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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-1β, 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-1β (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.

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 β 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.

Objective Weight regain after weight loss is common, and there is evidence to suggest negative effects on health because of weight cycling. This study sought to investigate the impact of weight regain in formerly obese mice on adipose tissue architecture and stromal cell function. Methods A diet-switch model was employed for obesity induction, weight loss, and weight regain in mice. Flow cytometry quantified adipose tissue leukocytes in adipose tissue. Liver and adipose tissue depots were compared to determine tissue-specific effects of weight cycling. Results Epididymal white adipose tissue of formerly obese mice failed to expand in response to repeat exposure to high-fat diet and retained elevated numbers of macrophages and T cells. Weight regain was associated with disproportionally elevated liver mass, hepatic triglyceride content, serum insulin concentration, and serum transaminase concentration. These effects occurred despite an extended 6-month weight loss cycle and they demonstrate that formerly obese mice maintain durable alterations in their physiological response to weight regain. Conditioned media from epididymal adipose tissue of formerly obese mice inhibited adipogenesis of 3T3-L1 preadipocytes, suggesting a potential mechanism to explain failed epididymal adipose tissue expansion during weight regain. Conclusions Metabolic abnormalities related to defects in adipose tissue expansion and ongoing dysfunction manifest in formerly obese mice during weight regain.

Aging, like obesity, is associated with metabolic and inflammatory alterations within adipose tissue in older individuals. Younger females are protected from adipose inflammation, but older post-menopausal females exhibit exaggerated visceral adiposity correlated with increased disease risk. Obesity accelerates the onset and progression of age-associated diseases, but it is unclear if aging and obesity drive adipose tissue dysfunction in a sexually dimorphic fashion. We investigated adipose tissue metabolism and inflammation in a diet-induced obesity model in young and old mice. We identified age related sex differences in adipose tissue macrophages (ATMs), fibrosis and lipid metabolism in male and female visceral fat depot (GWAT). Although aging normalized body weights between the sexes, females remained protected from proinflammatory ATMs and stimulated lipolysis failed to adversely affect the inflammatory state even with obesity. Older obese males had augmented CD11c+ ATMs and higher insulin levels, while females showed increased visceral adiposity and exaggerated Pparγ, and Pgc1α expression. Obesity in aging demonstrated similar expression of GWAT p53, p16, p21, Timp1 and Tgfβ1 in both sexes. Our studies suggest that even with aging, female GWAT shows an attenuated inflammatory response compared to males due to an efficient oxidative metabolism combined with an active tissue remodeling state.

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.

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.

Insulin bolus calculators have proven effective in improving glycemia and patient safety. Insulin calculators are increasingly being implemented for inpatient hospital care. Multidisciplinary teams are often involved in the design and review of the efficacy and utilization for these calculators. At times, unintended consequences and benefits of utilization are found on review. Integration of our insulin calculator into our electronic health record system was a multidisciplinary effort. During implementation, several obstacles to effective care were identified and are discussed in the following manuscript. We describe the barriers to utilization and potential pitfalls in clinical integration. We further describe benefits in patient education, time of insulin administration versus meal delivery, variations in insulin bolus for ketone correction, variation in care, and maximum bolus administration. Sharing lessons learned from experiences using electronic insulin calculator order sets will further our goals of improved patient care in the hospital setting.

The coronavirus disease 2019 (COVID-19) pandemic has forced us to consider the physiologic role of obesity in the response to infectious disease. There are significant disparities in morbidity and mortality by sex, weight, and diabetes status. Numerous endocrine changes might drive these varied responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, including hormone and immune mediators, hyperglycemia, leukocyte responses, cytokine secretion, and tissue dysfunction. Studies of patients with severe COVID-19 disease have revealed the importance of innate immune responses in driving immunopathology and tissue injury. In this review we will describe the impact of the metabolically induced inflammation (meta-inflammation) that characterizes obesity on innate immunity. We consider that obesity-driven dysregulation of innate immune responses may drive organ injury in the development of severe COVID-19 and impair viral clearance.

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.

Summary Background: Insulin dosing in hospitalized pediatric patients is challenging and requires dosing to be matched with the specific clinical and nutritional circumstances. We implemented a customized subcutaneous insulin bolus dose calculator tool integrated with the electronic health record to improve patient care. Here we describe this tool, its utilization and safety, and assess user satisfaction and perceptions of the tool. Methods: Blood glucose results for all patients who received insulin with and without the calculator tool were compared to assess safety. To assess user perceptions and satisfaction, a survey was sent to all identified users who interacted with the tool during the period from May 2015 to the end of November 2015. Survey responses were summarized, mean user satisfaction calculated, and correlation of Likert scale items with overall satisfaction assessed. Results: Hypoglycemia rates (2.2% and 2.9%, p = 0.17) and severe hypoglycemia rates (0.04% and 0.1%, p = 0.21) were similar for the groups that received insulin with and without the calculator tool. Overall satisfaction for all survey respondents was high (4.05, SD = 0.83). Physicians indicated a slightly higher satisfaction than nurses (4.33 versus 3.94, p = 0.04). User agreement with improvement of quality of care showed the highest correlation with overall satisfaction (r = 0.80, 95% CI 0.7 –0.87). Conclusion: Implementation of an insulin calculator tool streamlined ordering and administration of insulin in a pediatric academic institution while maintaining patient safety. Users indicated high overall satisfaction with the tool. Citation: Ateya MB, Aiyagari R, Moran C, Singer K. .:Insulin bolus calculator in a pediatric hospital: Safety and user perceptions. Appl Clin Inform 2017; 8: 529–540 https://doi.org/10.4338/ACI-2016-11-RA-0187

