Maternal High-Fat Diet During Pre-Conception and Gestation Predisposes Adult Female Offspring to Metabolic Dysfunction in Mice.

The risk of obesity in adulthood is subject to programming in the womb. Maternal obesity contributes to programming of obesity and metabolic disease risk in the adult offspring. With the increasing prevalence of obesity in women of reproductive age there is a need to understand the ramifications of maternal high-fat diet (HFD) during pregnancy on offspring's metabolic heath trajectory.

Obesity results in adipose tissue T cell exhaustion.

Despite studies implicating adipose tissue T cells (ATT) in the initiation and persistence of adipose tissue inflammation, fundamental gaps in knowledge regarding ATT function impedes progress toward understanding how obesity influences adaptive immunity. We hypothesized that ATT activation and function would have tissue-resident-specific properties and that obesity would potentiate their inflammatory properties. We assessed ATT activation and inflammatory potential within mouse and human stromal vascular fraction (SVF).

Wnt/β-catenin signaling regulates adipose tissue lipogenesis and adipocyte-specific loss is rigorously defended by neighboring stromal-vascular cells.

Objective: Canonical Wnt/β-catenin signaling is a well-studied endogenous regulator of mesenchymal cell fate determination, promoting osteoblastogenesis and inhibiting adipogenesis. However, emerging genetic evidence in humans links a number of Wnt pathway members to body fat distribution, obesity, and metabolic dysfunction, suggesting that this pathway also functions in adipocytes. Recent studies in mice have uncovered compelling evidence that the Wnt signaling pathway plays important roles in adipocyte metabolism, particularly under obesogenic conditions.

Regulation of adipose tissue inflammation and systemic metabolism in murine obesity by polymer implants loaded with lentiviral vectors encoding human interleukin-4.

Dysfunctional adipose tissue plays a central role in the pathogenesis of the obesity-related metabolic disease, including type 2 diabetes. Targeting adipose tissue using biopolymer implants is a novel therapeutic approach for metabolic disease. We transplanted porous poly(lactide-co-glycolide) (PLG) implants coated with human interleukin-4 (hIL-4)-expressing lentivirus into epididymal white adipose tissue (eWAT) of mice fed a high-fat diet.

Weight Regain in Formerly Obese Mice Hastens Development of Hepatic Steatosis Due to Impaired Adipose Tissue Function.

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.

Cholesterol 25-hydroxylase (CH25H) as a promoter of adipose tissue inflammation in obesity and diabetes.

Objective: Expansion of visceral adipose tissue (VAT) and metabolic inflammation are consequences of obesity and associated with type 2 diabetes (T2DM). Metabolically activated adipose tissue macrophages (ATMs) undergo qualitative and quantitative changes that influence their inflammatory responses. How these cells contribute to insulin resistance (IR) in humans is not well understood.

Adipose tissue dendritic cell signals are required to maintain T cell homeostasis and obesity-induced expansion.

Adipose tissue derived chronic inflammation is a critical component of obesity induced type II diabetes. Major histocompatibility complex II (MHCII) mediated T cell activation within adipose tissue is one mechanism that contributes to this phenotype. However, the contribution of dendritic cells as professional antigen presenting cells in adipose issue has not previously been explored.

The long noncoding RNA Blnc1 orchestrates homeostatic adipose tissue remodeling to preserve metabolic health.

Objective: Long noncoding RNAs (lncRNAs) are emerging as powerful regulators of adipocyte differentiation and gene expression. However, their significance in adipose tissue metabolism and physiology has not been demonstrated in vivo. We previously identified Blnc1 as a conserved lncRNA regulator of brown and beige adipocyte differentiation.

Frontline Science: Rapid adipose tissue expansion triggers unique proliferation and lipid accumulation profiles in adipose tissue macrophages.

Obesity-related changes in adipose tissue leukocytes, in particular adipose tissue macrophages (ATMs) and dendritic cells (ATDCs), are implicated in metabolic inflammation, insulin resistance, and altered regulation of adipocyte function. We evaluated stromal cell and white adipose tissue (WAT) expansion dynamics with high fat diet (HFD) feeding for 3-56 days, quantifying ATMs, ATDCs, endothelial cells (ECs), and preadipocytes (PAs) in visceral epididymal WAT and subcutaneous inguinal WAT. To better understand mechanisms of the early response to obesity, we evaluated ATM proliferation and lipid accumulation.

Adipocyte hypertrophy-hyperplasia balance contributes to weight loss after bariatric surgery.

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.

Macrophage Proliferation Sustains Adipose Tissue Inflammation in Formerly Obese Mice.

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.

Adipose Tissue Dendritic Cells Are Independent Contributors to Obesity-Induced Inflammation and Insulin Resistance.

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.

Adipose tissue fibrosis, hypertrophy, and hyperplasia: Correlations with diabetes in human obesity.

Objective: The relationship between adipose tissue fibrosis, adipocyte hypertrophy, and preadipocyte hyperplasia in the context of obesity and the correlation of these tissue-based phenomena with systemic metabolic disease are poorly defined. The goal of this study was to clarify the relationship between adipose tissue fibrosis, adipocyte hypertrophy, and preadipocyte hyperplasia in human obesity and determine the correlation of these adipose-tissue based phenomena with diabetes.

