Ye J, Gao Z, Yin J, He Q. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab 293: E1118-E1128, 2007. First published July 31, 2007; doi:10.1152/ajpendo.00435.2007.-Chronic inflammation and reduced adiponectin are widely observed in the white adipose tissue in obesity. However, the cause of the changes remains to be identified. In this study, we provide experimental evidence that hypoxia occurs in adipose tissue in obese mice and that adipose hypoxia may contribute to the endocrine alterations. The adipose hypoxia was demonstrated by a reduction in the interstitial partial oxygen pressure (PO2), an increase in the hypoxia probe signal, and an elevation in expression of the hypoxia response genes in ob/ob mice. The adipose hypoxia was confirmed in dietary obese mice by expression of hypoxia response genes. In the adipose tissue, hypoxia was associated with an increased expression of inflammatory genes and decreased expression of adiponectin. In dietary obese mice, reduction in body weight by calorie restriction was associated with an improvement of oxygenation and a reduction in inflammation. In cell culture, inflammatory cytokines were induced by hypoxia in primary adipocytes and primary macrophages of lean mice. The transcription factor NF-B and the TNF-␣ gene promoter were activated by hypoxia in 3T3-L1 adipocytes and NIH3T3 fibroblasts. In addition, adiponectin expression was reduced by hypoxia, and the reduction was observed in the gene promoter in adipocytes. These data suggest a potential role of hypoxia in the induction of chronic inflammation and inhibition of adiponectin in the adipose tissue in obesity.partial oxygen pressure; obesity; type 2 diabetes; insulin resistance IN OBESITY, chronic inflammation and reduced adiponectin in the white adipose tissue (WAT) contribute to pathogenesis of insulin resistance, which links obesity to many complications, such as type 2 diabetes and cardiovascular diseases (23,24,30). The chronic inflammation is indicated by an increased expression of proinflammatory cytokines and elevated infiltration of macrophages into adipose tissue. Of the proinflammatory cytokines, TNF-␣ and IL-6 reduce insulin sensitivity and impair the homeostasis of lipid and glucose metabolism. Monocyte chemoattractant protein-1 (MCP-1) promotes macrophage infiltration into adipose tissue. Although expression of these cytokines is increased in adipose tissue of obese subjects, it is not clear what induces expression of these inflammatory cytokines in obesity. A decrease in adiponectin (ACRP30) production contributes to pathogenesis of insulin resistance (23). However, it remains to be investigated what obesityassociated factor leads to suppression of adiponectin.Systemic hypoxia is associated with insulin resistance in human and animal. In patients with obstructive sleep apnea or sleep-disordered breathing, intermittent hypoxia is associated with a high risk for insulin resistance (...

Recent studies suggest that adipose tissue hypoxia (ATH) may contribute to endocrine dysfunction in adipose tissue of obese mice. In this study, we examined hypoxia's effects on metabolism in adipocytes. We determined the dynamic relationship of ATH and adiposity in ob/ob mice. The interstitial oxygen pressure (Po(2)) was monitored in the epididymal fat pads for ATH. During weight gain from 39.5 to 55.5 g, Po(2) declined from 34.8 to 20.1 mmHg, which are 40-60% lower than those in the lean mice. Insulin receptor-beta (IRbeta) and insulin receptor substrate-1 (IRS-1) were decreased in the adipose tissue of obese mice, and the alteration was observed in 3T3-L1 adipocytes after hypoxia (1% oxygen) treatment. Insulin-induced glucose uptake and Akt Ser(473) phosphorylation was blocked by hypoxia in the adipocytes. This effect of hypoxia exhibited cell type specificity, as it was not observed in L6 myotubes and betaTC6 cells. In response to hypoxia, free fatty acid (FFA) uptake was reduced and lipolysis was increased in 3T3-L1 adipocytes. The molecular mechanism of decreased fatty acid uptake may be related to inhibition of fatty acid transporters (FATP1 and CD36) and transcription factors (PPARgamma and C/EBPalpha) by hypoxia. The hypoxia-induced lipolysis was observed in vivo after femoral arterial clamp. Necrosis and apoptosis were induced by hypoxia in 3T3-L1 adipocytes. These data suggest that ATH may promote FFA release and inhibit glucose uptake in adipocytes by inhibition of the insulin-signaling pathway and induction of cell death.