With the increasing prevalence of obesity in women of reproductive age there is a need to understand the ramifications of this on offspring. The purpose of this study is to investigate the programming effects of maternal obesity during preconception and the preconception/gestational period on adiposity and adipose tissue inflammation in offspring using an animal model. Adult female C57Bl/6J mice were assigned either normal diet, high fat diet (HFD) prior to pregnancy, or HFD prior to and through pregnancy. Some offspring were maintained on normal diet while others started HFD later in life. Offspring were assessed for body composition and metabolic responses. Lipid storing tissues were evaluated for expansion and inflammation. Male offspring from the preconception group had the greatest weight gain, most subcutaneous adipose tissue, and largest liver mass when introduced to postnatal HFD. Male offspring of the preconception/gestation group had worsened glucose tolerance and an increase in resident (CD11c−) adipose tissue macrophages (ATMs) when exposed to postnatal HFD. Female offspring had no significant difference in any parameter between the diet treatment groups. In conclusion, this study demonstrates that prenatal and pregnancy windows have independent programming effects on offspring. Preconception exposure affects body composition and adiposity while gestation exposure affects metabolism and tissue immune cell phenotypes.

Prenatal testosterone (T)-treated female sheep exhibit an enhanced inflammatory and oxidative stress state in the visceral adipose tissue (VAT) but not in the subcutaneous (SAT), while surprisingly maintaining insulin sensitivity in both depots. In adult sheep, adipose tissue is predominantly composed of white adipocytes which favor lipid storage. Brown/beige adipocytes that make up the brown adipose tissue (BAT) favor lipid utilization due to thermogenic uncoupled protein 1 expression and are interspersed amidst white adipocytes, more so in epicardiac (ECAT) and perirenal (PRAT) depots. The impact of prenatal T-treatment on ECAT and PRAT depots are unknown. As BAT imparts a metabolically healthy phenotype, the depot-specific impact of prenatal T-treatment on inflammation, oxidative stress, differentiation and insulin sensitivity could be dictated by the distribution of brown adipocytes. This hypothesis was tested by assessing markers of oxidative stress, inflammation, adipocyte differentiation, fibrosis and thermogenesis in adipose depots from control and prenatal T (100 mg T propionate twice a week from days 30–90 of gestation) -treated female sheep at 21 months of age. Our results show prenatal T-treatment induces depot-specific changes in inflammation, oxidative stress state, collagen accumulation, and differentiation with changes being more pronounced in the VAT. Prenatal T-treatment also increased thermogenic gene expression in all depots indicative of increased browning with effects being more prominent in VAT and SAT. Considering that inflammatory and oxidative stress are also elevated, the increased brown adipocyte distribution is likely a compensatory response to maintain insulin sensitivity and function of organs in the proximity of respective depots.

Objective: We aimed to examine if myeloid leukocyte profiles are associated with metabolic impairment in children and adolescents with obesity, and if sex, age, or race influence this relationship.Methods: 282 children ages 8–17 were evaluated. Predictor measures were absolute neutrophil counts (ANC), absolute monocyte count, monocyte subtypes and C reactive protein (CRP). Outcome variables were waist circumference, fasting glucose and insulin, HOMA-IR, HbA1c (%) and lipid profiles. Pearson correlation coefficients were used to determine associations between predictor and outcome variables. Wilcoxon two-sample tests were used to evaluate differences by sex.Results: CRP (p < 0.0001), ANC (p < 0.0018), and classical monocytes (p = 0.05) were significantly higher in children with obesity. CRP, ANC and classical monocytes showed positive correlations with waist circumference, insulin, HOMA-IR and triglycerides. CRP was positively associated with ANC overall (p = 0.05). ANC demonstrated positive correlation with monocytes (p < 0.001). The associations between predictor and outcome variables were influenced by sex, race, and age.Conclusions: CRP and myeloid leukocyte populations, specifically classical monocytes and neutrophils associate with both body composition and metabolic parameters in children with obesity suggesting that these cells may play a critical role in metabolic impairment. Race, gender and age interactions between monocytes and metabolic parameters were significant.

