Abstract:Our results indicate that small-molecule-mediated inhibition of the CD40-TRAF6 interaction is a promising therapeutic strategy for the treatment of metabolic complications of obesity by improving glucose tolerance, by reducing the accumulation of immune cells to the adipose tissue and by skewing of the immune response towards a more anti-inflammatory profile.
“…Nonetheless, we observed that these differences are specific to adipose tissue, which is in line with the unique nature of adipose tissue T regs and their unique functional capacity compared with other induced T reg populations (e.g., spleen) [48,49]. metabolism [17,19]. Certainly, CD40 expression on nonhematopoietic cells is an important contributor.…”
Section: Discussionsupporting
confidence: 54%
“…CD40 deficiency in T cells potentiated adipose tissue inflammation during obesity, suggesting a protective function for CD40 signaling [29,30]. By contrast, a chemical blockade of CD40-TRAF6 signaling, but not signaling through TRAF2/3/5, protected mice from obesity-induced insulin resistance and hepatosteatosis [17,19]. Obviously, variable results in these studies may be attributed to differences in the diet used to induce obesity, to environmental conditions, to differences in gut microbiota, or to the genetic background strains.…”
Section: Introductionmentioning
confidence: 99%
“…Some studies have identified a beneficial role for costimulation in maintaining a T reg pool, both systemically and in adipose tissue, which is protective against obesity-induced inflammation and metabolic disease [5,13]. In many other instances, loss of costimulation has been shown to alter energy use and inflammation in animal models [14][15][16][17][18][19].…”
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. CD40 was highly expressed on adipose tissue macrophages in mice, and CD40/CD40L signaling promoted the expression of antigen-presenting cell markers in adipose tissue macrophages. When fed a high fat diet, Cd40-deficient mice had reduced accumulation of con- ) in lean and obese fat was similar between wildtype and knockout mice. Adipose tissue macrophage content and inflammatory gene expression in fat did not differ between obese wild-type and knockout mice; however, major histocompatibility complex class II and CD86 expression on adipose tissue macrophages was reduced in visceral fat from knockout mice. Similar results were observed in chimeric mice with hematopoietic Cd40-deficiency. Nonetheless, neither whole body nor hematopoietic disruption of CD40 ameliorated obesityinduced insulin resistance in mice. In human adipose tissue, CD40 expression was positively correlated with CD80 and CD86 expression in obese patients with type 2 diabetes. These findings indicate that CD40 signaling in adipose tissue macrophages regulates major histocompatibility complex class II and CD86 expression to control the expansion of CD4 + T cells; however, this is largely dispensable for the development of obesity-induced inflammation and insulin resistance in mice.
“…Nonetheless, we observed that these differences are specific to adipose tissue, which is in line with the unique nature of adipose tissue T regs and their unique functional capacity compared with other induced T reg populations (e.g., spleen) [48,49]. metabolism [17,19]. Certainly, CD40 expression on nonhematopoietic cells is an important contributor.…”
Section: Discussionsupporting
confidence: 54%
“…CD40 deficiency in T cells potentiated adipose tissue inflammation during obesity, suggesting a protective function for CD40 signaling [29,30]. By contrast, a chemical blockade of CD40-TRAF6 signaling, but not signaling through TRAF2/3/5, protected mice from obesity-induced insulin resistance and hepatosteatosis [17,19]. Obviously, variable results in these studies may be attributed to differences in the diet used to induce obesity, to environmental conditions, to differences in gut microbiota, or to the genetic background strains.…”
Section: Introductionmentioning
confidence: 99%
“…Some studies have identified a beneficial role for costimulation in maintaining a T reg pool, both systemically and in adipose tissue, which is protective against obesity-induced inflammation and metabolic disease [5,13]. In many other instances, loss of costimulation has been shown to alter energy use and inflammation in animal models [14][15][16][17][18][19].…”
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. CD40 was highly expressed on adipose tissue macrophages in mice, and CD40/CD40L signaling promoted the expression of antigen-presenting cell markers in adipose tissue macrophages. When fed a high fat diet, Cd40-deficient mice had reduced accumulation of con- ) in lean and obese fat was similar between wildtype and knockout mice. Adipose tissue macrophage content and inflammatory gene expression in fat did not differ between obese wild-type and knockout mice; however, major histocompatibility complex class II and CD86 expression on adipose tissue macrophages was reduced in visceral fat from knockout mice. Similar results were observed in chimeric mice with hematopoietic Cd40-deficiency. Nonetheless, neither whole body nor hematopoietic disruption of CD40 ameliorated obesityinduced insulin resistance in mice. In human adipose tissue, CD40 expression was positively correlated with CD80 and CD86 expression in obese patients with type 2 diabetes. These findings indicate that CD40 signaling in adipose tissue macrophages regulates major histocompatibility complex class II and CD86 expression to control the expansion of CD4 + T cells; however, this is largely dispensable for the development of obesity-induced inflammation and insulin resistance in mice.
“…7C). Additional pathways linked to diabetic complications, including TRAF6, complement, platelet activation and RAGE receptor 35–38 were also enriched, albeit to a lesser extent. Regardless of magnitude, the combined effects of the complication pathways activated in TBDM and linked to TB susceptibility suggest bidirectional pathological interactions between TB and DM.Figure 7Increased activity of pathways associated with epigenetic regulation in diabetic TB patients.…”
Comorbid diabetes mellitus (DM) increases tuberculosis (TB) risk and adverse outcomes but the pathological interactions between DM and TB remain incompletely understood. We performed an integrative analysis of whole blood gene expression and plasma analytes, comparing South Indian TB patients with and without DM to diabetic and non-diabetic controls without TB. Luminex assay of plasma cytokines and growth factors delineated a distinct biosignature in comorbid TBDM in this cohort. Transcriptional profiling revealed elements in common with published TB signatures from cohorts that excluded DM. Neutrophil count correlated with the molecular degree of perturbation, especially in TBDM patients. Body mass index and HDL cholesterol were negatively correlated with molecular degree of perturbation. Diabetic complication pathways including several pathways linked to epigenetic reprogramming were activated in TBDM above levels observed with DM alone. Our data provide a rationale for trials of host-directed therapies in TBDM, targeting neutrophilic inflammation and diabetic complication pathways to address the greater morbidity and mortality associated with this increasingly prevalent dual burden of communicable and non-communicable diseases.
“…Obesity and related complications are controlled by interconnected protein networks, which can be targeted for obesity management [2]. Recently, numerous researchers have reported important target proteins along with their inhibitors as anti-obesity drugs to combat obesity and related complications [3,4]. Nonetheless, proper obesity management still needs novel anti-obesity drugs that target obesity-associated molecules.…”
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