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Erythropoietin signaling: a novel regulator of white adipose tissue inflammation during diet-induced obesity.

Alnaeeli M, Raaka BM, Gavrilova O, Teng R, Chanturiya T, Noguchi CT - Diabetes (2014)

Bottom Line: Using comprehensive in vivo and in vitro analyses in mice, EPO treatment inhibited WAT inflammation, normalized insulin sensitivity, and reduced glucose intolerance.Remarkably, and prior to any detectable changes in body weight or composition, EPO treatment reduced M1-like Mф and increased M2-like Mф in WAT, while decreasing inflammatory monocytes.These anti-inflammatory effects were found to be driven, at least in part, by direct EPO-R response in Mф via Stat3 activation, where EPO effects on M2 but not M1 Mф required interleukin-4 receptor/Stat6.

View Article: PubMed Central - PubMed

Affiliation: Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.

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Endogenous EPO/EPO-R signaling regulates WAT Mф infiltration and subtype shift. WT C57BL/6 and age-matched ∆EpoR male mice with obesity induced by HFD feeding for 12 weeks were used. A: EPO-R expression levels were determined in SVF relative to β-actin. Shown are body weight and fat mass before and after DIO (B) and EPO-R expression analysis by qRT-PCR in different immune cell subsets (C) from spleens in which Mф were FACS-purified based on F4/80 expression and dendritic cells, B-cells, and T-cells that were purified by magnetic activated cell sorting through positive selection of CD11c+ (dendritic cells), CD19+ (B-cells), and CD3+ (T-cells) cells. Shown are percentage and numbers of circulating blood inflammatory monocytes (D); cytokine and chemokine gene expression profile of perigonadal SVF (E); protein levels of TNF-α, IL-10, and CCL2 (F); percentage and numbers of total Mф (G); and representative H&E-stained histology sections of perigonadal WAT (H). MGL-1+, MGL-1−, and CD11c+ Mф subset percentages (dot plots) and numbers per gram of perigonadal fat tissue (I), gene expression determined relative to β-actin (J), and serum and WAT IL-4 levels (K) are shown. Results are mean ± SEM for n = 5 mice per group, representative of three independent experiments with similar results. *P < 0.05; **P < 0.01 WT vs. ∆EpoR. DC, dendritic cells.
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Figure 7: Endogenous EPO/EPO-R signaling regulates WAT Mф infiltration and subtype shift. WT C57BL/6 and age-matched ∆EpoR male mice with obesity induced by HFD feeding for 12 weeks were used. A: EPO-R expression levels were determined in SVF relative to β-actin. Shown are body weight and fat mass before and after DIO (B) and EPO-R expression analysis by qRT-PCR in different immune cell subsets (C) from spleens in which Mф were FACS-purified based on F4/80 expression and dendritic cells, B-cells, and T-cells that were purified by magnetic activated cell sorting through positive selection of CD11c+ (dendritic cells), CD19+ (B-cells), and CD3+ (T-cells) cells. Shown are percentage and numbers of circulating blood inflammatory monocytes (D); cytokine and chemokine gene expression profile of perigonadal SVF (E); protein levels of TNF-α, IL-10, and CCL2 (F); percentage and numbers of total Mф (G); and representative H&E-stained histology sections of perigonadal WAT (H). MGL-1+, MGL-1−, and CD11c+ Mф subset percentages (dot plots) and numbers per gram of perigonadal fat tissue (I), gene expression determined relative to β-actin (J), and serum and WAT IL-4 levels (K) are shown. Results are mean ± SEM for n = 5 mice per group, representative of three independent experiments with similar results. *P < 0.05; **P < 0.01 WT vs. ∆EpoR. DC, dendritic cells.

Mentions: To investigate the role of endogenous EPO/EPO-R signaling during obesity-induced WAT inflammation, we used DIO in ∆EpoR mice (39). The absence of EPO-R expression in ∆EpoR WAT (adipocytes and SVF) and Mф were confirmed (Figs. 3B and 7A). ∆EpoR mice maintained on normal chow become obese and glucose intolerant as they age (36). Baseline measurements prior to the onset of HFD feeding showed ∆EpoR mice (6–8 weeks old) to have slightly higher body weight and fat mass compared with age-matched WT controls (Fig. 7B). However, after 12 weeks of HFD feeding, there was no significant difference in final body weight or fat mass between ∆EpoR and their age-matched WT controls (Fig. 7B).