Background Weight loss by surgery or lifestyle changes is strongly recommended for obese individuals to improve metabolic health, but the underlying impairments that persist from a history of obesity remain unclear. Recent investigations demonstrate a persistent inflammatory state with weight loss and bariatric surgery, but the mechanism and impact are not fully understood. Additionally, these studies have not been performed in females although women are the majority of individuals undergoing weight loss interventions. Methods The goal of this study was to determine the sex differences in metabolically induced inflammation after dietary weight loss (WL) or bariatric surgery. Following a 60% high-fat diet (HFD) for 12 weeks, C57Bl/6j mice underwent either a dietary switch to normal chow for WL or vertical sleeve gastrectomy (VSG) and were evaluated 8 weeks after intervention. WL effects on myelopoiesis were further evaluated with bone marrow chimeras. Results Both sexes had a decrease in adiposity and total weight following WL or VSG intervention. With HFD, females had very little inflammation and no further increase with WL, but males had persistent inflammation even after WL despite metabolic improvement. Interestingly, after VSG, myeloid inflammation was increased in the livers of males and to a lesser extent in females. Conclusions These studies demonstrate that regardless of sex, it is critical to assess an individuals’ history of obesity rather than just rely on current weight status in medical decision-making. There are long-lasting effects on tissue inflammation in both sexes especially with surgical weight loss. Dietary change is overall most effective to improve meta-inflammation in obese males on its own or in combination with surgical weight loss.

Obesity is a global health epidemic, closely associated with cardiovascular diseases (CVD), hypertension, type 2 diabetes, and atherosclerosis. Obese adipose tissue is a site and source for inflammation that is strongly associated with these metabolic diseases. In obese mice models, males exhibit profound adipose tissue macrophage (ATM) accumulation in gonadal white adipose tissue (GWAT) linked to insulin resistance, while females are protected even with enhanced adiposity. This dampened inflammation may directly explain reduced metabolic and cardiovascular disease in young women. However, it is not clear what metabolic and inflammatory responses occur in post-menopausal models. We hypothesized an increased inflammatory response would occur in obese older females. We challenged male and female C57Bl6/j mice to 16-24 weeks of 60% high fat diet (HFD) starting at 6 weeks of age (young) or 10 month of age (old). Animal body weights and metabolic depot (adipose and liver) weights were measured at the completion of diet challenge. Flow cytometry was used to determine ATM populations in visceral (GWAT) compared to subcutaneous inguinal WAT (IWAT). Lipolysis was stimulated with a beta3 adrenergic receptor (ADRB3) agonist CL-316, 243 and free fatty acids (FFA), glycerol, and triglyceride (TG) levels assessed in serum and liver. Obesity in young mice led to fat accumulation in GWAT and IWAT of both males and females. In old male animals, fat pads did not expand, and liver weights were as a result larger than in females. Both young and old females had reduced adipose inflammation compared to males. ADRB3 activation had no effect on adipose tissue weights but significantly increased liver weights in obese young females. Obese CL treated young and old female mice showed elevated FFA compared to levels induced in males. Lipolysis promoted appearance of crown like structures (CLS) in both obese young and old males and females, due to CD11c- ATM accumulation. Obesity during aging continues to lead to enhanced inflammation in males along with steatosis but females continue to be protected with appropriate storage of fatty acids with very little induced inflammation. Sex differences in inflammation that persist in aging demonstrate that differences in meta-inflammation may explain sex differences in metabolic and cardiovascular diseases regardless of age and need to be further explored for targeted treatment strategies.

Obesity causes dramatic proinflammatory changes in the adipose tissue immune environment, but relatively little is known regarding how this inflammation responds to weight loss (WL). To understand the mechanisms by which meta-inflammation resolves during WL, we examined adipose tissue leukocytes in mice after withdrawal of a high-fat diet. After 8 weeks of WL, mice achieved similar weights and glucose tolerance values as age-matched lean controls but showed abnormal insulin tolerance. Despite fat mass normalization, total and CD11c+ adipose tissue macrophage (ATM) content remained elevated in WL mice for up to 6 months and was associated with persistent fibrosis in adipose tissue. ATMs in formerly obese mice demonstrated a proinflammatory profile, including elevated expression of interferon-γ, tumor necrosis factor-α, and interleukin-1β. T-cell–deficient Rag1−/− mice showed a degree of ATM persistence similar to that in WT mice, but with reduced inflammatory gene expression. ATM proliferation was identified as the predominant mechanism by which ATMs are retained in adipose tissue with WL. Our study suggests that WL does not completely resolve obesity-induced ATM activation, which may contribute to the persistent adipose tissue damage and reduced insulin sensitivity observed in formerly obese mice.

It is well known in clinical and animal studies that women and men have different disease risk as well as different disease physiology. Women of reproductive age are protected from metabolic and cardiovascular disease compared with postmenopausal women and men. Most murine studies are skewed toward the use of male mice to study obesity-induced metabolic dysfunction because of similar protection in female mice. We have investigated dietary obesity in a mouse model and have directly compared inflammatory responses in males and females. In this review we will summarize what is known about sex differences in diet-induced inflammation and will summarize our data on this topic. It is clear that sex differences in high-fat diet-induced inflammatory activation are due to cell intrinsic differences in hematopoietic responses to obesogenic cues, but further research is needed to understand what leads to sexually dimorphic responses.

