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Sci Rep
 2018
DOI: 10.1038/s41598-018-28371-4
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Eosinophils support adipocyte maturation and promote glucose tolerance in obesity

Eun Hui Lee
1
,
Michal Itan
2
,
Jinsun Jang
3
et al.

Abstract: Accumulating data have indicated a fundamental role of eosinophils in regulating adipose tissue homeostasis. Here, we performed whole-genome RNA sequencing of the small intestinal tract, which suggested the presence of impaired lipid metabolism in eosinophil-deficient ΔdblGATA mice. ΔdblGATA mice fed a high-fat diet (HFD) showed reduced body fat mass, impaired enlargement of adipocytes, decreased expression of adipogenic genes, and developed glucose intolerance. HFD induced accumulation of eosinophils in the p… Show more

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Pluripotent mesenchymal stem cells in bone marrow differentiate into adipocytes, osteoblasts and other cells. Balanced cytodifferentiation of stem cells is essential for the formation and maintenance of bone marrow; however, the mechanisms that control this balance remain largely unknown. Whereas cytokines such as interleukin-1 (IL-1) and tumour-necrosis factor-alpha (TNF-alpha) inhibit adipogenesis, the ligand-induced transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-gamma), is a key inducer of adipogenesis. Therefore, regulatory coupling between cytokine- and PPAR-gamma-mediated signals might occur during adipogenesis. Here we show that the ligand-induced transactivation function of PPAR-gamma is suppressed by IL-1 and TNF-alpha, and that this suppression is mediated through NF-kappaB activated by the TAK1/TAB1/NF-kappaB-inducing kinase (NIK) cascade, a downstream cascade associated with IL-1 and TNF-alpha signalling. Unlike suppression of the PPAR-gamma transactivation function by mitogen-activated protein kinase-induced growth factor signalling through phosphorylation of the A/B domain, NF-kappaB blocks PPAR-gamma binding to DNA by forming a complex with PPAR-gamma and its AF-1-specific co-activator PGC-2. Our results suggest that expression of IL-1 and TNF-alpha in bone marrow may alter the fate of pluripotent mesenchymal stem cells, directing cellular differentiation towards osteoblasts rather than adipocytes by suppressing PPAR-gamma function through NF-kappaB activated by the TAK1/TAB1/NIK cascade.

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“…Excess calorie intake results in chronic inflammation in adipose tissue involving an infiltration of various immune cells [22][23][24][25][26] . In obesity, the infiltrated immune cells promote the production of pro-inflammatory cytokines that inhibit adipogenesis and insulin signalling 27,28 . The total numbers of cells isolated from the perigonadal WAT of HFD-fed ΔdblGATA and WT mice were not significantly different (p = 0.1263, data not shown).…”
Section: Discussion
“…We suggest that an altered immune environment in the perigonadal fat of HFD-fed ΔdblGATA accounts for the decreased expression of adipogenic genes. The exposure of preadipocytes to pro-inflammatory cytokines inhibits adipogenesis by reducing the expression of Pparg and inhibiting the adipogenic action of insulin 28 . Th1 cytokines, including IFN-γ, can inhibit insulin signalling and lipid droplet formation 27,42 , while Th2 cytokines, including IL-4 and IL-13, can suppress inflammatory responses in adipose tissue 43 .…”

The modern rise in obesity and its strong association with insulin resistance and type 2 diabetes have elicited interest in the underlying mechanisms of these pathologies. The discovery that obesity itself results in an inflammatory state in metabolic tissues ushered in a research field that examines the inflammatory mechanisms in obesity. Here, we summarize the unique features of this metabolic inflammatory state, termed metaflammation and defined as low-grade, chronic inflammation orchestrated by metabolic cells in response to excess nutrients and energy. We explore the effects of such inflammation in metabolic tissues including adipose, liver, muscle, pancreas, and brain and its contribution to insulin resistance and metabolic dysfunction. Another area in which many unknowns still exist is the origin or mechanism of initiation of inflammatory signaling in obesity. We discuss signals or triggers to the inflammatory response, including the possibility of endoplasmic reticulum stress as an important contributor to metaflammation. Finally, we examine anti-inflammatory therapies for their potential in the treatment of obesity-related insulin resistance and glucose intolerance.

