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• W3199229216 abstract "•SOCS3 suppresses severe systemic inflammation associated with high-fat diet•SOCS3 deficiency on high-fat diet accelerates excess myeloid hematopoiesis•SOCS3 controls gut dysbiosis on high-fat diet The suppressors of cytokine signaling (SOCS) proteins are negative regulators of cytokine signaling required to prevent excessive cellular responses. In particular, SOCS3 is involved in the regulation of metabolic syndromes, such as obesity and diabetes, by suppressing leptin and insulin signals. SOCS3 also suppresses the inflammatory response associated with metabolic stress, but this specific role remains undefined. Wild-type mice on a high-fat diet (HFD) exhibited only fatty liver, whereas systemic deletion of SOCS3 resulted in excessive myeloid hematopoiesis and hepatic inflammation. In addition, depletion of the gut microbiota resulted in considerable improvement in excess granulopoiesis and splenomegaly, halting the progression of systemic inflammation in SOCS3KO mice on the HFD. This result suggests that intestinal dysbiosis is involved in inflammation associated with SOCS3KO. Although contributing to diet-induced obesity and fatty liver, SOCS3 is nevertheless critical to suppress excess myeloid hematopoiesis and severe systemic inflammation associated with intestinal dysbiosis on HFD. The suppressors of cytokine signaling (SOCS) proteins are negative regulators of cytokine signaling required to prevent excessive cellular responses. In particular, SOCS3 is involved in the regulation of metabolic syndromes, such as obesity and diabetes, by suppressing leptin and insulin signals. SOCS3 also suppresses the inflammatory response associated with metabolic stress, but this specific role remains undefined. Wild-type mice on a high-fat diet (HFD) exhibited only fatty liver, whereas systemic deletion of SOCS3 resulted in excessive myeloid hematopoiesis and hepatic inflammation. In addition, depletion of the gut microbiota resulted in considerable improvement in excess granulopoiesis and splenomegaly, halting the progression of systemic inflammation in SOCS3KO mice on the HFD. This result suggests that intestinal dysbiosis is involved in inflammation associated with SOCS3KO. Although contributing to diet-induced obesity and fatty liver, SOCS3 is nevertheless critical to suppress excess myeloid hematopoiesis and severe systemic inflammation associated with intestinal dysbiosis on HFD. High-fat diets (HFDs) accelerate chronic diseases such as type 2 diabetes mellitus, cardiovascular disease, inflammatory bowel disease, allergy, and certain types of cancer via low-grade inflammation. The inflammatory environment develops in the central nervous system, including the hypothalamus, and in the peripheral tissues, including the liver, adipose tissue, skeletal muscle, and intestine (Duan et al., 2018Duan Y. Zeng L. Zheng C. Song B. Li F. Kong X. Xu K. Inflammatory links between high fat diets and diseases.Front. Immunol. 2018; 9: 2649Crossref PubMed Scopus (113) Google Scholar). In recent years, it has been revealed that HFD affects bone marrow (BM) components and hematopoietic stem cell (HSC) homeostasis through gut bacteria dysbiosis. For example, HFD loading alters the gut microbiota and changes the BM niche by increasing ectopic fat accumulation in BM, increasing fatty marrow via the activation of peroxisome proliferator-activated receptor γ2 (PPARγ2) and shifts HSCs toward granulocyte hematopoiesis (Luo et al., 2015Luo Y. Chen G.L. Hannemann N. Ipseiz N. Kronke G. Bauerle T. Munos L. Wirtz S. Schett G. Bozec A. Microbiota from obese mice regulate hematopoietic stem cell differentiation by altering the bone niche.Cell Metab. 