Microarray analysis of Adipose tissue of Short-term HFD-fed mice
ABSTRACT: Tissue inflammation is a key factor underlying insulin resistance in established obesity. Several models of immuno-compromised mice are protected from obesity-induced insulin resistance. However, it is unanswered whether inflammation triggers systemic insulin resistance or vice versa in obesity. The purpose of this study was to assess these questions. 8-week-old C57BL/6J male mice was treated with 60% HFD for 0 day (NCD), 3 days, and 7 days. Eipididymal fat was fractionated. Each groups have three replicates.
Project description:Cytokines of the IL-1 family are important modulators of obesity-induced inflammation and the development of systemic insulin resistance. Here, we report that IL-37, a newly-described antiinflammatory member of the IL-1 family, affects obesity-induced inflammation and insulin resistance. IL-37 transgenic mice (IL-37tg) did not develop an obese phenotype in response to a high-fat diet (HFD). Unlike WT mice, IL-37tg mice exhibited reduced numbers of adipose tissue macrophages and preserved glucose tolerance and insulin sensitivity after 16 weeks of HFD. A short-term HFD intervention revealed that the IL-37-mediated improvement in glucose tolerance is independent of bodyweight. IL-37tg mice manifested a beneficial metabolic profile with higher circulating levels of the anti-inflammatory adipokine adiponectin. In vitro treatment of differentiating adipocytes with recombinant IL-37 reduced adipogenesis. The beneficial effects of recombinant IL-37 involved activation of AMPK signaling. In humans, steady-state IL-37 adipose tissue mRNA levels were positively correlated with insulin sensitivity, lower adipose tissue levels of leptin and a lower inflammatory status of the adipose tissue. These findings reveal IL-37 as an important anti-inflammatory modulator during obesity-induced inflammation and insulin resistance in both mice and humans and suggest that IL-37 is a potential target for the treatment of obesity-induced insulin resistance and type 2 diabetes. Gene arrays were performed on epidydimal white adipose tissue samples from wild type and human IL37-overexpressing transgenic mice fed a high fat diet for 16 weeks.
Project description:Obesity and insulin resistance are associated with oxidative stress, which may be implicated in their progression. The kinase JNK1 emerged as a promising drug target for the treatment of obesity and type-2 diabetes. However, JNK1 is a key mediator of the oxidative stress response, promoting either cell dead or survival depending on magnitude and context of its activation. Furthermore, JNK inactivation shortens lifespan in drosophila and c. elegans. To learn on the safety and efficacy of long-term JNK inhibition in vertebrates, we investigated mice lacking JNK1 (JNK1-/-) exposed over a long period to an obesogenic high-fat diet (HFD). JNK1-/- mice chronically fed an HFD developed more skin oxidative damage because of reduced catalase expression, but also showed sustained protection from obesity, adipose tissue inflammation, steatosis, and insulin resistance, paralleled by decreased oxidative damage in fat and liver. We conclude that JNK1 is a relatively safe drug target for obesity-related diseases. RNA was collected from liver, skin and epididymal fat tissues from JNK1 KO mice and WT mice fed in high fat diet. Each condition was run in quadruplicate
Project description:Lipid overload and adipocyte dysfunction are key to the development of insulin resistance and can be induced by a high-fat diet. CD1d-restricted invariant natural killer T (iNKT) cells have been proposed as mediators between lipid overload and insulin resistance, but recent studies found decreased iNKT cell numbers and marginal effects of iNKT cell depletion on insulin resistance under high-fat diet conditions. Here, we focused on the role of iNKT cells under normal conditions. We showed that iNKT cell–deficient mice on a low-fat diet, considered a normal diet for mice, displayed a distinctive insulin resistance phenotype without overt adipose tissue inflammation. Insulin resistance was characterized by adipocyte dysfunction, including adipocyte hypertrophy, increased leptin, and decreased adiponectin levels. The lack of liver abnormalities in CD1d-null mice together with the enrichment of CD1d-restricted iNKT cells in both mouse and human adipose tissue indicated a specific role for adipose tissue–resident iNKT cells in the development of insulin resistance. Strikingly, iNKT cell function was directly modulated by adipocytes, which acted as lipid antigen-presenting cells in a CD1d-mediated fashion. Based on these findings, we propose that, especially under low-fat diet conditions, adipose tissue–resident iNKT cells maintain healthy adipose tissue through direct interplay with adipocytes and prevent insulin resistance. four samples
Project description:Natural killer (NK) cells contribute to the development of obesity-associated insulin resistance. We demonstrate that in mice obesity promotes the expansion of interleukin-6 receptor (IL6Ra)-expressing NK cells, which also express a number of other myeloid lineage genes such as the colony-stimulating-factor 1 receptor (Csf1r). Selective ablation of Csf1r- expressing NK cells prevents obesity and insulin resistance. Moreover, conditional inactivation of IL6Ra or Stat3 in NK cells limits obesity-associated formation of myeloid signature NK cells, protects from obesity, insulin resistance and obesity-associated inflammation. Also in humans IL6Ra+ NK cells increase in obesity, correlate with markers of systemic low-grade inflammation and their gene expression profile overlaps with characteristic gene sets of NK cells in obese mice. Collectively, we demonstrate that obesity-associated inflammation and metabolic disturbances depend on IL-6/Stat3-dependent formation of distinct NK cells, which may provide a novel target for the treatment of obesity, metaflammation-associated pathologies and diabetes. Overall design: RNA sequencing of two types of NK cells from mouse and human (IL6Ra negative NK cells vs. IL6Ra positive NK cells) and mouse organs (IL6Ra_NKdel vs. IL6Ra_NKflox)
Project description:Natural killer T (NKT) cells are important therapeutic targets in various disease models and under clinical trials for cancer patients. However, their function in obesity and type 2 diabetes remains unclear. Our data show that adipose tissues of both mice and humans contain a population of type-1 NKT cells, whose abundance decreases with increased adiposity and insulin resistance. Although loss-of-function of NKT cells had no effect on glucose tolerance in animals with prolonged high-fat diet (HFD) feeding, activation of NKT cells by lipid agonist α-galactosylceramide (αGalCer) enhances alternative macrophage polarization in adipose tissue and improves glucose homeostasis in animals at different stages of obesity. Furthermore, the effect of NKT cells is largely mediated by the IL-4/STAT6 signaling axis in obese adipose tissue. Thus, our data identifies a novel therapeutic target for the treatment of obesity-associated inflammation and type-2 diabetes. Wild type and CD1d1 antigen (CD1d) knockout mice were fed a high fat diet for 4 days. On day 0 and 2 mice were injected intraperitoneally with α-galactosylceramide (αGalCer) or vehicle. On day 4 mice were killed and gene expression was profiled in epididymal adipose tissue.
