted January to May 2022. For this study, interviews from 31 women were analyzed using the framework approach to thematic analysis. Data analyses were performed between August and October 2023. Main Outcomes and Measures: Descriptive themes of participant experiences of gender and gender-based barriers in academic medicine. Results: A total of 31 women clinician-scientists (8 identifying as Asian [25.8%], 14 identifying as White [45.2%], and 9 identifying as members of a minority group underrepresented in medicine [29.0%]; 14 aged 40-49 years [45.2%] and 14 aged 50-59 years [45.2%]) were included. Among them, 17 participants (54.8%) had children who required adult supervision or care, 7 participants (22.6%) had children who did not require supervision or care, and 6 participants (19.4%) did not have children. There were 4 dominant themes identified within participant experiences in academic medicine: the mental burden of gendered expectations at work and home, inequitable treatment of women in bureaucratic processes, subtle and less subtle professional exclusion of women, and value of communities built on shared identities, experiences, and solidarity. Conclusions and Relevance: This study found that women perceived the institution of academic medicine as a male-centric system misaligned with the needs of women, with associated feelings of exclusion, disillusionment, and loss of trust in their institutions. Findings suggest that the confluence of domestic obligations and unaccommodating institutional environments may make it difficult for women clinician-scientists to achieve established timelines of career progression and productivity; these findings may have long-term implications for the well-being and retention of women in academic medicine.

The Disproportionate Effects of the COVID-19 Pandemic on the Time Allocation of Recipients of NIH Career Development Awards Who Are Women or Caregivers of Dependents.

PURPOSE: To understand time allocation of a national medical faculty cohort 1.5-2 years after the COVID-19 pandemic began, compared to before. METHOD: From August 2021-April 2022, the authors conducted a retrospective survey of 1,430 clinician-researchers who received National Institutes of Health career-development awards between 2006-2009 asking about domestic and professional time allocation pre-pandemic and at the time of surveys (TOS). Of 915 respondents (64%), the 830 who remained in academic positions constituted the analytic sample. Multivariable regression models identified demographic factors associated with each time outcome and change in time between pre-pandemic and TOS, and having experienced ≥8-hour increase of total self-reported weekly professional work hours and domestic labor hours. RESULTS: Median self-reported weekly professional work hours were 55 hours/week pre- pandemic and 60 at TOS. On multivariable analysis, significant predictors of self-reported weekly professional work hours at TOS were having a non-child other dependent (+2.6 hours, P = .03), academic rank (associate -3.1 hours, assistant -9.0 hours; P < .001), and specialty (P < .001). Average self-reported TOS weekly domestic-labor hours were 23.1 among men and 30.2 among women (P < .001). Predictors of total self-reported TOS weekly domestic hours were being a woman (+5.6 hours; P < .001) and having children requiring supervision (+10.2 hours; P < .001). Overall, 9.3% of men (42/450) and 21.6% of women (88/407) experienced a ≥ 8 hour increase in domestic labor (P < .001). On multivariable analysis, women had higher odds of substantial domestic-labor increase (OR = 2.33, 95% CI: 1.47, 3.68), as did those with children requiring supervision (OR = 1.93, 95% CI: 1.25, 2.98) or other dependents (OR = 1.83, 95% CI: 1.13, 2.98). CONCLUSIONS: This study illuminates demands on women and faculty with dependents during the COVID-19 pandemic and suggests increased flexibility and resources are of heightened importance.

The Influence of Maternal High Fat Diet During Lactation on Offspring Hematopoietic Priming.