2015; 22: 886-894Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). In addition, in Spred1 knockout (KO) mice, abnormalities in the intestinal flora contribute to enhanced ERK signaling in HSCs, causing marked granulocyte hyperplasia, and this phenomenon is alleviated by depletion of the gut microbiota (Tadokoro et al., 2018Tadokoro Y. Hoshii T. Yamazaki S. Eto K. Ema H. Kobayashi M. Ueno M. Ohta K. Arai Y. Hara E. et al.Spred1 safeguards hematopoietic homeostasis against diet-induced systemic stress.Cell Stem Cell. 2018; 22: 713-725.e718Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar). These dysbiosis-mediated abnormalities in the gut may be important for controlling low-grade inflammation via hematopoiesis, but the detailed mechanisms and regulators of the intestinal-blood cell association remain unclear. The suppressors of cytokine signaling (SOCS) family is required to prevent spontaneous inflammation associated with excessive cytokine responses. The SOCS family contains eight proteins, SOCS1-7 and CIS (cytokine inducible SH2 containing protein), and is characterized by the presence of an SH2 domain that mediates interaction with signaling proteins, such as the JAK kinases and/or cytokine receptors, and a C-terminal SOCS Box motif. Regulation of signaling by IL-6 and G-CSF by SOCS3 appears to be important in preventing inflammation (Croker et al., 2003Croker B.A. Krebs D.L. Zhang J.G. Wormald S. Willson T.A. Stanley E.G. Robb L. Greenhalgh C.J. Forster I. Clausen B.E. et al.SOCS3 negatively regulates IL-6 signaling in vivo.Nat. Immunol. 2003; 4: 540-545Crossref PubMed Scopus (644) Google Scholar, Croker et al., 2004Croker B.A. Metcalf D. Robb L. Wei W. Mifsud S. DiRago L. Cluse L.A. Sutherland K.D. Hartley L. Williams E. et al.SOCS3 is a critical physiological negative regulator of G-CSF signaling and emergency granulopoiesis.Immunity. 2004; 20: 153-165Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar). Furthermore, SOCS3 is strongly associated with obesity and insulin resistance. Inhibition of SOCS3 in obese mice improves insulin sensitivity and fatty liver, and it also normalizes the increased expression of sterol regulatory element binding protein (SREBP)-1c, which is the key regulator of fatty acid synthesis in the liver (Ueki et al., 2004Ueki K. Kondo T. Tseng Y.H. Kahn C.R. Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance, and the metabolic syndrome in the mouse.Proc. Natl. Acad. Sci. U S A. 2004; 101: 10422-10427Crossref PubMed Scopus (313) Google Scholar). These findings indicate that the inhibition of SOCS3 is a promising therapeutic target for improving glucose tolerance and HFD-induced inflammatory effects. Herein, we show systemic homozygous SOCS3 KO results in marked myeloid hematopoiesis and lethal inflammation under conditions of HFD loading. In these mice, myeloid cells invaded the liver and eventually caused systemic inflammation; however, inflammation was substantially improved by depletion of the gut microbiota using antibiotics. Complete SOCS3 deficiency in mice causes embryonic lethality due to the uncontrolled actions of leukemia inhibitory factor signaling (Roberts et al., 2001Roberts A.W. Robb L. Rakar S. Hartley L. Cluse L. Nicola N.A. Metcalf D. Hilton D.J. Alexander W.S. Placental defects and embryonic lethality in mice lacking suppressor of cytokine signaling 3.Proc. Natl. Acad. Sci. U S A. 2001; 98: 9324-9329Crossref PubMed Scopus (249) Google Scholar). To overcome the embryonic lethality of SOCS3 deficiency, we used a tamoxifen-inducible Cre-recombinase, Rosa26-CreERT2 in combination with a homozygous floxed SOCS3 allele (Socs3fl/fl). To investigate the significant roles of SOCS3 in HFD, Socs3-KO genotypes were generated by treatment with tamoxifen. To explore the combined effect of both SOCS3 deficiency and HFD-load in inflammation, mice were established as indicated: SOCS3 deficiency in mice on HFD diet (S3-HFD, tamoxifen-treated Socs3fl/fl; Rosa26-CreERT2) or control chow (S3-chow, tamoxifen-treated Socs3fl/fl; Rosa26-CreERT2); functionally normal SOCS3 on HFD diet (WT-HFD, vehicle-treated Socs3fl/fl; Rosa26-CreERT2) or on control chow (WT-chow, vehicle-treated Socs3fl/fl; Rosa26-CreERT2) (Figure S1). Previously, we confirmed highly efficient Cre-ERT2-dependent recombination of the floxed Socs3 allele in the hematopoietic organs of tamoxifen-, but not vehicle-treated mice, using Southern blotting (Ushiki et al., 2016Ushiki T. Huntington N.D. Glaser S.P. Kiu H. Georgiou A. Zhang J.G. Metcalf D. Nicola N.A. Roberts A.W. Alexander W.S. Rapid inflammation in mice lacking both SOCS1 and SOCS3 in hematopoietic cells.PLoS One. 2016; 11: e0162111Crossref PubMed Scopus (19) Google Scholar). Near-complete tamoxifen-induced inactivation of the Socs3 allele was also confirmed in the trunk of Socs3 deficient mice, but not in intracranial organs, using genomic PCR (Figure S2). The S3-chow mice were lighter than WT-chow mice at 28 weeks of age. Furthermore, mice fed the HFD (WT-HFD) developed obesity; however, S3-HFD mice were significantly protected from diet-induced obesity. Thus, SOCS3KO restricts weight gain, especially that caused by HFD (Figure 1A). As for food intake at 15 weeks of age, intake (g/day) did not differ with HFD. Caloric intake (kcal/day) in WT-HFD was significantly higher than that in WT-chow, and the same was observed in S3-HFD compared with that in S3-chow. However, the intake (kcal/day) in WT-HFD and S3-HFD did not differ significantly (Figure 1B). Lipid intake (g/day) displayed the same trend as caloric intake. A significant increase between chow and HFD was evident in both WT and SOCS3-deficient models (Figure 1C). Therefore, the amount of food and the nutritional value of the food ingested cannot explain the significant weight difference observed between WT and SOCS3-deficient mice on the HFD. In parallel with the body weight change, the development of fatty liver and secretion of liver triglyceride (TG) were suppressed in S3-HFD mice on day 30 after tamoxifen treatment (Figures 1D and 1E) and myeloid infiltrations were observed in SOCS3-deficient mice (Figure 1D). Regarding movement, on day 30 after tamoxifen treatment, open field total distance was lower in the HFD group than in the control diet group in WT mice. The total distance was low in the chow group, and it did not change with HFD feeding in SOCS3-deficient mice (Figure 1F). The open field total movement duration agreed with the total distance trend observed (Figure 1G). The rotary momentum test revealed lower scores in WT-HFD mice than in normal diet. The scores of both SOCS3-deficient groups, HFD and normal diet, were lower than those of WT-chow mice on day 30 after tamoxifen treatment (Figure 1H). Respiratory exchange ratio appeared low in the HFD groups, for both WT and SOCS3-deficient mice, on day 30 after tamoxifen (Figure 1I). Blood glucose levels were higher in the WT-HFD group than in the S3-chow group, but there was no other difference (Figure 1J). Insulin resistance testing indicated lower blood glucose level in SOCS3KO mice than in WT mice on day 14 after tamoxifen treatment (Figure 1K), suggesting that the systemic effects of SOCS3-deficiency improved HFD-induced insulin resistance. It has been reported that the circulating leptin concentration is higher in wild-type mice on an HFD than in mice on chow, whereas the leptin concentration in SOCS3 haploinsufficient mice on an HFD is not significantly higher than that in mice on chow (Howard et al., 2004Howard J.K. Cave B.J. Oksanen L.J. Tzameli I. Bjorbaek C. Flier J.S. Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3.Nat. Med. 2004; 10: 734-738Crossref PubMed Scopus (378) Google Scholar). Consistent with this, the plasma leptin level was significantly increased by HFD in WT mice, and this was alleviated in S3 mice (Figure 1L). Thus, SOCS3 deficiency ameliorated HFD-induced obesity and hepatic lipid secretion that cannot be attributed to improved metabolism and increased energy expenditure alone. In some cases, various types of tumors develop or are promoted in SOCS3-deficient mice including gastric and pancreatic cancer (Inagaki-Ohara et al., 2014Inagaki-Ohara K. Mayuzumi H. Kato S. Minokoshi Y. Otsubo T. Kawamura Y.I. Dohi T. Matsuzaki G. Yoshimura A. Enhancement of leptin receptor signaling by SOCS3 deficiency induces development of gastric tumors in mice.Oncogene. 