Project description:Insulin resistance drives the development of type 2 diabetes (T2D). In liver, diacylglycerol (DAG) is a key mediator of lipid-induced insulin resistance. DAG activates protein kinase C epsilon (PKCÎµ), which phosphorylates and inhibits the insulin receptor. In rats, a 3-day high fat diet produces hepatic insulin resistance through this mechanism, and knockdown of hepatic PKCÎµ protects against high fat diet-induced hepatic insulin resistance. Here we employ a systems level approach to uncover additional signaling pathways involved in high fat diet-induced hepatic insulin resistance. We used quantitative phosphoproteomics to map global in vivo changes in hepatic protein phosphorylation in chow-fed, high fat-fed, and high fat-fed with PKCÎµ knockdown rats to distinguish the impact of lipid- and PKCÎµ-induced protein phosphorylation.
Project description:Obesity is linked to the development of metabolic disorders. Expansion of white adipose tissue (WAT) from hypertrophy of pre-existing adipocytes and/or differentiation of precursors into new mature adipocytes contributes to obesity. We found that Nck2 expression is largely restricted to WAT, raising the hypothesis that it may play a unique function in that tissue. Using mice lacking Nck2, we found that Nck2 regulates adipocyte hypertrophy thus contributing to increased adiposity and progressive glucose intolerance, insulin resistance and hepatic steatosis. These findings were recapitulated in humans such that Nck2 expression in omental WAT was inversely correlated with the degree of obesity. Mechanistically, Nck2 deficiency promoted the induction of an adipocyte differentiation program and signaling by the PERK-eIF2α-ATF4 pathway in agreement with a role for the unfolded protein response in adipogenesis. These findings uncover Nck2 as a novel regulator of adipogenesis and that perturbation in its functionality contributes to adiposity-related metabolic disorders. Differential gene expression profile between epididymal white adipose tissue of Nck2-/- and Nck2+/+ mice by RNA sequencing (Illumina HiSEq 2000)
Project description:Sanchez2017 - Inflammatory responses during acute hyperinsulinemia
This model is described in the article:
The CD4+ T cell regulatory
network mediates inflammatory responses during acute
hyperinsulinemia: a simulation study
Mariana E. Martinez-Sanchez, Marcia
Hiriart, Elena R. Alvarez-Buylla
BMC Systems Biology
Obesity is frequently linked to insulin resistance, high
insulin levels, chronic inflammation, and alterations in the
behaviour of CD4+ T cells. Despite the biomedical importance of
this condition, the system-level mechanisms that alter CD4+ T
cell differentiation and plasticity are not well understood. We
model how hyperinsulinemia alters the dynamics of the CD4+ T
regulatory network, and this, in turn, modulates cell
differentiation and plasticity. Different polarizing
microenvironments are simulated under basal and high levels of
insulin to assess impacts on cell-fate attainment and
robustness in response to transient perturbations. In the
presence of high levels of insulin Th1 and Th17 become more
stable to transient perturbations, and their basin sizes are
augmented, Tr1 cells become less stable or disappear, while
TGF? producing cells remain unaltered. Hence, the model
provides a dynamic system-level framework and explanation to
further understand the documented and apparently paradoxical
role of TGF? in both inflammation and regulation of immune
responses, as well as the emergence of the adipose Treg
phenotype. Furthermore, our simulations provide new predictions
on the impact of the microenvironment in the coexistence of the
different cell types, suggesting that in pro-Th1, pro-Th2 and
pro-Th17 environments effector and regulatory cells can
coexist, but that high levels of insulin severely diminish
regulatory cells, especially in a pro-Th17 environment. This
work provides a first step towards a system-level formal and
dynamic framework to integrate further experimental data in the
study of complex inflammatory diseases.
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