Obesity and metabolic diseases are rising among women of reproductive age, increasing offspring metabolic risk. Maternal nutritional interventions during lactation present an opportunity to modify offspring outcomes. We previously demonstrated in mice that adult male offspring have metabolic impairments and increased adipose tissue macrophages (ATM) when dams are fed high fat diet (HFD) during the postnatal lactation window (HFD PN). We sought to understand the effect of HFD during lactation on early-life inflammation. HFD PN offspring were evaluated at postnatal day 16 to 19 for tissue weight and gene expression. Profiling of adipose tissue and bone marrow immune cells was conducted through lipidomics, in vitro myeloid colony forming unit assays, and flow cytometry. HFD PN mice had more visceral gonadal white adipose tissue (GWAT) and subcutaneous fat. Adipose tissue RNA sequencing demonstrated enrichment of inflammation, chemotaxis, and fatty acid metabolism and concordant changes in GWAT lipidomics. Bone marrow (BM) of both HFD PN male and female offspring had increased monocytes (CD45+Ly6G-CD11b+CD115+) and B cells (CD45+Ly6G-CD11b-CD19+). Similarly, serum from HFD PN offspring enhanced in vitro BM myeloid colonies in a toll-like receptor 4-dependent manner. We identified that male HFD PN offspring had increased GWAT pro-inflammatory CD11c+ ATMs (CD45+CD64+). Maternal exposure to HFD alters milk lipids enhancing adiposity and myeloid inflammation even in early life. Future studies are needed to understand the mechanisms driving this pro-inflammatory state of both BM and ATMs, the causes of the sexually dimorphic phenotypes, and the feasibility of intervening in this window to improve metabolic health.

Pneumosepsis survival in the setting of obesity leads to persistent steatohepatitis and metabolic dysfunction.

BACKGROUND: As critical care practice evolves, the sepsis survivor population continues to expand, often with lingering inflammation in many organs, including the liver. Given the concurrently increasing population of patients with NAFLD, in this study, we aimed to understand the long-term effect of sepsis on pre-existing NAFLD and hyperglycemia. METHODS: Male mice were randomized to a high-fat diet or a control diet (CD). After 24 weeks on diet, mice were inoculated with Klebsiella pneumoniae (Kpa). Serial glucose tolerance tests, and insulin and pyruvate challenge tests were performed 1 week before infection and at 2 and 6 weeks after infection. Whole tissue RNA sequencing and histological evaluation of the liver were performed. To test whether persistent inflammation could be reproduced in other abnormal liver environments, mice were also challenged with Kpa after exposure to a methionine-choline-deficient high-fat diet. Finally, a retrospective cohort of 65,139 patients was analyzed to evaluate whether obesity was associated with liver injury after sepsis. RESULTS: After Kpa inoculation, high-fat diet mice had normalized fasting blood glucose without a change in insulin sensitivity but with a notable decrease in pyruvate utilization. Liver examination revealed focal macrophage collections and a unique inflammatory gene signature on RNA analysis. In the clinical cohort, preobesity, and class 1 and class 2 obesity were associated with increased odds of elevated aminotransferase levels 1-2 years after sepsis. CONCLUSIONS: The combination of diet-induced obesity and pneumosepsis survival in a murine model resulted in unique changes in gluconeogenesis and liver inflammation, consistent with the progression of benign steatosis to steatohepatitis. In a cohort study, obese patients had an increased risk of elevated aminotransferase levels 1-2 years following sepsis.

Workplace Harassment, Cyber Incivility, and Climate in Academic Medicine.