Background:Sepsis induces inflammation in response to infection and is a major cause of mortality and hospitalization in children. Obesity induces chronic inflammation leading to many clinical manifestations. Our understanding of the impact of obesity on diseases, such as infection and sepsis, is limited. The objective of this study was to evaluate the association of obesity with organ dysfunction, mortality, duration, and charges during among US children hospitalized with infection.Methods:Retrospective study of hospitalizations in children with infection aged 0 to 20 years, using the 2009 Kids’ Inpatient Database.Results:Of 3.4 million hospitalizations, 357 701 were for infection, 5685 of which were reported as obese children. Obese patients had higher rates of organ dysfunction (7.35% vs 5.5%, P < .01), longer hospital stays (4.1 vs 3.5 days, P < .001), and accrued higher charges (US$29 019 vs US$21 200, P < .001). In multivariable analysis, mortality did not differ by obesity status (odds ratio: 0.56, 95% confidence interval: 0.23-1.34), however severity of illness modified the association between obesity status and the other outcomes.Conclusions:While there was no difference in in-hospital mortality by obesity diagnosis, variation in organ dysfunction, hospital stay, and hospital charges according to obesity status was mediated by illness severity. Findings from this study have significant implications for targeted approaches to mitigate the burden of obesity on infection and sepsis.

Among potential contributors for the increased incidence of metabolic diseases is the developmental exposure to endocrine-disrupting chemicals such as bisphenol A (BPA). BPA is an estrogenic chemical used in a variety of consumer products. Evidence points to interactions of BPA with the prevailing environment. The aim of this study was to assess the effects of prenatal exposure to BPA on postnatal metabolic outcomes, including insulin resistance, adipose tissue distribution, adipocyte morphometry, and expression of inflammatory markers in adipose tissue as well as to assess whether postnatal overfeeding would exacerbate these effects. Findings indicate that prenatal BPA exposure leads to insulin resistance in adulthood in the first breeder cohort ( study 1), but not in the second cohort ( study 2), which is suggestive of potential differences in genetic susceptibility. BPA exposure induced adipocyte hypertrophy in the visceral fat depot without an accompanying increase in visceral fat mass or increased CD68, a marker of macrophage infiltration, in the subcutaneous fat depot. Cohens effect size analysis found the ratio of visceral to subcutanous fat depot in the prenatal BPA-treated overfed group to be higher compared with the control-overfed group. Altogether, these results suggest that exposure to BPA during fetal life at levels found in humans can program metabolic outcomes that lead to insulin resistance, a forerunner of type 2 diabetes, with postnatal obesity failing to manifest any interaction with prenatal BPA relative to insulin resistance and adipocyte hypertrophy.

Males are known to have profound adipose tissue macrophage (ATM) accumulation in gonadal white adipose tissue (GWAT) during obesity, whereas females are protected from such an inflammatory response even with increased adiposity. The inflammatory tone in males is linked to insulin resistance and might be the underlying cause for sex differences in metabolic disease. Factors regulating the meta-inflammatory response remain unclear but enhanced lipid storage in females may explain the reduced inflammatory response to high-fat diets. In this study, we evaluated lean and obese females with stimulated lipolysis to understand whether a stress release of free fatty acids (FFAs) could induce female ATMs. We demonstrate that in both lean and obese females, GWAT CD11c(−) resident ATMs accumulate with β-3 adrenergic receptor–stimulated lipolysis. Lipolysis elevated serum FFA, triglyceride, and IL-6 levels in females that corresponded to significant phosphorylated hormone-sensitive lipase and adipose triglyceride lipase protein expression in obese female GWAT compared with males. Increased lipolytic response in obese females was associated with crown-like structures and induced Il6, Mcp1, Arg1, and Mgl1 expression in obese female GWAT, suggesting an environment of lipid clearance and adipose remodeling. With this finding we next investigated whether lipid storage and lipolytic mediators differed by sex. Diacylglycerol, ceramides, phospholipids, and certain fatty acid species associated with inflammation were elevated in male GWAT compared with obese female GWAT. Overall, our data demonstrate a role for GWAT lipid storage and lipolytic metabolites to induce inflammation in males and induce remodeling in females that might explain sex differences in overall metabolic health.

PURPOSE OF REVIEW: As the ongoing epidemic of adult and childhood obesity grows, it puts a greater burden on individuals and the healthcare system due to increased prevalence of obesity-associated diseases. An important area that has gained much attention recently is the sex and gender difference related to obesity and associated complications. Basic science and clinical studies have now improved our understanding of obesity and have discovered adipose tissue biology to be key in metabolism. RECENT FINDINGS: There is evidence related to the sex dichotomy in obesity in a variety of areas including adipocyte function, sex hormone effects, genetics, and metabolic inflammation leading to critical differences in adipose tissue biology. SUMMARY: The sex and gender difference in adipose tissue is a factor that should be considered when studying an individuals’ risk for obesity and metabolic dysfunction. This understanding is important for strategizing treatment and prevention measures.