Erythropoietin signaling: a novel regulator of white adipose tissue inflammation during diet-induced obesity.

Alnaeeli M, Raaka BM, Gavrilova O, Teng R, Chanturiya T, Noguchi CT - Diabetes (2014)

Endogenous EPO/EPO-R signaling regulates WAT Mф infiltration and subtype shift. WT C57BL/6 and age-matched ∆EpoR male mice with obesity induced by HFD feeding for 12 weeks were used. A: EPO-R expression levels were determined in SVF relative to β-actin. Shown are body weight and fat mass before and after DIO (B) and EPO-R expression analysis by qRT-PCR in different immune cell subsets (C) from spleens in which Mф were FACS-purified based on F4/80 expression and dendritic cells, B-cells, and T-cells that were purified by magnetic activated cell sorting through positive selection of CD11c+ (dendritic cells), CD19+ (B-cells), and CD3+ (T-cells) cells. Shown are percentage and numbers of circulating blood inflammatory monocytes (D); cytokine and chemokine gene expression profile of perigonadal SVF (E); protein levels of TNF-α, IL-10, and CCL2 (F); percentage and numbers of total Mф (G); and representative H&E-stained histology sections of perigonadal WAT (H). MGL-1+, MGL-1−, and CD11c+ Mф subset percentages (dot plots) and numbers per gram of perigonadal fat tissue (I), gene expression determined relative to β-actin (J), and serum and WAT IL-4 levels (K) are shown. Results are mean ± SEM for n = 5 mice per group, representative of three independent experiments with similar results. *P < 0.05; **P < 0.01 WT vs. ∆EpoR. DC, dendritic cells.
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Figure 7: Endogenous EPO/EPO-R signaling regulates WAT Mф infiltration and subtype shift. WT C57BL/6 and age-matched ∆EpoR male mice with obesity induced by HFD feeding for 12 weeks were used. A: EPO-R expression levels were determined in SVF relative to β-actin. Shown are body weight and fat mass before and after DIO (B) and EPO-R expression analysis by qRT-PCR in different immune cell subsets (C) from spleens in which Mф were FACS-purified based on F4/80 expression and dendritic cells, B-cells, and T-cells that were purified by magnetic activated cell sorting through positive selection of CD11c+ (dendritic cells), CD19+ (B-cells), and CD3+ (T-cells) cells. Shown are percentage and numbers of circulating blood inflammatory monocytes (D); cytokine and chemokine gene expression profile of perigonadal SVF (E); protein levels of TNF-α, IL-10, and CCL2 (F); percentage and numbers of total Mф (G); and representative H&E-stained histology sections of perigonadal WAT (H). MGL-1+, MGL-1−, and CD11c+ Mф subset percentages (dot plots) and numbers per gram of perigonadal fat tissue (I), gene expression determined relative to β-actin (J), and serum and WAT IL-4 levels (K) are shown. Results are mean ± SEM for n = 5 mice per group, representative of three independent experiments with similar results. *P < 0.05; **P < 0.01 WT vs. ∆EpoR. DC, dendritic cells.
Mentions: To investigate the role of endogenous EPO/EPO-R signaling during obesity-induced WAT inflammation, we used DIO in ∆EpoR mice (39). The absence of EPO-R expression in ∆EpoR WAT (adipocytes and SVF) and Mф were confirmed (Figs. 3B and 7A). ∆EpoR mice maintained on normal chow become obese and glucose intolerant as they age (36). Baseline measurements prior to the onset of HFD feeding showed ∆EpoR mice (6–8 weeks old) to have slightly higher body weight and fat mass compared with age-matched WT controls (Fig. 7B). However, after 12 weeks of HFD feeding, there was no significant difference in final body weight or fat mass between ∆EpoR and their age-matched WT controls (Fig. 7B).

Bottom Line: Using comprehensive in vivo and in vitro analyses in mice, EPO treatment inhibited WAT inflammation, normalized insulin sensitivity, and reduced glucose intolerance.Remarkably, and prior to any detectable changes in body weight or composition, EPO treatment reduced M1-like Mф and increased M2-like Mф in WAT, while decreasing inflammatory monocytes.These anti-inflammatory effects were found to be driven, at least in part, by direct EPO-R response in Mф via Stat3 activation, where EPO effects on M2 but not M1 Mф required interleukin-4 receptor/Stat6.

View Article: PubMed Central - PubMed

Affiliation: Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.

Show MeSH
Related in: MedlinePlus