Importance: The culture of academic medicine may foster mistreatment that disproportionately affects individuals who have been marginalized within a given society (minoritized groups) and compromises workforce vitality. Existing research has been limited by a lack of comprehensive, validated measures, low response rates, and narrow samples as well as comparisons limited to the binary gender categories of male or female assigned at birth (cisgender). Objective: To evaluate academic medical culture, faculty mental health, and their relationship. Design, Setting, and Participants: A total of 830 faculty members in the US received National Institutes of Health career development awards from 2006-2009, remained in academia, and responded to a 2021 survey that had a response rate of 64%. Experiences were compared by gender, race and ethnicity (using the categories of Asian, underrepresented in medicine [defined as race and ethnicity other than Asian or non-Hispanic White], and White), and lesbian, gay, bisexual, transgender, queer (LGBTQ+) status. Multivariable models were used to explore associations between experiences of culture (climate, sexual harassment, and cyber incivility) with mental health. Exposures: Minoritized identity based on gender, race and ethnicity, and LGBTQ+ status. Main Outcomes and Measures: Three aspects of culture were measured as the primary outcomes: organizational climate, sexual harassment, and cyber incivility using previously developed instruments. The 5-item Mental Health Inventory (scored from 0 to 100 points with higher values indicating better mental health) was used to evaluate the secondary outcome of mental health. Results: Of the 830 faculty members, there were 422 men, 385 women, 2 in nonbinary gender category, and 21 who did not identify gender; there were 169 Asian respondents, 66 respondents underrepresented in medicine, 572 White respondents, and 23 respondents who did not report their race and ethnicity; and there were 774 respondents who identified as cisgender and heterosexual, 31 as having LGBTQ+ status, and 25 who did not identify status. Women rated general climate (5-point scale) more negatively than men (mean, 3.68 [95% CI, 3.59-3.77] vs 3.96 [95% CI, 3.88-4.04], respectively, P < .001). Diversity climate ratings differed significantly by gender (mean, 3.72 [95% CI, 3.64-3.80] for women vs 4.16 [95% CI, 4.09-4.23] for men, P < .001) and by race and ethnicity (mean, 4.0 [95% CI, 3.88-4.12] for Asian respondents, 3.71 [95% CI, 3.50-3.92] for respondents underrepresented in medicine, and 3.96 [95% CI, 3.90-4.02] for White respondents, P = .04). Women were more likely than men to report experiencing gender harassment (sexist remarks and crude behaviors) (71.9% [95% CI, 67.1%-76.4%] vs 44.9% [95% CI, 40.1%-49.8%], respectively, P < .001). Respondents with LGBTQ+ status were more likely to report experiencing sexual harassment than cisgender and heterosexual respondents when using social media professionally (13.3% [95% CI, 1.7%-40.5%] vs 2.5% [95% CI, 1.2%-4.6%], respectively, P = .01). Each of the 3 aspects of culture and gender were significantly associated with the secondary outcome of mental health in the multivariable analysis. Conclusions and Relevance: High rates of sexual harassment, cyber incivility, and negative organizational climate exist in academic medicine, disproportionately affecting minoritized groups and affecting mental health. Ongoing efforts to transform culture are necessary.

Age-associated adipose tissue inflammation promotes monocyte chemotaxis and enhances atherosclerosis.

Although aging enhances atherosclerosis, we do not know if this occurs via alterations in circulating immune cells, lipid metabolism, vasculature, or adipose tissue. Here, we examined whether aging exerts a direct pro-atherogenic effect on adipose tissue in mice. After demonstrating that aging augmented the inflammatory profile of visceral but not subcutaneous adipose tissue, we transplanted visceral fat from young or aged mice onto the right carotid artery of Ldlr-/- recipients. Aged fat transplants not only increased atherosclerotic plaque size with increased macrophage numbers in the adjacent carotid artery, but also in distal vascular territories, indicating that aging of the adipose tissue enhances atherosclerosis via secreted factors. By depleting macrophages from the visceral fat, we identified that adipose tissue macrophages are major contributors of the secreted factors. To identify these inflammatory factors, we found that aged fat transplants secreted increased levels of the inflammatory mediators TNFα, CXCL2, and CCL2, which synergized to promote monocyte chemotaxis. Importantly, the combined blockade of these inflammatory mediators impeded the ability of aged fat transplants to enhance atherosclerosis. In conclusion, our study reveals that aging enhances atherosclerosis via increased inflammation of visceral fat. Our study suggests that future therapies targeting the visceral fat may reduce atherosclerosis disease burden in the expanding older population.

Constitutive bone marrow adipocytes suppress local bone formation.

BM adipocytes (BMAd) are a unique cell population derived from BM mesenchymal progenitors and marrow adipogenic lineage precursors. Although they have long been considered to be a space filler within bone cavities, recent studies have revealed important physiological roles in hematopoiesis and bone metabolism. To date, the approaches used to study BMAd function have been confounded by contributions by nonmarrow adipocytes or by BM stromal cells. To address this gap in the field, we have developed a BMAd-specific Cre mouse model to deplete BMAds by expression of diphtheria toxin A (DTA) or by deletion of peroxisome proliferator-activated receptor gamma (Pparg). We found that DTA-induced loss of BMAds results in decreased hematopoietic stem and progenitor cell numbers and increased bone mass in BMAd-enriched locations, including the distal tibiae and caudal vertebrae. Elevated bone mass appears to be secondary to enhanced endosteal bone formation, suggesting a local effect caused by depletion of BMAd. Augmented bone formation with BMAd depletion protects mice from bone loss induced by caloric restriction or ovariectomy, and it facilitates the bone-healing process after fracture. Finally, ablation of Pparg also reduces BMAd numbers and largely recapitulates high-bone mass phenotypes observed with DTA-induced BMAd depletion.