2014; 33: 74-84Crossref PubMed Scopus (43) Google Scholar; Lesina et al., 2011Lesina M. Kurkowski M.U. Ludes K. Rose-John S. Treiber M. Klöppel G. Yoshimura A. Reindl W. Sipos B. Akira S. et al.Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer.Cancer Cell. 2011; 19: 456-469Abstract Full Text Full Text PDF PubMed Scopus (589) Google Scholar). These neoplasms were not detected on day 30 after tamoxifen in all phenotypes examined (Table S1). Thus, neoplasm is not associated with obesity resistance. While SOCS3-deficiency improved obesity and fatty liver, the mice rapidly became unwell when fed the HFD from day 32 after tamoxifen treatment, and their median survival was 65.5 days after tamoxifen-induced deletion of SOCS3. In contrast, several S3-chow mice became moribund from day 106 after tamoxifen treatment; however, they did not reach 50% mean survival over a 6-month observation period. The control group mice (WT-chow, WT-HFD) did not become unwell (Figure 2A). All mice were analyzed upon initial signs of disease (hereinafter referred to as moribund). Inflammation was observed in the spleen and liver from day 30 after tamoxifen administration; thus, we defined this period as the pre-inflammation phase. Only S3-HFD mice showed marked neutrophilia in the blood (Figure 2B) and considerable splenomegaly (Figure 2C) in the pre-inflammation phase. Furthermore, S3-chow mice subsequently exhibited splenomegaly around the median survival time. Thus, SOCS3KO mice on a normal diet developed splenomegaly; however, spleen weight of these mice was significantly lower than that of the S3-HFD group and neutrophilia was not observed (Figures 2D and 2E). Thus, HFD is necessary to induce neutrophilia and more significant splenomegaly. Pathological analysis revealed that the S3-HFD group displayed hepatic inflammation without fatty liver in the pre-inflammation phase. Moribund S3-HFD mice often displayed inflammatory skin lesions such as pachyderma, alopecia, and/or ulcers (Figure 2F), and autopsies also revealed splenomegaly, lymphadenopathy, and inflammation in the liver, fat, lung, and kidney (Figure 2G). Thus, as SOCS3-deficient mice on normal chow or WT mice on the HFD did not display excessive granulopoiesis, the combination of SOCS3 deficiency and HFD induced rapid granulopoiesis from day 30 after tamoxifen treatment, suggesting that granulopoiesis contributed to systemic inflammation. Lymphoid follicle structure collapsed due to increasing numbers of CD11b+Gr-1+ granulocytes in the spleen (Figures 3A and 3B ) under SOCS3 deficiency, but the percentage of granulocytes was significantly higher in the S3-HFD group than in the S3-chow group. Next, we investigated granulocyte maturation in the spleen in the pre-inflammation phase (Figure 3C). In brief, hematopoietic cells undergoing granulopoiesis were separated into subpopulations #1 to #5 by FACS analysis using c-Kit and Ly-6G markers, and granulocyte differentiation and maturation stages were classified as follows: subpopulation #1 comprised mainly myeloblasts, #2 contained an abundance of promyelocytes, #3 mainly myelocytes, #4 mainly metamyelocytes, and #5 mainly band cells and segmented cells. Cells undergoing granulocytic maturation (#4-#5) were predominant in SOCS3KO mice on both normal chow and HFD (Figure 3D). In addition, considering the extensive splenomegaly in S3-HFD, mature granulopoiesis is likely more active in the S3-HFD group than the S3-chow group. Colony assays revealed increased myeloid progenitor cells (CFU-GM, CFU-G, and CFU-M) in the spleen in SOCS3-deficient mice, with the HFD driving higher numbers of myeloid progenitor colonies in S3-HFD mice (Figure 3E). Thus, SOCS3 