Men have a higher risk of metabolic and cardiovascular disease than pre-menopausal women, but the mechanisms of these differences are elusive. Chronic myeloid inflammation during obesity contributes to metabolic disease risk and is significantly more robust in males. Given the paucity of data on male sex hormones contributing to macrophage responses in obesity, our objective was to understand the role of androgens in promoting obesity-induced myeloid inflammation. Male and female C57Bl/6J mice were fed a 60% high fat diet for 24 weeks. Glucose tolerance and insulin sensitivity were measured. Monocyte transfer experiments assessed sex differences in bone marrow myeloid responses to obesity independent of host sex. Gonadectomy, mice deficient of androgen receptor signaling (ARtfm) and monocyte specific androgen receptor (AR) knockout mice (LysMAR-/y) were used to model androgen deficiency. Compared to males, females had dampened inflammatory responses with reduced CD11c+ ATMs and cytokines, even with increased adiposity. RNASeq demonstrated sex differences in gene pathways of both metabolic and inflammatory activation in ATMs. Male monocytes transferred into females remained primed for pro-inflammatory response and induced an increase in adiposity. Castrated males exposed to high fat diet had impaired glucose tolerance and increased insulin sensitivity with increased adiposity and lower numbers of CD11c+ ATMs. These same findings were seen in ARtfm mice. Testosterone enhanced palmitate-stimulated myeloid colony production, and this response was dampened in castrated, ARtfm, and LysMAR-/y mice. These studies demonstrate that androgens play a critical role in enhanced metabolic dysfunction and enhanced myeloid inflammation in response to obesogenic cues. Androgen driven myeloid inflammation leads to metabolic dysfunction in a cell-autonomous manner driving sex-differences in obesity induced meta-inflammation. Disclosure C.A. Griffin: None. S. Abrishami: None. M. Varghese: None. K. Singer: None.

Men and post-menopausal women are at greater risk for cardiovascular diseases and diabetes than younger women. In obese rodent models, males exhibit profound adipose tissue macrophage (ATM) accumulation in gonadal white adipose tissue (GWAT) linked to insulin resistance, while females are protected even with enhanced adiposity. We hypothesize that these inflammatory differences may be a result of altered lipolysis responses and that females would have enhanced ATM accumulation when lipolysis is induced. Lipolysis was stimulated with a beta3 adrenergic receptor (ADRB3) agonist CL-316, 243 in C57Bl6/j male and female mice fed 16 weeks of 60% high fat diet (HFD). GWAT leukocytes were isolated after 18 h and evaluated by flow cytometry. Lipogenic, lipolytic, oxidative and inflammatory gene expression along with immunofluorescence were performed. ADRB3 activation did not alter adipose tissue weights, but significantly reduced liver weights in obese females. Obese CL treated female mice showed elevated serum free fatty acid (FFA) and triglyceride (TG) levels compared to levels induced in males. Lipid overload impaired TG storage and utilization genes- Lpl, Fasn, Acsl1, Hsl, and Glut4 expression in obese females. Lipolysis promoted appearance of crown like structures (CLS) in males and females but only induced Il6 proinflammatory cytokine and Mcp1 chemokine expression in obese female GWAT. Activated lipolysis triggered CD11c- ATM accumulation in lean females but in both obese male and female GWAT. Obese males showed a marked reduction in GWAT dendritic cells (DC) but a significant reduction in both GWAT and inguinal WAT DCs of obese females. While obese females are resistant to inflammation, this study shows that induced lipolysis elevates FFA levels, alters lipid metabolism and increased CD11c- ATMs and CLSs in obese females. Elucidating the link between lipolysis and inflammation can better explain sex differences in overall metabolic health leading to targeted treatment strategies. Disclosure M. Varghese: None. S. Abrishami: None. K. Singer: None.

Objective: To evaluate the effect of overweight and obesity on outcomes and resource use among patients with sepsis in the pediatric intensive care unit (PICU). Design: Retrospective analysis of clinical characteristics, resource use, and mortality among children 0 to 20 years of age admitted to the C.S. MottChildren’s Hospital PICU (University of Michigan) between January 2009 and December 2015, with a diagnostic code for sepsis at admission (based on International Classification of Diseases, Ninth Revision- Clinical Modification codes) and with weight and height measurements at PICU admission. Measurements and Main Results: A total of 454 participants met the inclusion criteria. Seventy-six were categorized as underweight (body mass index [BMI] percentile 5th and 85th percentile as overweight/obese. After descriptive and bivariate analyses, multivariate regression methods were used to assess the independent effect of obesity status on mortality and the use of PICU technology after adjustment for patient age and illness severity at admission. Of the 378 patients studied, 41.3% were overweight/obese. There was no difference in microbiologic etiology of sepsis ( P = .36), median PICU length of stay in days (5.4 vs 5.6; P = .61), or PICU mortality (6.4% vs 7.2%; P = .76) by weight status. The use of specialized PICU technology including extracorporeal membrane oxygenation (odds ratio [OR]: 2.77, 95% confidence interval [CI]:1.13-6.79) and continuous renal replacement therapy (OR: 4.58, 95% CI: 1.16-18.0) was higher among overweight/obese patients, compared with normal weight patients. Conclusions: Although PICU mortality and length of stay were similar for obese–overweight patients and normal weight critically ill children with sepsis, there was significantly higher use of specialized organ-supportive technology among obese patients, likely indicating higher occurrence of multiple organ dysfunction.