Lipolysis of bone marrow adipocytes is required to fuel bone and the marrow niche during energy deficits.

To investigate roles for bone marrow adipocyte (BMAd) lipolysis in bone homeostasis, we created a BMAd-specific Cre mouse model in which we knocked out adipose triglyceride lipase (ATGL, Pnpla2 gene). BMAd-Pnpla2-/- mice have impaired BMAd lipolysis, and increased size and number of BMAds at baseline. Although energy from BMAd lipid stores is largely dispensable when mice are fed ad libitum, BMAd lipolysis is necessary to maintain myelopoiesis and bone mass under caloric restriction. BMAd-specific Pnpla2 deficiency compounds the effects of caloric restriction on loss of trabecular bone in male mice, likely due to impaired osteoblast expression of collagen genes and reduced osteoid synthesis. RNA sequencing analysis of bone marrow adipose tissue reveals that caloric restriction induces dramatic elevations in extracellular matrix organization and skeletal development genes, and energy from BMAd is required for these adaptations. BMAd-derived energy supply is also required for bone regeneration upon injury, and maintenance of bone mass with cold exposure.

Operational Constraints and Gender Biases: A Qualitative Analysis of Physician Parenting Experiences.

Objective: Although parenting responsibilities are correlated with gender disparities in professional development and salary, the nature of parental challenges is not well characterized. The aims of this study were to (1) illuminate faculty physicians' experiences with parenting and (2) identify system challenges and opportunities for improvement. Materials and Methods: In October 2019, a survey about parenting was sent to all physician faculty at a large Midwest academic medical center. Qualitative analysis of free-text response to the survey item "is there anything you wish to share about your experience of pregnancy or parenting as a physician" was performed. Themes were inductively identified and developed from the responses in a team-based iterative approach. Results: Of 2069 total physician faculty, 1085 (52.4%) responded to the survey and 253 (23%) of the respondents provided free-text comments. From these comments, the authors identified three themes as sources of challenges for physician parents: operational constraints, gender biases, and nontraditional or nonheteronormative family structures. Operational factors pertained to lack of scheduling flexibility, childcare challenges, lactation, colleague coverage, and transparency of policies. Responses indicated that gender biases are encountered by all genders, and expectations built on assumptions of "traditional" gender roles and family structure are problematic for many physician parents. Conclusion: Addressing the challenges and opportunities identified in the study is critical to building a more supportive institutional culture around parenting and to increase gender parity in academic medicine.

Monocyte Trafficking and Polarization Contribute to Sex Differences in Meta-Inflammation.

Obesity is associated with systemic inflammation and immune cell recruitment to metabolic tissues. Sex differences have been observed where male mice challenged with high fat diet (HFD) exhibit greater adipose tissue inflammation than females demonstrating a role for sex hormones in differential inflammatory responses. Circulating monocytes that respond to dietary lipids and chemokines and produce cytokines are the primary source of recruited adipose tissue macrophages (ATMs). In this study, we investigated sexual dimorphism in biological pathways in HFD-fed ATMs from male and female mice by RNA-seq. We also conducted chemotaxis assays to investigate sex differences in the migration of monocytes isolated from bone marrow from male and female mice toward a dietary saturated lipid - palmitate (PA), and a chemokine - monocyte chemoattractant protein 1 (MCP1), factors known to stimulate myeloid cells in obesity. ATM RNA-Seq demonstrated sex differences of both metabolic and inflammatory activation, including pathways for chemokine signaling and leukocyte trans-endothelial migration. In vivo monocyte transfer studies demonstrated that male monocytes traffic to female adipose tissue to generate ATMs more readily. In chemotaxis assays, lean male monocytes migrated in greater numbers than females toward PA and MCP1. With short-term HFD, male and female monocytes migrated similarly, but in chronic HFD, male monocytes showed greater migration than females upon PA and MCP1 stimulation. Studies with monocytes from toll-like receptor 4 knockout mice (Tlr4-/- ) demonstrated that both males and females showed decreased migration than WT in response to PA and MCP1 implying a role for TLR4 in monocyte influx in response to meta-inflammation. Overall, these data demonstrate the role of sexual dimorphism in monocyte recruitment and response to metabolic stimuli that may influence meta-inflammation in obesity.