deficiency enhanced granulopoiesis without HFD in the spleen and maturation of granulocytes was similar in the S3-chow and S3-HFD groups. However, hematopoiesis indicated by myeloid progenitor cell number was significantly higher in the S3-HFD group than in the S3-chow group. SOCS3 deficiency improved HFD-induced obesity and ectopic fat accumulation (Figures 1A and 1E); however, myeloid infiltration was observed in the liver. These myeloid cells were observed in the entire liver, including the hepatic vein area, portal region, and liver parenchyma on day 30 after tamoxifen treatment during the pre-inflammation phase (Figure 4A). Additionally, analysis was performed on day 14 post-tamoxifen treatment, but at this time hepatic infiltration and splenomegaly were not observed, and in the serum, liver enzyme activities did not differ among the groups. The total cholesterol level was higher in the S3-HFD and WT-HFD groups than in the S3-chow and WT-chow groups (Figure 4B). In the pre-inflammatory phase (day 30 after tamoxifen treatment), the inflammation marker TNF-α was increased in the liver, but IL-6 in the S3-HFD group did not mirror this trend. Unexpectedly, marked Ly6G RNA expression was observed in the S3-HFD group, indicating excess neutrophil infiltration and blood cells in the liver as local inflammation (Figure 4C). Furthermore, elevation in CD11b, CD14, and CD68 RNA expression indicated monocyte and macrophage infiltration in the liver in the S3-HFD group. Although inflammasome markers IL-1β and Caspase-1 were not increased in the pre-inflammation phase (Figure 4D) in all phenotypes (day 30 after tamoxifen treatment), these genes were significantly increased in the S3-HFD group in the moribund phase (day 65 post-tamoxifen treatment) (Figure 4E). Furthermore, fatty acid synthetase including, fatty acid desaturase 1 (FADS-1), stearoyl-CoA desaturase 1 (SCD-1), elongation of very long chain fatty acids 6 (Elovl6), and SREBP-1 were present in the pre-inflammation phase (Oishi et al., 2017Oishi Y. Spann N.J. Link V.M. Muse E.D. Strid T. Edillor C. Kolar M.J. Matsuzaka T. Hayakawa S. Tao J. et al.SREBP1 contributes to resolution of pro-inflammatory TLR4 signaling by reprogramming fatty acid metabolism.Cell Metab. 2017; 25: 412-427Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar). The results indicated that FADS-1 was elevated by the HFD in the WT-HFD group, but this increase was abolished in the absence of SOCS3. In addition, SCD-1 expression was lower in the WT-HFD group than in the WT-chow group, and SCD-1 expression was low in the SOCS3-deficient groups, irrespective of diet. As fatty acid synthetase FADS-1 is classified as an anti-inflammatory gene (Gromovsky et al., 2018Gromovsky A.D. Schugar R.C. Brown A.L. Helsley R.N. Burrows A.C. Ferguson D. Zhang R. Sansbury B.E. Lee R.G. Morton R.E. et al.Delta-5 fatty acid desaturase FADS1 impacts metabolic disease by balancing proinflammatory and proresolving lipid mediators.Arterioscler. Thromb. Vasc. Biol. 2018; 38: 218-231Crossref PubMed Scopus (51) Google Scholar) and SCD-1 is classified as an inflammatory gene (Liu et al., 2010Liu X. Miyazaki M. Flowers M.T. Sampath H. Zhao M. Chu K. Paton C.M. Joo D.S. Ntambi J.M. Loss of Stearoyl-CoA desaturase-1 attenuates adipocyte inflammation: effects of adipocyte-derived oleate.Arterioscler. Thromb. Vasc. Biol. 2010; 30: 31-38Crossref PubMed Scopus (58) Google Scholar), intra-hepatic environment cannot be predicted only by fatty acid synthetase in the S3-HFD group. Regarding fat synthesis, low expression of FADS-1 and SCD-1 suppressed fat synthesis in the liver. SREBP-1 and Elovl6 expression levels were unchanged across all phenotypes (Figure S3). Given the excessive granulocyte infiltration into the liver, we next considered the specific role of hematopoietic loss of SOCS3. Mature myeloid-specific SOCS3KO mice (LysM; LysMCre Socs3fl/fl) were fed the HFD from 4 weeks of age. In LysMCre Socs3fl/fl mice, SOCS3 