Browsing by Author "Li, Honggui"

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    Adipocyte inducible 6-phosphofructo-2-kinase suppresses adipose tissue inflammation and promotes macrophage anti-inflammatory activation
    (Elsevier, 2021) Xu, Hang; Zhu, Bilian; Li, Honggui; Jiang, Boxiong; Wang, Yina; Yin, Qiongli; Cai, James; Glaser, Shannon; Francis, Heather; Alpini, Gianfranco; Wu, Chaodong; Medicine, School of Medicine
    Obesity-associated inflammation in white adipose tissue (WAT) is a causal factor of systemic insulin resistance. To better understand how adipocytes regulate WAT inflammation, the present study generated chimeric mice in which inducible 6-phosphofructo-2-kinase was low, normal, or high in WAT while the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (Pfkfb3) was normal in hematopoietic cells, and analyzed changes in high-fat diet (HFD)-induced WAT inflammation and systemic insulin resistance in the mice. Indicated by proinflammatory signaling and cytokine expression, the severity of HFD-induced WAT inflammation in WT → Pfkfb3+/- mice, whose Pfkfb3 was disrupted in WAT adipocytes but not hematopoietic cells, was comparable with that in WT → WT mice, whose Pfkfb3 was normal in all cells. In contrast, the severity of HFD-induced WAT inflammation in WT → Adi-Tg mice, whose Pfkfb3 was over-expressed in WAT adipocytes but not hematopoietic cells, remained much lower than that in WT → WT mice. Additionally, HFD-induced insulin resistance was correlated with the status of WAT inflammation and comparable between WT → Pfkfb3+/- mice and WT → WT mice, but was significantly lower in WT → Adi-Tg mice than in WT → WT mice. In vitro, palmitoleate decreased macrophage phosphorylation states of Jnk p46 and Nfkb p65 and potentiated the effect of interleukin 4 on suppressing macrophage proinflammatory activation. Taken together, these results suggest that the Pfkfb3 in adipocytes functions to suppress WAT inflammation. Moreover, the role played by adipocyte Pfkfb3 is attributable to, at least in part, palmitoleate promotion of macrophage anti-inflammatory activation.
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    Adipose Tissue Inflammation and Systemic Insulin Resistance in Mice with Diet-induced Obesity Is Possibly Associated with Disruption of PFKFB3 in Hematopoietic Cells
    (Elsevier, 2021) Zhu, Bilian; Guo, Xin; Xu, Hang; Jiang, Boxiong; Li, Honggui; Wang, Yina; Yin, Qiongli; Zhou, Tianhao; Cai, James J.; Glaser, Shannon; Meng, Fanyin; Francis, Heather; Alpini, Gianfranco; Wu, Chaodong; Medicine, School of Medicine
    Obesity-associated inflammation in white adipose tissue (WAT) is a causal factor of systemic insulin resistance; however, precisely how immune cells regulate WAT inflammation in relation to systemic insulin resistance remains to be elucidated. The present study examined a role for 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in hematopoietic cells in regulating WAT inflammation and systemic insulin sensitivity. Male C57BL/6J mice were fed a high-fat diet (HFD) or low-fat diet (LFD) for 12 weeks and examined for WAT inducible 6-phosphofructo-2-kinase (iPFK2) content, while additional HFD-fed mice were treated with rosiglitazone and examined for PFKFB3 mRNAs in WAT stromal vascular cells (SVC). Also, chimeric mice in which PFKFB3 was disrupted only in hematopoietic cells and control chimeric mice were also fed an HFD and examined for HFD-induced WAT inflammation and systemic insulin resistance. In vitro, adipocytes were co-cultured with bone marrow-derived macrophages and examined for adipocyte proinflammatory responses and insulin signaling. Compared with their respective levels in controls, WAT iPFK2 amount in HFD-fed mice and WAT SVC PFKFB3 mRNAs in rosiglitazone-treated mice were significantly increased. When the inflammatory responses were analyzed, peritoneal macrophages from PFKFB3-disrputed mice revealed increased proinflammatory activation and decreased anti-inflammatory activation compared with control macrophages. At the whole animal level, hematopoietic cell-specific PFKFB3 disruption enhanced the effects of HFD feeding on promoting WAT inflammation, impairing WAT insulin signaling, and increasing systemic insulin resistance. In vitro, adipocytes co-cultured with PFKFB3-disrupted macrophages revealed increased proinflammatory responses and decreased insulin signaling compared with adipocytes co-cultured with control macrophages. These results suggest that PFKFB3 disruption in hematopoietic cells only exacerbates HFD-induced WAT inflammation and systemic insulin resistance.