Diet-induced obesity in mice impairs host defense against Klebsiella pneumonia in vivo and glucose transport and bactericidal functions in neutrophils in vitro.

Obesity impairs host defense against Klebsiella pneumoniae, but responsible mechanisms are incompletely understood. To determine the impact of diet-induced obesity on pulmonary host defense against K. pneumoniae, we fed 6-wk-old male C57BL/6j mice a normal diet (ND) or high-fat diet (HFD) (13% vs. 60% fat, respectively) for 16 wk. Mice were intratracheally infected with Klebsiella, assayed at 24 or 48 h for bacterial colony-forming units, lung cytokines, and leukocytes from alveolar spaces, lung parenchyma, and gonadal adipose tissue were assessed using flow cytometry. Neutrophils from uninfected mice were cultured with and without 2-deoxy-d-glucose (2-DG) and assessed for phagocytosis, killing, reactive oxygen intermediates (ROI), transport of 2-DG, and glucose transporter (GLUT1-4) transcripts, and protein expression of GLUT1 and GLUT3. HFD mice had higher lung and splenic bacterial burdens. In HFD mice, baseline lung homogenate concentrations of IL-1ß, IL-6, IL-17, IFN-γ, CXCL2, and TNF-α were reduced relative to ND mice, but following infection were greater for IL-6, CCL2, CXCL2, and IL-1ß (24 h only). Despite equivalent lung homogenate leukocytes, HFD mice had fewer intraalveolar neutrophils. HFD neutrophils exhibited decreased Klebsiella phagocytosis and killing and reduced ROI to heat-killed Klebsiella in vitro. 2-DG transport was lower in HFD neutrophils, with reduced GLUT1 and GLUT3 transcripts and protein (GLUT3 only). Blocking glycolysis with 2-DG impaired bacterial killing and ROI production in neutrophils from mice fed ND but not HFD. Diet-induced obesity impairs pulmonary Klebsiella clearance and augments blood dissemination by reducing neutrophil killing and ROI due to impaired glucose transport.

Sex hormones regulate metainflammation in diet-induced obesity in mice.

Men have a statistically higher risk of metabolic and cardiovascular disease than premenopausal women, but the mechanisms mediating these differences are elusive. Chronic inflammation during obesity contributes to disease risk and is significantly more robust in males. Prior work demonstrated that compared with obese males, obese females have reduced proinflammatory adipose tissue macrophages (ATMs). Given the paucity of data on how sex hormones contribute to macrophage responses in obesity, we sought to understand the role of sex hormones in promoting obesity-induced myeloid inflammation. We used gonadectomy, estrogen receptor-deficient alpha chimeras, and androgen-insensitive mice to model sex hormone deficiency. These models were evaluated in diet-induced obesity conditions (high-fat diet [HFD]) and in vitro myeloid assays. We found that ovariectomy increased weight gain and adiposity. Ovariectomized females had increased ATMs and bone marrow myeloid colonies compared with sham-gonadectomized females. In addition, castrated males exposed to HFD had improved glucose tolerance, insulin sensitivity, and adiposity with fewer Ly6chi monocytes and bone marrow myeloid colonies compared with sham-gonadectomized males, although local adipose inflammation was enhanced. Similar findings were observed in androgen-insensitive mice; however, these mice had fewer CD11c+ ATMs, implying a developmental role for androgens in myelopoiesis and adipose inflammation. We concluded that gonadectomy results in convergence of metabolic and inflammatory responses to HFD between the sexes, and that myeloid estrogen receptor alpha contributes minimally to diet-induced inflammatory responses, whereas loss of androgen-receptor signaling improves metabolic and inflammatory outcomes. These studies demonstrate that sex hormones play a critical role in sex differences in obesity, metabolic dysfunction, and myeloid inflammation.

Age and Sex: Impact on adipose tissue metabolism and inflammation.