Human adenovirus (HAdV) type 36 seropositivity has been linked to obesity in humans. That link is supported by a small number of studies using HAdV-36 infection of animals that are not natural hosts for HAdVs. In this study, we infected mice with mouse adenovirus type 1 (MAV-1), a mouse pathogen, to determine whether MAV-1 infected adipose tissue and was associated with adipose tissue inflammation and obesity. We detected MAV-1 in adipose tissue during acute MAV-1 infection, but we did not detect virus-induced increases in adipose tissue cytokine expression or histological evidence of adipose tissue inflammation during acute infection. MAV-1 did not persist in adipose tissue at later times, and we did not detect long-term adipose inflammation, increased adipose tissue mass, or body weight in infected mice. Our data indicate that MAV-1 is not associated with obesity in infected mice.

Objective Obesity has been associated with markers of increased systemic inflammation in both human and animal studies. Increased inflammation is linked to metabolic and cardiovascular disease. The objective of this study was to evaluate the association between percentile body fat and inflammation in a nationally representative sample of US children. Methods: 6,950 children 8-18 years of age between 1999 and 2004 were studied. Measurement of body fat percentage was measured by dual-energy X-ray absorptiometry scan and converted to an age- and sex-adjusted percentile. The main outcome measures were abnormal c-reactive protein (CRP > 1.0 mg/dl) and absolute neutrophil count (ANC > 6,600). Results Children with higher levels of body fat (≥70th percentile) had a higher odds of having elevated CRP (OR 2.88-10.69) and elevated ANC (OR 2.14-3.24) compared with children with body fat

Overnutrition during critical windows of development plays a significant role in life-long metabolic disease risk. Early exposure to excessive nutrition may result in altered programming leading to increased susceptibility to obesity, inflammation, and metabolic complications. This study investigated the programming effects of high-fat diet (HFD) exposure during the lactation period on offspring adiposity and inflammation. Female C57Bl/6J dams were fed a normal diet or a 60% HFD during lactation. Offspring were weaned onto a normal diet until 12 weeks of age when half were re-challenged with HFD for 12 weeks. Metabolic testing was performed throughout adulthood. At 24 weeks, adipose depots were isolated and evaluated for macrophage profiling and inflammatory gene expression. Males exposed to HFD during lactation had insulin resistance and glucose intolerance as adults. After re-introduction to HFD, males had increased weight gain and worsened insulin resistance and hyperglycemia. There was increased infiltration of pro-inflammatory CD11c+ adipose tissue macrophages, and bone marrow was primed to produce granulocytes and macrophages. Bone density was lower due to enhanced marrow adiposity. This study demonstrates that maternal HFD exposure during the lactational window programs offspring adiposity, inflammation, and impaired glucose homeostasis.

Predictors of weight loss responses are not well-defined. We hypothesized that adipose tissue phenotypic features related to remodeling would be associated with bariatric surgery weight loss responses. Visceral and subcutaneous adipose tissues collected from patients during bariatric surgery were studied with flow cytometry, immunohistochemistry, and QRTPCR, and results correlated with weight loss outcomes. Age, male sex, and a diagnosis of type 2 diabetes were associated with less weight loss. Adipocyte size was increased and preadipocyte frequency was decreased in visceral adipose tissue from diabetic subjects. Decreased adipose tissue preadipocyte frequency was associated with less weight loss in women but not men. These data suggest that phenotypic features of adipose tissue remodeling may predict responses to weight loss interventions.

An understanding of the events that initiate metabolic inflammation (metainflammation) can support the identification of targets for preventing metabolic disease and its negative effects on health. There is ample evidence demonstrating that the initiating events in obesity-induced inflammation start early in childhood. This has significant implications on our understanding of how early life events in childhood influence adult disease. In this Review we frame the initiating events of metainflammation in the context of child development and discuss what this reveals about the mechanisms by which this unique form of chronic inflammation is initiated and sustained into adulthood.

Metabolic and non-metabolic complications due to obesity are becoming more prevalent, yet our understanding of the mechanisms driving these is not. This is due to individual risk factor variability making it difficult to predict disease outcomes such as diabetes and insulin resistance. Gender is a critical factor in obesity outcomes with women having more adiposity but reduced metabolic complications compared to men. The role of immune system activation during obesity is an emerging field that links adiposity to metabolic syndrome. Furthermore, evidence from animal models suggests that sex differences exist in immune responses and, therefore, could be a possible mechanism leading to sex differences in metabolic disease. While there is still much to learn in the area of sex-differences research, this chapter will review the current knowledge and literature detailing the role of sex and sex hormones on adiposity and metabolically induced inflammation in obesity.