Methods: Visceral and subcutaneous adipose tissues from humans with obesity collected during bariatric surgery were studied with QRTPCR, immunohistochemistry, and flow cytometry for expression of collagens and fibrosis-related proteins, adipocyte size, and preadipocyte frequency.

CD40 promotes MHC class II expression on adipose tissue macrophages and regulates adipose tissue CD4+ T cells with obesity.

Obesity activates both innate and adaptive immune responses in adipose tissue, but the mechanisms critical for regulating these responses remain unknown. CD40/CD40L signaling provides bidirectional costimulatory signals between antigen-presenting cells and CD4(+) T cells, and CD40L expression is increased in obese humans. Therefore, we examined the contribution of CD40 to the progression of obesity-induced inflammation in mice.

Obesity-induced remodeling of the adipose tissue elastin network is independent of the metalloelastase MMP-12.

The extracellular matrix (ECM) plays important roles in maintaining adequate adipose tissue function and in metabolic regulation. Here we have examined the organization of a relatively unexplored adipose tissue ECM component, elastin and its response to diet induced obesity in mice. Additionally, we have explored the regulation and requirement of macrophage metalloelastase, MMP-12, in adipose tissue ECM remodeling in obesity.

Differences in Hematopoietic Stem Cells Contribute to Sexually Dimorphic Inflammatory Responses to High Fat Diet-induced Obesity.

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.

An MHC II-dependent activation loop between adipose tissue macrophages and CD4+ T cells controls obesity-induced inflammation.

An adaptive immune response triggered by obesity is characterized by the activation of adipose tissue CD4(+) T cells by unclear mechanisms. We have examined whether interactions between adipose tissue macrophages (ATMs) and CD4(+) T cells contribute to adipose tissue metainflammation. Intravital microscopy identifies dynamic antigen-dependent interactions between ATMs and T cells in visceral fat.

Obesity-Related Hormones in Low-Income Preschool-Age Children: Implications for School Readiness.

Mechanisms underlying socioeconomic disparities in school readiness and health outcomes, particularly obesity, among preschool-aged children are complex and poorly understood. Obesity can induce changes in proteins in the circulation that contribute to the negative impact of obesity on health; such changes may relate to cognitive and emotion regulation skills important for school readiness. We investigated obesity-related hormones, body mass index (BMI), and school readiness in a pilot study of low-income preschoolers attending Head Start (participating in a larger parent study).

Diet-induced obesity promotes myelopoiesis in hematopoietic stem cells.

Obesity is associated with an activated macrophage phenotype in multiple tissues that contributes to tissue inflammation and metabolic disease. To evaluate the mechanisms by which obesity potentiates myeloid activation, we evaluated the hypothesis that obesity activates myeloid cell production from bone marrow progenitors to potentiate inflammatory responses in metabolic tissues. High fat diet-induced obesity generated both quantitative increases in myeloid progenitors as well as a potentiation of inflammation in macrophages derived from these progenitors.

Adipose tissue macrophages function as antigen-presenting cells and regulate adipose tissue CD4+ T cells in mice.

The proinflammatory activation of leukocytes in adipose tissue contributes to metabolic disease. How crosstalk between immune cells initiates and sustains adipose tissue inflammation remains an unresolved question. We have examined the hypothesis that adipose tissue macrophages (ATMs) interact with and regulate the function of T cells.

Neuropeptide Y is produced by adipose tissue macrophages and regulates obesity-induced inflammation.

Neuropeptide Y (NPY) is induced in peripheral tissues such as adipose tissue with obesity. The mechanism and function of NPY induction in fat are unclear. Given the evidence that NPY can modulate inflammation, we examined the hypothesis that NPY regulates the function of adipose tissue macrophages (ATMs) in response to dietary obesity in mice.

CX3CR1 deficiency does not influence trafficking of adipose tissue macrophages in mice with diet-induced obesity.

Adipose tissue macrophages (ATMs) accumulate in fat during obesity and resemble foam cells in atherosclerotic lesions, suggesting that common mechanisms underlie both inflammatory conditions. CX(3)CR1 and its ligand fractalkine/CX(3)CL1 contribute to macrophage recruitment and inflammation in atherosclerosis, but their role in obesity-induced adipose tissue inflammation is unknown. Therefore, we tested the hypothesis that CX(3)CR1 regulates ATM trafficking to epididymal fat and contributes to the development of adipose tissue inflammation during diet-induced obesity.

Aging is associated with an increase in T cells and inflammatory macrophages in visceral adipose tissue.

Age-related adiposity has been linked to chronic inflammatory diseases in late life. To date, the studies on adipose tissue leukocytes and aging have not taken into account the heterogeneity of adipose tissue macrophages (ATMs), nor have they examined how age impacts other leukocytes such as T cells in fat. Therefore, we have performed a detailed examination of ATM subtypes in young and old mice using state of the art techniques.

MGL1 promotes adipose tissue inflammation and insulin resistance by regulating 7/4hi monocytes in obesity.

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.

The protein kinase IKKepsilon regulates energy balance in obese mice.

Obesity is associated with chronic low-grade inflammation that negatively impacts insulin sensitivity. Here, we show that high-fat diet can increase NF-kappaB activation in mice, which leads to a sustained elevation in level of IkappaB kinase epsilon (IKKepsilon) in liver, adipocytes, and adipose tissue macrophages. IKKepsilon knockout mice are protected from high-fat diet-induced obesity, chronic inflammation in liver and fat, hepatic steatosis, and whole-body insulin resistance.