Adipose tissue inflammation and systemic insulin resistance in mice with diet-induced obesity is possibly associated with disruption of PFKFB3 in hematopoietic cells

Abstract

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.

Bariatric surgery-induced weight loss and associated genome-wide DNA-methylation alterations in obese individuals

“…In addition, both genes are implicated in adipose tissue dysfunction, which characterizes severe obesity. TGF-α/SMAD6 signaling is implicated in the white adipocyte commitment of mesenchymal stem cells [ 63 ] and levels of expression of PFKB3 in adipose tissue affect both inflammation and insulin sensitivity [ 64 , 65 ]. Although the current evidence suggests that epigenetic modifications of these genes might be potential markers of obesity and associated diseases, further studies are required to define their functional relevance.…”

Different Effects of Leucine Supplementation and/or Exercise on Systemic Insulin Sensitivity in Mice

“…Considering the limited change of 4-week exercise time, the impact of relatively long exercise time on the body should be considered, which is the study we are planning to conduct in the future. In Marques' study (9), 16 weeks of moderate intensity exercise can improve the lipid status to promote the reduction of weight and obesity (10). Exercise combined with long-term LFD diet was found to reduce the weight of inguinal fat and liver inflammation significantly.…”

“…Mechanistically speaking, over-nutrition can activate the inflammatory signal pathway and release a large number of inflammatory cytokines to interfere with signal transduction, thus inducing adipose tissue (7) and liver (8) inflammation, which is a major reason for systemic insulin resistance. On the other hand, insulin resistance aggravates adipose tissue (9) and liver (10) inflammation. It leads to a vicious spiral and promotes the development of type 2 diabetes.…”

Bioinformatics Analysis of next generation sequencing data for Risk Prediction in Patients with Type 1 diabetes mellitus

“…KDM7A [61], LMNA (lamin A/C) [62], PFKFB3 [63], NEU1 [64], DUSP22 [65], ADORA2B [66], CRTC2 [67], GRN (granulin precursor) [68], CTSD (cathepsin D) [69], IGFBP4 [70], SMYD2 [71], OSM (oncostatin M) [72], INVS (inversin) [73], ANKFY1 [74], SEMA4D [75], PPM1A [76], IFNG (interferon gamma) [77], CTBP1 [78], ATP6 [79], COX2 [80], RPS19 [81], COX1 [82] and TLK1 [83] are potential biomarkers for the detection and prognosis of renal diseases. A previous study reported that LXN (latexin) [84], LMNA (lamin A/C) [85], PFKFB3 [86], NEU1 [87], TBK1 [88], GRN (granulin precursor) [89], CTSD (cathepsin D) [90], ACADS (acyl-CoA dehydrogenase short chain) [91], IRF7 [92], S1PR1 [93], ZAP70 [94], IDH1 [95], IL15 [96], PIK3R1 [97], OSM (oncostatin M) [98], SOCS3 [99], USP21 [100], CEP19 [101], KDM2A [102], TP53 [103], BRD2 [104], ATP6 [105], BRD4 [106], COX2 [107], RPS6 [108], ND2 [109], CYTB (cytochrome b) [110] and COX1 [111] are altered expressed in obesity. Altered expression of BCL3 [112], TRAF2 [113], NEU1 [114], SNAP29 [115], AGPAT2 [116], LPCAT3 [117], ADORA2B [118], CTSD (cathepsin D) [119], ACADS (acyl-CoA dehydrogenase short chain) [120], ACAD9 [121], E4F1 [122], IRF7 [123], TAF1 [124], S1PR1 [125], RASSF1 [126], ELAC2 [127], RNF146 [128], COX15 [129], SMYD2 [130], IDH1 [131], MTO1 [132], IL15 [133], PIK3R1 [13...…”