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“…Adipose tissue regulates energy homeostasis through the storage of excess calories and the secretion of adipocyte-derived secretory proteins such as leptin, adiponectin, and resistin 10,11 . However, excessive caloric Published: xx xx xxxx OPEN www.nature.com/scientificreports/ 2 SCIentIfIC REPORTS | (2018) 8:9894 | intake induces the overexpansion of adipocytes, which results in inflammatory responses within adipose tissue 12 .Obesity-related metabolic dysfunctions are associated with an excessive infiltration of immune cells and chronic inflammation in adipose tissue 13,14 .Here, we used eosinophil-deficient ∆dblGATA and wild-type (WT) mice to investigate the roles of eosinophils in obesity, adipose tissue maturation, and associated metabolic responses. We performed whole-genome RNA sequencing of the small intestinal tract, which suggested the presence of a defective lipid metabolism in the absence of eosinophils.…”
“…Obesity-related metabolic dysfunctions are associated with an excessive infiltration of immune cells and chronic inflammation in adipose tissue 13,14 .…”

Adipocytes have been studied with increasing intensity as a result of the emergence of obesity as a serious public health problem and the realization that adipose tissue serves as an integrator of various physiological pathways. In particular, their role in calorie storage makes adipocytes well suited to the regulation of energy balance. Adipose tissue also serves as a crucial integrator of glucose homeostasis. Knowledge of adipocyte biology is therefore crucial for understanding the pathophysiological basis of obesity and metabolic diseases such as type 2 diabetes. Furthermore, the rational manipulation of adipose physiology is a promising avenue for therapy of these conditions.

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“…Adipose tissue regulates energy homeostasis through the storage of excess calories and the secretion of adipocyte-derived secretory proteins such as leptin, adiponectin, and resistin 10,11 . However, excessive caloric Published: xx xx xxxx OPEN www.nature.com/scientificreports/ 2 SCIentIfIC REPORTS | (2018) 8:9894 | intake induces the overexpansion of adipocytes, which results in inflammatory responses within adipose tissue 12 .Obesity-related metabolic dysfunctions are associated with an excessive infiltration of immune cells and chronic inflammation in adipose tissue 13,14 .Here, we used eosinophil-deficient ∆dblGATA and wild-type (WT) mice to investigate the roles of eosinophils in obesity, adipose tissue maturation, and associated metabolic responses. We performed whole-genome RNA sequencing of the small intestinal tract, which suggested the presence of a defective lipid metabolism in the absence of eosinophils.…”
“…Obesity-related metabolic dysfunctions are associated with an excessive infiltration of immune cells and chronic inflammation in adipose tissue 13,14 .…”