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    Indole Alleviates Diet-induced Hepatic Steatosis and Inflammation in a Manner Involving Myeloid Cell PFKFB3
    (Wolters Kluwer, 2020-10) Ma, Linqiang; Li, Honggui; Hu, Jinbo; Zheng, Juan; Zhou, Jing; Botchlett, Rachel; Matthews, Destiny; Zeng, Tianshu; Chen, Lulu; Xiao, Xiaoqiu; Athrey, Giri; Threadgill, David W.; Li, Qingsheng; Glaser, Shannon; Francis, Heather; Meng, Fanyin; Li, Qifu; Alpini, Gianfranco; Wu, Chaodong; Medicine, School of Medicine
    Background and aims: Indole is a microbiota metabolite that exerts anti-inflammatory responses. However, the relevance of indole to human non-alcoholic fatty liver disease (NAFLD) is not clear. It also remains largely unknown whether and how indole acts to protect against NAFLD. The present study sought to examine the association between the circulating levels of indole and liver fat content in human subjects and explore the mechanisms underlying indole actions in mice with diet-induced NAFLD. Approach and results: In a cohort of 137 subjects, the circulating levels of indole were reversely correlated with body mass index. In addition, the circulating levels of indole in obese subjects were significantly lower than those in lean subjects and were accompanied with increased liver fat content. At the whole-animal level, treatment of high-fat diet (HFD)-fed C57BL/6J mice with indole caused significant decreases in the severity of hepatic steatosis and inflammation. In cultured cells, indole treatment stimulated the expression of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a master regulatory gene of glycolysis, and suppressed macrophage proinflammatory activation in a PFKFB3-dependent manner. Moreover, myeloid cell-specific PFKFB3 disruption exacerbated the severity of HFD-induced hepatic steatosis and inflammation and blunted the effect of indole on alleviating diet-induced NAFLD phenotype. Conclusions: Taken together, our results demonstrate that indole is relevant to human NAFLD and capable of alleviating diet-induced NAFLD phenotypes in mice in a myeloid cell PFKFB3-dependent manner. Therefore, indole mimetic and/or macrophage-specific PFKFB3 activation may be the viable preventive and/or therapeutic approaches for inflammation-associated diseases including NAFLD.
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    Methionine- and Choline-Deficient Diet-Induced Nonalcoholic Steatohepatitis Is Associated with Increased Intestinal Inflammation
    (Elsevier, 2021) Matthews, Destiny R.; Li, Honggui; Zhou, Jing; Li, Qingsheng; Glaser, Shannon; Francis, Heather; Alpini, Gianfranco; Wu, Chaodong; Medicine, School of Medicine
    Inflammation drives the pathogenesis of nonalcoholic steatohepatitis (NASH). The current study examined changes in intestinal inflammation during NASH. In male C57BL/6J mice, feeding a methionine- and choline-deficient diet (MCD) resulted in severe hepatic steatosis and inflammation relative to feeding a chow diet (CD). MCD-fed mice exhibited characteristics of mucosal and submucosal inflammatory responses compared with CD-fed mice. Moreover, intestinal phosphorylation states of c-Jun N-terminal protein kinase p46 and mRNA levels of IL-1B, IL-6, tumor necrosis factor alpha, and monocyte chemoattractant protein-1 were significantly higher and intestinal mRNA levels of IL-4 and IL-13 were significantly lower in MCD-fed mice compared with those in CD mice. Surprisingly, upon treatment with MCD-mimicking media, the proinflammatory responses in cultured intestinal epithelial CMT-93 cells did not differ significantly from those in CMT-93 cells treated with control media. In contrast, in RAW264.7 macrophages, MCD-mimicking media significantly increased the phosphorylation states of c-Jun N-terminal protein kinase p46 and mitogen-activated protein kinases p38 and mRNA levels of IL-1B, IL-6, IL-10, and tumor necrosis factor alpha under either basal or lipopolysaccharide-stimulated conditions. Collectively, these results suggest that increased intestinal inflammation is associated with NASH phenotype. Thus, elevated proinflammatory responses in macrophages likely contribute to, in large part, increased intestinal inflammation in NASH.