Age associated chronic inflammation is a major contributor to diseases with advancing age. Adipose tissue function is at the nexus of processes contributing to age-related metabolic disease and mediating longevity. Hormonal fluctuations in aging potentially regulate age-associated visceral adiposity and metabolic dysfunction. Visceral adiposity in aging is linked to aberrant adipogenesis, insulin resistance, lipotoxicity and altered adipokine secretion. Age-related inflammatory phenomena depict sex differences in macrophage polarization, changes in T and B cell numbers, and types of dendritic cells. Sex differences are also observed in adipose tissue remodeling and cellular senescence suggesting a role for sex steroid hormones in the regulation of the adipose tissue microenvironment. It is crucial to investigate sex differences in aging clinical outcomes to identify and better understand physiology in at-risk individuals. Early interventions aimed at targets involved in adipose tissue adipogenesis, remodeling and inflammation in aging could facilitate a profound impact on health span and overcome age-related functional decline.

Advantages of Studying the Metabolome in Response to Mixed-Macronutrient Challenges and Suggestions for Future Research Designs.

Evaluating the postprandial response to a dietary challenge containing all macronutrients-carbohydrates, lipids, and protein-may provide stronger insights of metabolic health than a fasted measurement. Metabolomic profiling deepens the understanding of the homeostatic and adaptive response to a dietary challenge by classifying multiple metabolic pathways and biomarkers. A total of 26 articles were identified that measure the human blood metabolome or lipidome response to a mixed-macronutrient challenge. Most studies were cross-sectional, exploring the baseline and postprandial response to the dietary challenge. Large variations in study designs were reported, including the macronutrient and caloric composition of the challenge and the delivery of the challenge as a liquid shake or a solid meal. Most studies utilized a targeted metabolomics platform, assessing only a particular metabolic pathway, however, several studies utilized global metabolomics and lipidomics assays demonstrating the expansive postprandial response of the metabolome. The postprandial response of individual amino acids was largely dependent on the amino acid composition of the test meal, with the exception of alanine and proline, 2 nonessential amino acids. Long-chain fatty acids and unsaturated long-chain acylcarnitines rapidly decreased in response to the dietary challenges, representing the switch from fat to carbohydrate oxidation. Studies were reviewed that assessed the metabolome response in the context of obesity and metabolic diseases, providing insight on how weight status and disease influence the ability to cope with a nutrient load and return to homeostasis. Results demonstrate that the flexibility to respond to a substrate load is influenced by obesity and metabolic disease and flexibility alterations will be evident in downstream metabolites of fat, carbohydrate, and protein metabolism. In response, we propose suggestions for standardization between studies with the potential of creating a study exploring the postprandial response to a multitude of challenges with a variety of macronutrients.

Weight Gain, Glucose Tolerance, and the Gut Microbiome of Male C57BL/6J Mice Housed on Corncob or Paper Bedding and Fed Normal or High-Fat Diet.

Understanding how differences in animal husbandry practices affect the reproducibility of research results is critical. We sought to understand how different beddings might influence dietary obesity studies. We compared the effects of paper and corncob bedding on weight gain, metabolism, and gut microbiome (GM) of mice fed a high-fat diet (HFD) or a normal diet (ND) and evaluated effects on fecal and cecal microbiomes collected from these cohorts after euthanasia. Male C57BL/6J mice at 5 wk age were allowed to acclimate to the facility and the assigned bedding for one week before being placed on HFD or remaining on the ND for 12 wk. Fecal pellets and cecal samples were collected and frozen for batched 16S sequencing. Mice had similar body weight, visceral gonadal white adipose tissue (GWAT), subcutaneous inguinal white adipose tissue (IWAT), liver and spleen weights and metabolic changes regardless of the bedding type. Baseline microbiota differences were detected one week after bedding assignment. After 12 wk, the GM showed significant differences depending on both bedding and diet. The effects of the bedding were not significantly different between endpoint fecal and cecal GM, despite the inherent differences in microbiota in fecal and cecal samples. A correlation was detected between diet and the relative abundance of Bacteroidetes and Verrucomicrobia: Akkermansia. In conclusion, this study demonstrates the importance of considering bedding type when performing dietary experiments.

Diet-dependent sex differences in the response to vertical sleeve gastrectomy.