Inflammation and insulin resistance associated with visceral obesity are important risk factors for the development of type 2 diabetes, atherosclerosis, and the metabolic syndrome. The 12/15‐lipoxygenase (12/15‐LO) enzyme has been linked to inflammatory changes in blood vessels that precede the development of atherosclerosis. The expression and role of 12/15‐LO in adipocytes have not been evaluated. We found that 12/15‐LO mRNA was dramatically upregulated in white epididymal adipocytes of high‐fat fed mice. 12/15‐LO was poorly expressed in 3T3‐L1 fibroblasts and was upregulated during differentiation into adipocytes. Interestingly, the saturated fatty acid palmitate, a major component of high fat diets, augmented expression of 12/15‐LO in vitro. When 3T3‐L1 adipocytes were treated with the 12/15‐LO products, 12‐hydroxyeicosatetranoic acid (12(S)‐HETE) and 12‐hydroperoxyeicosatetraenoic acid (12(S)‐HPETE), expression of proinflammatory cytokine genes, including tumor necrosis factor‐α (TNF‐α), monocyte chemoattractant protein 1 (MCP‐1), interleukin 6 (IL‐6), and IL‐12p40, was upregulated whereas anti‐inflammatory adiponectin gene expression was downregulated. 12/15‐LO products also augmented c‐Jun N‐terminal kinase 1 (JNK‐1) phosphorylation, a known negative regulator of insulin signaling. Consistent with impaired insulin signaling, we found that insulin‐stimulated 3T3‐L1 adipocytes exhibited decreased IRS‐1(Tyr) phosphorylation, increased IRS‐1(Ser) phosphorylation, and impaired Akt phosphorylation when treated with 12/15‐LO product. Taken together, our data suggest that 12/15‐LO products create a proinflammatory state and impair insulin signaling in 3T3‐L1 adipocytes. Because 12/15‐LO expression is upregulated in visceral adipocytes by high‐fat feeding in vivo and also by addition of palmitic acid in vitro, we propose that 12/15‐LO plays a role in promoting inflammation and insulin resistance associated with obesity.

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“…S1). Of note, genes associated with lipid metabolism, such as Retnlg, Alox15, and Drd2 [15][16][17] were included in the top 10 downregulated genes (Table S1). Additionally, a GO analysis of the downregulated genes and visualization of a functionally grouped network using the ClueGO plugin 18 suggested a defect in lipase activity (Table S3 and Fig.…”
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“…S1). Of note, genes associated with lipid metabolism, such as Retnlg, Alox15, and Drd2 [15][16][17] were included in the top 10 downregulated genes (Table S1). Additionally, a GO analysis of the downregulated genes and visualization of a functionally grouped network using the ClueGO plugin 18 suggested a defect in lipase activity (Table S3 and Fig.…”
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“…S1). Of note, genes associated with lipid metabolism, such as Retnlg, Alox15, and Drd2 [15][16][17] were included in the top 10 downregulated genes (Table S1). Additionally, a GO analysis of the downregulated genes and visualization of a functionally grouped network using the ClueGO plugin 18 suggested a defect in lipase activity (Table S3 and Fig.…”

Summary: We have developed ClueGO, an easy to use Cytoscape plug-in that strongly improves biological interpretation of large lists of genes. ClueGO integrates Gene Ontology (GO) terms as well as KEGG/BioCarta pathways and creates a functionally organized GO/pathway term network. It can analyze one or compare two lists of genes and comprehensively visualizes functionally grouped terms. A one-click update option allows ClueGO to automatically download the most recent GO/KEGG release at any time. ClueGO provides an intuitive representation of the analysis results and can be optionally used in conjunction with the GOlorize plug-in.Availability: http://www.ici.upmc.fr/cluego/cluegoDownload.shtmlContact: jerome.galon@crc.jussieu.frSupplementary information: Supplementary data are available at Bioinformatics online.

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“…Of note, genes associated with lipid metabolism, such as Retnlg, Alox15, and Drd2 [15][16][17] were included in the top 10 downregulated genes (Table S1). Additionally, a GO analysis of the downregulated genes and visualization of a functionally grouped network using the ClueGO plugin 18 suggested a defect in lipase activity (Table S3 and Fig. S2) and a significant decrease in the expression of Lpl was observed ( Fig.…”