was partially deleted in peripheral white blood cells and intraperitoneal cells (Figure S4). While systemic lethal inflammation was not observed, HFD-induced obesity was present in mature myeloid-specific SOCS3KO mice on the HFD (Figures 5A and 5B ). Myeloid-specific SOCS3KO mice exhibited mild HFD-induced fatty liver (Figure 5C); however SOCS3 deficiency showed there were trends of decrease in liver lipids in contrast to those in WT, thereby suppressing fatty liver in myeloid-specific SOCS3KO mice (Figure 5D). Inflammation was not observed in myeloid-specific SOCS3KO mice (Figure 5C). In addition, granulocytosis in peripheral blood and splenomegaly were not observed (Figures 5E and 5F). Next, we investigated the effect of deletion of SOCS3 in the entire hematopoietic system, including myeloid progenitors, using Vav-cre (VavCre Socs3fl/fl). In VavCre Socs3fl/fl mice, SOCS3 was completely deleted in peripheral white blood cells (Figure S4). The results in VavCre Socs3fl/fl mice were similar to those in LysMCre Socs3fl/fl mice: hepatic inflammation and excess neutrophilia-related systemic inflammation were not observed (Figures 5G and 5I). Hematopoietic-specific SOCS3KO mice displayed mild fatty liver (Figures 5G and 5H) but granulocytosis was not evident (Figures 5I and 5J). Differentiation and maturation of neutrophils in the spleen did not significantly differ between the VavCre Socs3fl/fl mice and controls (Figure 5K). These data suggest that the loss of SOCS3 in blood cells is not likely to be the cause of systemic inflammation, rather non-hematopoietic SOCS3 appears to be important. Considering the above results, and given the link among diet, gut biota, and hematopoiesis as previously described (Luo et al., 2015Luo Y. Chen G.L. Hannemann N. Ipseiz N. Kronke G. Bauerle T. Munos L. Wirtz S. Schett G. Bozec A. Microbiota from obese mice regulate hematopoietic stem cell differentiation by altering the bone niche.Cell Metab. 2015; 22: 886-894Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar; Tadokoro et al., 2018Tadokoro Y. Hoshii T. Yamazaki S. Eto K. Ema H. Kobayashi M. Ueno M. Ohta K. Arai Y. Hara E. et al.Spred1 safeguards hematopoietic homeostasis against diet-induced systemic stress.Cell Stem Cell. 2018; 22: 713-725.e718Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar), a meta 16S rRNA gene sequencing analysis of intestinal microbiota was performed. The principal coordinate analysis showed genetic differences among microbiota in all groups of mice (Figure 6A). Phylogenetic classification showed reduced Bifidobacteriales members in the HFD groups, including S3-HFD and WT-HFD. These were significantly altered by depletion of the gut microbiota with a cocktail of four antibiotics (4Abx, see STAR Methods) and phylogenetic classification indicated a dominance in Lactobacillales abundance in not only the HFD groups, but also the chow groups (Figure 6B). The survival of the S3-HFD group significantly improved following 4Abx treatment (Figure 6C). Thus, the intestinal tract was demonstrated as the primary inflammation-initiating organ. Interestingly, both granulopoiesis and splenomegaly were substantially reduced in the S3-HFD group (Figures 6D–6F), whereas there were no effects of 4Abx treatment on survival or granulopoiesis in WT mice. In addition, altered granulocyte-maturation in the spleen was also significantly reduced by microbiota depletion in S3-HFD mice (Figure 6G). mRNA levels of TNF-α in the colon decreased across all phenotypes after microbiota depletion (Figure 6H). Therefore, depletion of the gut microbiota might also suppress colon inflammation by improving dysbiosis. The data suggest that SOCS3 plays a key role in controlling systemic inflammation caused by enteric bacteria in the context of an HFD. Next, we checked the serum cytokine/chemokine levels that could affect granulopoiesis and inflammation. Although the differences were not statistically significant, GM-CSF, IL-17A, CCL-2, and