BackgroundDespite accumulating evidence on the role of glial cells and their associated chemicals in mechanisms of pain, few studies have addressed the potential role of chemokines in the descending facilitation of chronic pain. We aimed to study the hypothesis that CXCL1/CXCR2 axis in the periaqueductal gray (PAG), a co-restructure of the descending nociceptive system, is involved in descending pain facilitation.MethodsIntramedullary injection of Walker 256 mammary gland carcinoma cells of adult female Sprague Dawley rats was used to establish a bone cancer pain (BCP) model. RT-PCR, Western blot, and immunohistochemistry were performed to detect pNfkb, Cxcl1, and Cxcr2 and their protein expression in the ventrolateral PAG (vlPAG). Immunohistochemical co-staining with NeuN, GFAP, and CD11 were used to examine the cellular location of pNFκB, CXCL1, and CXCR2. The effects of NFκB and CXCR2 antagonists and CXCL1 neutralizing antibody on pain hypersensitivity were evaluated by behavioral testing.ResultsBCP induced cortical bone damage and persistent mechanical allodynia and increased the expression of pNFκB, CXCL1, and CXCR2 in vlPAG. The induced phosphorylation of NFκB was co-localized with GFAP and NeuN, but not with CD11. Micro-injection of BAY11-7082 attenuated BCP and reduced CXCL1 increase in the spinal cord. The expression level of CXCL1 in vlPAG showed co-localization with GFAP, but not with CD11 and NeuN. Micro-administration of CXCL1 neutralizing antibody from 6 to 9 days after inoculation attenuated mechanical allodynia. Furthermore, vlPAG application of CXCL1 elicited pain hypersensitivity in normal rats. Interestingly, CXCR2 was upregulated in vlPAG neurons (not with CD11 and GFAP) after BCP. CXCR2 antagonist SB225002 completely blocked the CXCL1-induced mechanical allodynia and attenuated BCP-induced pain hypersensitivity.ConclusionThe NFκB-dependent CXCL1-CXCR2 signaling cascade played a role in glial-neuron interactions and in descending facilitation of BCP.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1391-2) contains supplementary material, which is available to authorized users.

Inhibition of peroxisome proliferator-activated receptor ␥ (PPAR␥) function by TNF-␣ contributes to glucose and fatty acid metabolic disorders in inflammation and cancer, although the molecular mechanism is not fully understood. In this study, we demonstrate that nuclear translocation of HDAC3 is regulated by TNF-␣, and this event is required for inhibition of transcriptional activity of PPAR␥ by TNF-␣. HDAC3 is associated with IB␣ in the cytoplasm. After IB␣ degradation in response to TNF-␣, HDAC3 is subject to nuclear translocation, leading to an increase in HDAC3 activity in the nucleus. This event leads to subcellular redistribution of HDAC3. Knock-out of IB␣, but not p65 or p50, leads to disappearance of HDAC3 in the cytoplasm, which is associated with HDAC3 enrichment in the nucleus. These data suggest that inhibition of PPAR␥ by TNF-␣ is not associated with a reduction in the DNA binding activity of PPAR␥. Rather, these results suggest that IB␣-dependent nuclear translocation of HDAC3 is responsible for PPAR␥ inhibition by TNF-␣.PPAR␥ is a nuclear receptor in the family of peroxisome proliferatoractivated receptor (PPAR) 2 that includes PPAR␣, PPAR␥, and PPAR␦ (PPAR␤) (reviewed in Refs. 1 and 2). PPAR␥ is a master transcriptional regulator of lipid and glucose metabolism (reviewed in Refs. 1-3). Inhibition of PPAR␥ function by inflammatory cytokines may contribute to the loss of insulin sensitivity in obese subjects and loss of fat storage in cancer patients under cachexia. Although TNF-␣ is known to inhibit the ligand-dependent transcriptional activity of PPAR␥, the precise mechanism remains to be fully understood (4 -8). In this study, we addressed this issue by analyzing the molecular mechanism of TNF-␣ action on PPAR␥.The transcriptional activity of PPAR␥ is controlled by DNA binding activity and nuclear receptor cofactors that include corepressors and coactivators. PPARs form heterodimers with the retinoid X receptor (RXR), which is activated by 9-cis retinoic acid (9). It is generally believed that the heterodimer is associated with the nuclear receptor corepressor complex in the absence of PPAR␥ ligand. Upon activation by a ligand, the corepressor complex is replaced by coactivators leading to transcriptional initiation of target genes. The corepressor for PPAR␥ is a protein complex containing HDAC3 (histone deacetylase 3) and SMRT (silencing mediator for retinoic and thyroid hormone receptors) or NCoR (nuclear corepressor). RIP140 (receptor-interacting protein) may also be a component in the corepressor complex (10 -13). The coactivators of PPAR␥ include well established cofactors such as p300/ CBP, p160, and PGC-1 (PPAR␥ coactivator-1) (reviewed in Ref. 14), as well as the relatively new coactivators TRAP220 (thyroid hormone receptor-associated protein 220 or PBP, PPAR␥-binding protein) (15, 16), ARA70 (androgen receptor-associated protein) (17), and PRIP (PPAR␥-interacting protein, ASC-2/RAP250/TRBP/NRC) (18 -21). The coactivator p160 has three isoforms: SRC-1 (steroid receptor coactivator 1, ...