Excess caloric intake can lead to insulin resistance. The underlying reasons are complex but likely related to ectopic lipid deposition in nonadipose tissue. We hypothesized that the inability to appropriately expand subcutaneous adipose tissue may be an underlying reason for insulin resistance and beta cell failure. Mice lacking leptin while overexpressing adiponectin showed normalized glucose and insulin levels and dramatically improved glucose as well as positively affected serum triglyceride levels. Therefore, modestly increasing the levels of circulating full-length adiponectin completely rescued the diabetic phenotype in ob/ob mice. They displayed increased expression of PPARgamma target genes and a reduction in macrophage infiltration in adipose tissue and systemic inflammation. As a result, the transgenic mice were morbidly obese, with significantly higher levels of adipose tissue than their ob/ob littermates, leading to an interesting dichotomy of increased fat mass associated with improvement in insulin sensitivity. Based on these data, we propose that adiponectin acts as a peripheral "starvation" signal promoting the storage of triglycerides preferentially in adipose tissue. As a consequence, reduced triglyceride levels in the liver and muscle convey improved systemic insulin sensitivity. These mice therefore represent what we believe is a novel model of morbid obesity associated with an improved metabolic profile.

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“…Eosinophil-deficient mice gained less weight and perigonadal fat mass and displayed impaired glucose tolerance on a HFD. Excess caloric intake induces expansion of fat mass and accelerates development of insulin resistance 10 . To further examine the role of eosinophils in adipose tissue expansion and energy homeostasis, we fed 8-10-week-old male WT and ΔdblGATA mice with a HFD for 12 weeks and monitored their body weights weekly.…”
Section: Discussion
“…Although adipose tissue is rich in stem cells that can differentiate into fat cells to contain excess energy 46 , the pro-inflammatory microenvironment of adipose tissue induced by obesity is associated with the inhibition of adipocyte maturation and increased adipocyte death 10,12 . Our data demonstrate that adipocytes provide signals to promote eosinophil migration and survival, and that eosinophils support adipocyte maturation and protect adipose tissue against inflammatory changes.…”
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“…Eosinophil-deficient mice showed an impaired maturation of perigonadal adipocytes on a HFD. The inability of adipose tissue to expand to accommodate excess calories causes systemic insulin resistance and hyperglycaemia 19 . As we observed an impaired WAT development in HFD-fed ΔdblGATA mice, which showed glucose intolerance, we examined whether eosinophils are required for adipocyte maturation in diet-induced obesity.…”

Eosinophils and their associated cytokines IL-4 and IL-5 are emerging as central orchestrators of the immune-metabolic axis. Herein, we demonstrate that cross-talk between the Ig-superfamily receptor CD300f and IL-5 is a key checkpoint that modifies the ability of eosinophils to regulate metabolic outcomes. Generation of Il5 Tg /Cd300f −/− mice revealed marked and distinct increases in eosinophil levels and their production of IL-4 in the white and brown adipose tissues. Consequently, Il5 Tg /Cd300f −/− mice had increased alternatively activated macrophage accumulation in the adipose tissue. Cd300f −/− mice displayed age-related accumulation of eosinophils and macrophages in the adipose tissue and decreased adipose tissue weight, which was associated with decreased diet-induced weight gain and insulin resistance. Notably, Il5 Tg /CD300f −/− were protected from diet-induced weight gain and glucose intolerance. These findings highlight the cross-talk between IL-5 receptor and CD300f as a novel pathway regulating adipose tissue eosinophils and offer new entry points for therapeutic intervention for obesity and its complications.

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“…Adipocytes support the migration and survival of eosinophils. Since eosinophils are resident cells in the adipose tissue 20 and ΔdblGATA mice showed an impairment of adipocyte maturation, we questioned whether adipocytes support the migration or survival of eosinophils. Eosinophils migrate in a manner dependent on CCL11 and its receptor, CC chemokine receptor (CCR) 3 2,21 .…”
Section: Isolation Of Eosinophils.
“…Eosinophils were isolated from the peritoneal cavity of CD3-IL-5 transgenic mice as described 20 and used for chemotaxis assay and co-culture with adipocyte-differentiated 3T3-L1 cells. Total cells were extracted and subjected to lymphocyte depletion using a MACS ® system with antibodies against CD90.2 and CD45R (Miltenyi Biotec, Auburn, CA, USA).…”
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