To describe the clinical course, resource use, and mortality of patients with leukemia admitted to the pediatric intensive care unit with sepsis and nonsepsis diagnoses over a 10-yr period.Retrospective analysis.Tertiary medical-surgical pediatric intensive care unit at C.S. Mott Children's Hospital, University of Michigan.All patients with leukemia admitted to the pediatric intensive care unit from January 1, 1998, to December 31, 2008.None; chart review.Clinical course was characterized by demographics, leukemia diagnosis, phase of therapy, leukocyte count on admission, presence of sepsis, steroid administration, intensity of care, and Pediatric Risk of Mortality score on admission to the pediatric intensive care unit. The primary outcome was survival to pediatric intensive care unit discharge. Among 68 single admissions to the pediatric intensive care unit with leukemia during the study period, 33 (48.5%) were admitted with sepsis. Admission to the pediatric intensive care unit for sepsis was associated with greater compromise of hemodynamic and renal function and use of stress dose steroids (p = .016), inotropic and/or vasopressor drugs (p = .01), and renal replacement therapy (p = .028) than nonsepsis admission. There was higher mortality among children with sepsis than other diagnoses (52% vs. 17%, p = .004). Also, mortality among children with sepsis was higher among those with acute lymphoblastic leukemia (60% vs. 44%) compared with acute myelogenous leukemia. Administration of stress dose steroids was associated with higher mortality (50% vs. 17%, p = .005) and neutropenia. Patients with acute lymphoblastic leukemia and sepsis showed the greatest mortality and resource use.Patients with acute leukemia and sepsis had a much higher mortality rate compared with previously described sepsis mortality rates for the general pediatric intensive care unit patient populations. Patients who received steroids had an increased mortality rate, but given the retrospective nature of this study, we maintain a position of equipoise with regard to this association. Variation in mortality and resource use by leukemia type suggests further research is needed to develop targeted intervention strategies to enhance patient outcomes.

Proinflammatory adipose tissue macrophages (ATMs) contribute to obesity-associated disease morbidity. We will provide an update of the current state of knowledge regarding the phenotypic and functional diversity of ATMs in lean and obese mice and humans.The phenotypic diversity of ATMs is now known to include more than two types requiring an expansion of the simple concept of an M2 to M1 shift with obesity. Potential functions for ATMs now include the regulation of fibrosis and response to acute lipolysis in states of caloric restriction. Novel pathways that can potentiate ATM action have been identified, which include inflammasome activation and the response to lipodystrophic adipose tissue. Studies provide a new appreciation for the ability of ATMs to respond dynamically to the adipose tissue microenvironment.ATMs play a key role in shaping the inflammatory milieu within adipose tissue, and it is now apparent that ATM heterogeneity is acutely shaped by the adipose tissue environment. To account for the new findings, we propose a new nomenclature for ATM subtypes that takes into account their diversity.

Adipose tissue macrophages (ATMs) play a critical role in obesity-induced inflammation and insulin resistance. Distinct subtypes of ATMs have been identified that differentially express macrophage galactose-type C-type lectin 1 (MGL1/CD301), a marker of alternatively activated macrophages. To evaluate if MGL1 is required for the anti-inflammatory function of resident (type 2) MGL1(+) ATMs, we examined the effects of diet-induced obesity (DIO) on inflammation and metabolism in Mgl1(-/-) mice. We found that Mgl1 is not required for the trafficking of type 2 ATMs to adipose tissue. Surprisingly, obese Mgl1(-/-) mice were protected from glucose intolerance, insulin resistance, and steatosis despite having more visceral fat. This protection was caused by a significant decrease in inflammatory (type 1) CD11c(+) ATMs in the visceral adipose tissue of Mgl1(-/-) mice. MGL1 was expressed specifically in 7/4(hi) inflammatory monocytes in the blood and obese Mgl1(-/-) mice had lower levels of 7/4(hi) monocytes. Mgl1(-/-) monocytes had decreased half-life after adoptive transfer and demonstrated decreased adhesion to adipocytes indicating a role for MGL1 in the regulation of monocyte function. This study identifies MGL1 as a novel regulator of inflammatory monocyte trafficking to adipose tissue in response to DIO.

Study Objective Oligomenorrhea in active adolescent females of normal weight is presumed to be related to hypoestrogenism secondary to physical activity and decreased fat mass. We hypothesized that active adolescents with oligomenorrhea would have lower estrogen levels than normal controls with similar levels of cardiovascular fitness. Design/Participants Twenty healthy participants between the ages of 16 and 20 years were recruited at least 2 years postmenarche. Adolescents reporting fewer than 9 cycles a year (n = 6) were compared to 14 controls with monthly menstrual cycles. Histories of eating disorder, hirsutism, severe acne, depression, or amenorrhea were cause for exclusion. Main Outcome Measures Body composition and bone density were measured by total body dual x-ray absorpitometry. Cardiovascular fitness was evaluated by measuring oxygen consumption during exercise. Control subjects were matched by age, body mass index (BMI), and fitness level. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, progesterone, and estradiol were obtained. Statistical analysis was performed using SAS 9.1. Results Cardiovascular fitness in both groups was within normal limits for age. No significant differences in BMI, estradiol concentrations, or bone density were found, but trunk fat mass was lower in adolescents with oligomenorrhea who also reported more frequent exercise. Testosterone concentrations and LH/FSH ratios were significantly higher in participants with irregular menstrual cycles (P = 0.0018 and Conclusion Adolescents with oligomenorrhea were leaner, yet they had higher testosterone levels and a greater LH/FSH ratio than their BMI-matched, cyclic counterparts. We hypothesize that, in active adolescents of normal weight, elevated androgen and LH concentrations are linked to ovarian dysfunction, which can masquerade as exercise-induced oligomenorrhea.

