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.
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.
Abstract
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.
Dynamic changes of adipose tissue leukocytes, including adipose tissue macrophage (ATM) and adipose tissue dendritic cells (ATDCs), contribute to obesity-induced inflammation and metabolic disease. ...However, clear discrimination between ATDC and ATM in adipose tissue has limited progress in the field of immunometabolism. In this study, we use CD64 to distinguish ATM and ATDC, and investigated the temporal and functional changes in these myeloid populations during obesity. Flow cytometry and immunostaining demonstrated that the definition of ATM as F4/80
CD11b
cells overlaps with other leukocytes and that CD45
CD64
is specific for ATM. The expression of core dendritic cell genes was enriched in CD11c
CD64
cells (ATDC), whereas core macrophage genes were enriched in CD45
CD64
cells (ATM). CD11c
CD64
ATDCs expressed MHC class II and costimulatory receptors, and had similar capacity to stimulate CD4
T cell proliferation as ATMs. ATDCs were predominantly CD11b
conventional dendritic cells and made up the bulk of CD11c
cells in adipose tissue with moderate high-fat diet exposure. Mixed chimeric experiments with Ccr2
mice demonstrated that high-fat diet-induced ATM accumulation from monocytes was dependent on CCR2, whereas ATDC accumulation was less CCR2 dependent. ATDC accumulation during obesity was attenuated in Ccr7
mice and was associated with decreased adipose tissue inflammation and insulin resistance. CD45
CD64
ATM and CD45
CD64
CD11c
ATDCs were identified in human obese adipose tissue and ATDCs were increased in s.c. adipose tissue compared with omental adipose tissue. These results support a revised strategy for unambiguous delineation of ATM and ATDC, and suggest that ATDCs are independent contributors to adipose tissue inflammation during obesity.
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.
Women of reproductive age are protected from metabolic disease relative to postmenopausal women and men. Most preclinical rodent studies are skewed toward the use of male mice to study ...obesity-induced metabolic dysfunction because of a similar protection observed in female mice. How sex differences in obesity-induced inflammatory responses contribute to these observations is unknown. We have compared and contrasted the effects of high fat diet-induced obesity on glucose metabolism and leukocyte activation in multiple depots in male and female C57Bl/6 mice. With both short term and long term high fat diet, male mice demonstrated increased weight gain and CD11c+ adipose tissue macrophage content compared with female mice despite similar degrees of adipocyte hypertrophy. Competitive bone marrow transplant studies demonstrated that obesity induced a preferential contribution of male hematopoietic cells to circulating leukocytes and adipose tissue macrophages compared with female cells independent of the sex of the recipient. Sex differences in macrophage and hematopoietic cell in vitro activation in response to obesogenic cues were observed to explain these results. In summary, this report demonstrates that male and female leukocytes and hematopoietic stem cells have cell-autonomous differences in their response to obesity that contribute to an amplified response in males compared with females.
Background: Diet-induced obesity leads to a chronic low grade inflammation with production of activated macrophages associated with systemic sexually dimorphic metabolic dysfunction.
Results: Males have enhanced myelopoiesis and a proinflammatory response to obesity compared with females.
Conclusion: Sex differences in myelopoiesis result in dimorphic responses to obesity-induced inflammation.
Significance: Given differences in inflammatory responses, targeted treatment strategies are probably required for males and females.
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.
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.
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 (
) 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.
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.
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.
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<0.001) and lumbar spine aBMD (p<0.001) with increasing percent body fat and total fat mass, with less consistent patterns for pelvic aBMD.
Our findings of regional differences in the relationship of adiposity to aBMD in children and adolescents with significant interactions by gender and race/ethnicity emphasizes the need for further investigations to understand the impact of adiposity on bone health outcomes.
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