CCL-4 were higher in S3-HFD mice than in WT mice and normalized by the depletion of the gut microbiota. IL-6 and S100A8/A9 were higher in S3-chow than in WT, however compositions of gut microbiota such as Bifidobacteriales and Clostridiales are similar in S3-chow and WT-HFD, indicating SOCS3 deficiency itself potentially contributed to elevation of these cytokines. In addition, levels of these cytokines were reduced by the depletion of gut microbiota, indicating these cytokines were enhanced by gut microbiota-associated inflammation. Although, gene expression of TNF-α in the liver of S3-HFD mice was high (Figure 4), there were no differences in the serum protein levels (Figure 7A). Regarding the origin of IL-17A from Th17 cells, which are abundant in the gut, especially the duodenum (Esplugues et al., 2011Esplugues E. Huber S. Gagliani N. Hauser A.E. Town T. Wan Y.Y. O'Connor Jr., W. Rongvaux A. Van Rooijen N. Haberman A.M. et al.Control of TH17 cells occurs in the small intestine.Nature. 2011; 475: 514-518Crossref PubMed Scopus (453) Google Scholar), we checked IL-17A- and IL-17-related genes in the duodenum. In addition, Th17 cells also express the chemokine receptor CCR6 in a cell-specific manner. However, there was no significant difference in the expression levels of IL-17A- and IL-17-related genes and CCR6 between WT and SOCS3-deficient mice in the duodenum before microbiota depletion (Figure S5). Regarding hematopoiesis in the BM, myeloid hyperplasia persisted in SOCS3-deficient mice with microbiota depletion (Table S1), and Gram staining revealed no bacteria in all groups (Table S2). In addition, HSCs (Lineage−Sca-1+c-Kit+; LSK cells and CD34- LSK cells) and myeloid progenitors (common myeloid progenitor; CMP and granulocyte-macrophage progenitor; GMP) were significantly higher in S3-HFD mice than WT mice. However, these differences were variably alleviated by 4Abx treatment (Figure 7B). Combined with the observation that the elevated leukocyte count observed in S3-HFD mice was reversed by microbiota depletion, the existence of myeloproliferative diseases was unlikely in these mice. Previously, systemic SOCS3 haploinsufficiency has been shown to attenuate diet-induced obesity by improving insulin resistance and enhancing leptin sensitivity (Howard et al., 2004Howard J.K. Cave B.J. Oksanen L.J. Tzameli I. Bjorbaek C. Flier J.S. Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3.Nat. Med. 2004; 10: 734-738Crossref PubMed Scopus (378) Google Scholar). Thus, SOCS3KO is expected to improve obesity and obesity-associated metabolic complications. In fact, while aortic dissection is associated with arteriosclerosis or hypertension, smooth muscle specific SOCS3KO (Hirakata et al., 2020Hirakata S. Aoki H. Ohno-Urabe S. Nishihara M. Furusho A. Nishida N. Ito S. Hayashi M. Yasukawa H. Imaizumi T. et al.Genetic deletion of Socs3 in smooth muscle cells ameliorates aortic dissection in mice.JACC Basic Transl. Sci. 2020; 5: 126-144Crossref PubMed Scopus (8) Google Scholar) or conversely SOCS3 expression in macrophages (Ohno-Urabe et al., 2018Ohno-Urabe S. Aoki H. Nishihara M. Furusho A. Hirakata S. Nishida N. Ito S. Hayashi M. Yasukawa H. Imaizumi T. et al.Role of macrophage Socs3 in the pathogenesis of aortic dissection.J. Am. Heart Assoc. 2018; 7: e007389Crossref PubMed Scopus (18) Google Scholar) protected against aortic dissection via inflammation control. However, systemic homogeneous SOCS3KO resulted in systemic inflammation due to excess myeloid hematopoiesis, particularly granulopoiesis. SOCS3 is reportedly associated with HFD-induced low-grade inflammation in local organs (Duan et al., 2018Duan Y. Zeng L. Zheng C. Song B. Li F. Kong X. Xu K. Inflammatory links between high fat diets and diseases.Front. Immunol. 