Survivors of sepsis often experience long-term cognitive and functional decline. Previous studies utilizing lipopolysaccharide injection and cecal ligation and puncture in rodent models of sepsis have demonstrated changes in depressive-like behavior and learning and memory after sepsis, as well as evidence of myeloid inflammation and cytokine expression in the brain, but the long-term course of neuroinflammation after sepsis remains unclear. Here, we utilize cecal ligation and puncture with greater than 80% survival as a model of sepsis. We found that sepsis survivor mice demonstrate deficits in extinction of conditioned fear, but no acquisition of fear conditioning, nearly two months after sepsis. These cognitive changes occur in the absence of neuronal loss or changes in synaptic density in the hippocampus. Sepsis also resulted in infiltration of monocytes and neutrophils into the CNS at least two weeks after sepsis in a CCR2 independent manner. Cellular inflammation is accompanied by long-term expression of pro-inflammatory cytokine and chemokine genes, including TNFα and CCR2 ligands, in whole brain homogenates. Gene expression analysis of microglia revealed that while microglia do express anti-microbial genes and damage-associated molecular pattern molecules of the S100A family of genes at least 2 weeks after sepsis, they do not express the cytokines observed in whole brain homogenates. Our results indicate that in a naturalistic model of infection, sepsis results in long-term neuroinflammation, and that this sustained inflammation is likely due to interactions among multiple cell types, including resident microglia and peripherally derived myeloid cells.

In obese adolescents, body mass index (BMI) is a poor predictor of insulin resistance, and the potential role of diminished physical activity has not been quantitated. We measured possible determinants of sensitivity to insulin in 53 adolescent females with a BMI between the 10th and the 95th percentile. We hypothesized that across weight and fitness spectra, relative fat mass, rather than BMI, and cardiovascular fitness would be predictors of insulin resistance. We measured body composition by total-body dual x-ray absorptiometry. Self-reported weekly frequency of aerobic exercise for 1 h (RDE) was recorded, and maximal oxygen consumption (VO(2)max) was measured. Insulin sensitivity was estimated by homeostasis model assessment index (HOMA(IR)) derived from fasting glucose and insulin concentrations. BMI was not related to HOMA(IR) (P = 0.20), RDE showed a marginal relationship (P = 0.049), whereas percent body fat and VO(2)max were significantly related to HOMA(IR) (P = 0.01 and 0.0008, respectively). In a multiple regression model, VO(2)max was a more critical determinant of insulin resistance than percent body fat (P = 0.03 vs. P = 0.67) or RDE (P = 0.01 vs. 0.51). For prevention strategies in youth, physical inactivity may represent a greater metabolic risk than obesity alone.

Objective In adults, obesity has been associated with several health outcomes including increased bone density. Our objective was to evaluate the association between percent body fat and fat mass with bone mineral density (BMD) in a nationally representative population of children and adolescents. Study design A total of 8,348 participants 8–18 years of age from the National Health and Nutrition Examination Survey (NHANES) 1999–2006 had whole body DXA scans performed. We conducted linear regressions to examine the relationship between percent body fat and fat mass with outcome variables of total body, pelvic and lumbar spine areal BMD (aBMD), controlling for lean body mass and assessing for gender and race/ethnicity interactions. Results We found evidence of gender and race/ethnicity interactions with percent body fat and total fat mass for the different BMD areas. Generally, there were decreases in total body aBMD (p

We describe a 13-year-old male with multiple endocrine neoplasia syndrome type 2B with medullary thyroid carcinoma who was diagnosed with ectopic adrenocorticotropin-dependent Cushing syndrome. This report highlights the importance of monitoring for paraneoplastic syndrome in MEN and clues to the diagnosis of this complication provided by growth patterns.

Activating mutations of the TSH receptor (TSHR) are rare, with few reported cases of long-term follow-up.We present a follow-up report on a patient with neonatal thyrotoxicosis known to have a rare activating mutation of the TSHR, a heterozygous substitution in exon 10 (p.Ile568Thr). Initial treatment included total thyroidectomy at age 2 ½ years, resulting in iatrogenic hypothyroidism and hypoparathyroidism. The patient was treated with levothyroxine replacement to maintain TSH levels within normal range, as well as calcitriol and calcium carbonate to treat postsurgical hypoparathyroidism. However, 4 years later, while euthyroid, he developed a palpable 1-cm midline neck mass.Functional imaging with 123-I thyroid scan demonstrated active thyroid tissue within the thyroglossal duct remnant and in the tracheoesophageal groove. Surgical removal of the neck mass revealed cytologically bland thyroid follicular cells.These findings suggest that even after total thyroidectomy, patients with TSHR-activating mutations are at risk to develop significant quantities of functional thyroid tissue related to the hypertrophy of residual foci in the thyroid bed and in the thyroglossal duct remnant. These residual foci may enlarge and secrete thyroid hormones autonomously, decreasing the patient's levothyroxine requirement. Surveillance with serial physical examination and biochemical monitoring is recommended; suspicious findings can be further evaluated with functional thyroid imaging (99-m technetium or radioiodine 123-I thyroid scans) to adequately identify residual foci of thyroid tissue, which may require further treatment with surgical excision or radioablation.