Nearly 80% of patients that receive bariatric surgery are women, yet mechanistic preclinical studies have focused on males. The goal of this study was to determine the metabolic impact of diet- and surgery-induced weight loss in males, females, and ovariectomized females. All mice were fed a 60% high-fat diet (HFD) before undergoing either vertical sleeve gastrectomy (VSG) or sham surgery. Mice either remained on an HFD or were switched to a standard chow diet postsurgically. When maintained on an HFD, males and females decreased fat mass and improved oral glucose tolerance after VSG. After dietary intervention, additional adiposity was lost in both surgical groups. Ovariectomized females showed a blunted decrease in fat mass on an HFD, but lost significant adiposity after dietary intervention. Energy expenditure was impacted by dietary and not surgical intervention across all groups. Males decreased hepatic triglyceride levels after VSG, which was further decreased after dietary intervention. Intact and ovariectomized females had a blunted decrease in hepatic triglycerides after VSG, but a significant decrease after dietary intervention. The more pronounced effect of VSG on hepatic lipids in males is strongly associated with changes in hepatic expression of genes and microRNAs previously linked to hepatic lipid regulation and systemic energy homeostasis. These data highlight the importance of postsurgical diet on metabolic outcomes across sexes. Furthermore, these data suggest the impact of VSG on hepatic triglycerides is diet-dependent in females and support the hypothesis that males and females achieve similar metabolic outcome, at least within the liver, via distinct mechanisms.NEW & NOTEWORTHY These data highlight the interaction of postsurgical diet after bariatric surgery on metabolic outcomes across sexes. These data suggest the impact of VSG on hepatic triglycerides is diet-dependent in females and support the hypothesis that males and females achieve similar metabolic outcome, at least within the liver, via distinct mechanisms.

Insulin Receptor-Expressing T Cells Appear in Individuals at Risk for Type 1 Diabetes and Can Move into the Pancreas in C57BL/6 Transgenic Mice.

Insulin receptor (IR) expression on the T cell surface can indicate an activated state; however, the IR is also chemotactic, enabling T cells with high IR expression to physically move toward insulin. In humans with type 1 diabetes (T1D) and the NOD mouse model, a T cell-mediated autoimmune destruction of insulin-producing pancreatic ß cells occurs. In previous work, when purified IR+ and IR- T cells were sorted from diabetic NOD mice and transferred into irradiated nondiabetic NOD mice, only those that received IR+ T cells developed insulitis and diabetes. In this study, peripheral blood samples from individuals with T1D (new onset to 14 y of duration), relatives at high-risk for T1D, defined by positivity for islet autoantibodies, and healthy controls were examined for frequency of IR+ T cells. High-risk individuals had significantly higher numbers of IR+ T cells as compared with those with T1D (p < 0.01) and controls (p < 0.001); however, the percentage of IR+ T cells in circulation did not differ significantly between T1D and control subjects. With the hypothesis that IR+ T cells traffic to the pancreas in T1D, we developed a (to our knowledge) novel mouse model exhibiting a FLAG-tagged mouse IR on T cells on the C57BL/6 background, which is not susceptible to developing T1D. Interestingly, these C57BL/6-CD3FLAGmIR/mfm mice showed evidence of increased IR+ T cell trafficking into the islets compared with C57BL/6 controls (p < 0.001). This transgenic animal model provides a (to our knowledge) novel platform for investigating the influence of IR expression on T cell trafficking and the development of insulitis.

Obesity-induced inflammation: The impact of the hematopoietic stem cell niche.

Obesity and obesity-related diseases like type 2 diabetes (T2D) are prominent global health issues; therefore, there is a need to better understand the mechanisms underlying these conditions. The onset of obesity is characterized by accumulation of proinflammatory cells, including Ly6chi monocytes (which differentiate into proinflammatory macrophages) and neutrophils, in metabolic tissues. This shift toward chronic, low-grade inflammation is an obese-state hallmark and highly linked to metabolic disorders and other obesity comorbidities. The mechanisms that induce and maintain increased inflammatory myelopoiesis are of great interest, with a recent focus on how obesity affects more primitive hematopoietic cells. The hematopoietic system is constantly replenished by proper regulation of hematopoietic stem and progenitor (HSPC) pools in the BM. While early research suggests that chronic obesity promotes expansion of myeloid-skewed HSPCs, the involvement of the hematopoietic stem cell (HSC) niche in regulating obesity-induced myelopoiesis remains undefined. In this review, we explore the role of the multicellular HSC niche in hematopoiesis and inflammation, and the potential contribution of this niche to the hematopoietic response to obesity. This review further aims to summarize the potential HSC niche involvement as a target of obesity-induced inflammation and a driver of obesity-induced myelopoiesis.