2018; 9: 2649Crossref PubMed Scopus (113) Google Scholar; Sachithanandan et al., 2010Sachithanandan N. Fam B.C. Fynch S. Dzamko N. Watt M.J. Wormald S. Honeyman J. Galic S. Proietto J. Andrikopoulos S. et al.Liver-specific suppressor of cytokine signaling-3 deletion in mice enhances hepatic insulin sensitivity and lipogenesis resulting in fatty liver and obesity.Hepatology. 2010; 52: 1632-1642Crossref PubMed Scopus (75) Google Scholar), however, obvious systemic inflammation and excess granulopoiesis has not been reported. Systemic haploinsufficiency or neural cell-specific SOCS3KO was originally reported to enhance hypothalamic leptin signals and reduce weight gain in mice on an HFD (Howard et al., 2004Howard J.K. Cave B.J. Oksanen L.J. Tzameli I. Bjorbaek C. Flier J.S. Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3.Nat. Med. 2004; 10: 734-738Crossref PubMed Scopus (378) Google Scholar; Mori et al., 2004Mori H. Hanada R. Hanada T. Aki D. Mashima R. Nishinakamura H. Torisu T. Chien K.R. Yasukawa H. Yoshimura A. Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity.Nat. Med. 2004; 10: 739-743Crossref PubMed Scopus (486) Google Scholar). In our study, mice were fed an HFD to examine “systemic” homogeneous SOCS3KO effects on obesity. The results demonstrated that there were no differences in dietary intake across all genotypes, thus the amounts of consumed calories and fat intake were the same between the S3-HFD and WT-HFD groups. As tamoxifen cannot easily transit the blood–brain barrier, Cre recombinase cannot be efficiently released in the CreERT system in intracranial organs. In turn, this resulted in low SOCS3 deletion rates and presumably no accentuation of leptin signals in intracranial organs, including the hypothalamus. SOCS3KO mice on the HFD received high calories without increasing activity and energy consumption. In addition, the phenotype differed from brain-specific SOCS3KO mice (Mori et al., 2004Mori H. Hanada R. Hanada T. A" @default.
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• W3199229216 title "Altered microbiota by a high-fat diet accelerates lethal myeloid hematopoiesis associated with systemic SOCS3 deficiency" @default.
• W3199229216 cites W1595293335 @default.
• W3199229216 cites W1645591373 @default.
• W3199229216 cites W1858198717 @default.
• W3199229216 cites W190173933 @default.
• W3199229216 cites W1979640981 @default.
• W3199229216 cites W1984052117 @default.
• W3199229216 cites W1998002161 @default.
• W3199229216 cites W1998292935 @default.
• W3199229216 cites W1999906527 @default.
• W3199229216 cites W2024734221 @default.
• W3199229216 cites W2028035581 @default.
• W3199229216 cites W2040810264 @default.
• W3199229216 cites W2042621509 @default.
• W3199229216 cites W2049349390 @default.
• W3199229216 cites W2052179757 @default.
• W3199229216 cites W2069970595 @default.
• W3199229216 cites W2069986569 @default.
• W3199229216 cites W2080283023 @default.
• W3199229216 cites W2086971705 @default.
• W3199229216 cites W2090015946 @default.
• W3199229216 cites W2094771034 @default.
• W3199229216 cites W2099459010 @default.
• W3199229216 cites W2101365364 @default.
• W3199229216 cites W2110389012 @default.
• W3199229216 cites W2111858111 @default.
• W3199229216 cites W2113757912 @default.
• W3199229216 cites W2131536322 @default.
• W3199229216 cites W2147495692 @default.
• W3199229216 cites W2152181022 @default.
• W3199229216 cites W2155509873 @default.
• W3199229216 cites W2157182132 @default.
• W3199229216 cites W2167062509 @default.
• W3199229216 cites W2167923209 @default.
• W3199229216 cites W2170595651 @default.
• W3199229216 cites W2187560597 @default.
• W3199229216 cites W2512640298 @default.
• W3199229216 cites W2534231512 @default.
• W3199229216 cites W2566581841 @default.
• W3199229216 cites W2766145247 @default.
• W3199229216 cites W2786720274 @default.
• W3199229216 cites W2801524389 @default.
• W3199229216 cites W2883251903 @default.
• W3199229216 cites W2901557220 @default.
• W3199229216 cites W3127257307 @default.
• W3199229216 cites W2998923970 @default.
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