Pro-inflammatory macrophages coupled with glycolysis remodel adipose vasculature by producing platelet-derived growth factor-B in obesity

Abstract

Adipose tissue macrophages (ATMs) play a central role in tissue remodeling and homeostasis. However, whether ATMs promote adipose angiogenesis in obesity remains unclear. We examined the impact of ATMs deletion on adipose angiogenesis and tissue expansion in the epididymal white adipose tissue (eWAT) of high-fat diet (HFD)-fed mice by using liposome-encapsulated clodronate. We further elucidated the induction mechanisms of platelet-derived growth factor (PDGF)-B in macrophages in response to obesity-associated metabolic stresses, since it plays a significant role in the regulation of pericyte behavior for the initiation of neoangiogenesis during tissue expansion. ATM depletion prevented adipose tissue expansion in HFD-fed mice by inhibiting pericyte detachment from vessels, resulting in less vasculature in eWAT. The lipopolysaccharide (LPS) stimulation and high glucose concentration augmented glucose incorporation and glycolytic capacity with the induction of Pdgfb mRNA. This effect was mediated through extracellular signal-regulated kinase (ERK) among mitogenactivated protein kinases coupled with glycolysis in RAW264.7 macrophages. The Pdgfb induction system was distinct from that of inflammatory cytokines mediated by mechanistic target of rapamycin complex 1 (mTORC1) and NFκB signaling. Thus, obesity-associated hyperglycemia and chronic inflammation fuels ERK signaling coupled with glycolysis in pro-inflammatory macrophages, which contribute to the expansion of eWAT through PDGF-B-dependent vascular remodeling.The excessive expansion of white adipose tissue (WAT) disturbs systemic metabolic homeostasis. Insufficient vascular development in obese WAT induces chronic inflammation, resulting in systemic insulin resistance and metabolic dysfunction 1-6 . Hypoxia due to vascular rarefaction in growing WAT is one trigger inducing pro-angiogenic factors 7 . Vascular endothelial growth factor (VEGF)-A is a well-characterized pro-angiogenic factor that stimulates endothelial proliferation 1,2 . Endothelial proliferation in mature vessels is suppressed by pericytes and perivascular cells 7-10 . We recently reported an important role for platelet-derived growth factor (PDGF)-B in pericyte behavior during WAT expansion in obesity 11 . Increased PDGF-B stimulates the dissociation of CD13 + pericytes from adipose vessels via its receptor PDGFRβ, resulting in endothelial cell proliferation at pericyte-detached vessel areas in WAT during diet-induced obesity 11 . F4/80 + CD11c + pro-inflammatory macrophages promote chronic inflammation by producing inflammatory cytokines, including tumor necrosis factor (TNF) α and interleukin (IL)-6 12,13 . Macrophages secrete angiogenic factors under tissue remodeling conditions in tumors, wounded skin, bone, and adipose tissues 5,14-16 . Consistent with these findings, we reported the up-regulated expression of PDGF-B in F4/80 + CD11c + macrophages in the open Scientific RepoRtS | (2020) 10:670 | https://doi.org/10.1038/s41598-019-57368-w www.nature.com/scientificreports www.nature.com/scie...

Adipose endothelial cells mastering adipose tissues metabolic fate

“…On the other hand, obesity-damaged AdECs could directly activate endothelial TLR-MyD88 signalling to drive M1 macrophages accumulation through production of GM-CSF, which is well known for promoting monocyte differentiation towards M1 pro-inflammatory macrophages [ 25 ]. Moreover, ATMs could regulate the formation of AdECs by producing po-angiogenic factors, such as the platelet-derived growth factor-B (PDGF-B) [ 26 ]. These findings suggest that AdECs harbour immunosuppressive feedback mechanisms that are triggered as a result of macrophage activation.…”

Multi–Omics Analysis of Key microRNA–mRNA Metabolic Regulatory Networks in Skeletal Muscle of Obese Rabbits

“…Additionally, glycolysis/gluconeogenesis pathways play an essential role in the process of carbohydrate metabolism in various tissues of the body. The disorder of this pathway can cause the occurrence of human myopathy and is closely associated with function of adipose tissue macrophages (ATMs) in a high–fat diet–induced model of mice for responding to cellular insulin resistance [ 42 , 43 ]. The Gene Expression Omnibus (GEO) database of humans from non-insulin dependent diabetes mellitus (NIDDM) and obesity found that the biosynthesis of amino acids and notch signaling pathway were down regulated in adipose tissues [ 44 ].…”

Innate Immune Cells in the Adipose Tissue in Health and Metabolic Disease

“…Activation of HIF-1 (via VHL deletion) elevates the glycolytic enzyme pyru-vate kinase M2, which in turn downregulates the IL-33-ST2 pathway, thus directly impacting ILC-2 maturation [317]. Finally, in obese mice, it was recently demonstrated that palmitate upregulates ATM glycolysis and HIF-1 activation and induces IL-1β in macrophages [318]. Thus, enhanced glycolysis and HIF-1α activation in ATM could be partially driving the low-grade inflammation in obesity.…”

“…Fewer studies addressed the role of HIFs in myeloid cell populations (LysMCre) in the context of diet-induced obesity, again with contrasting results. Myeloid cell-specific HIF-1 deletion protects against adipose tissue inflammation and reduces macrophage crown-like structure formation [318,322]. However the role in glucose and insulin tolerance is controversial, with one study showing that myeloid HIF-1 deletion protected from the development of systemic insulin resistance in obese mice [322], whereas the second study showed no effect [318].…”

“…Myeloid cell-specific HIF-1 deletion protects against adipose tissue inflammation and reduces macrophage crown-like structure formation [318,322]. However the role in glucose and insulin tolerance is controversial, with one study showing that myeloid HIF-1 deletion protected from the development of systemic insulin resistance in obese mice [322], whereas the second study showed no effect [318]. In another study, however, deletion of HIF-1 in myeloid cells had no effect on the inflammatory state of adipose tissue after a shorter (8 weeks) high-fat-feeding protocol, and the transgenic mice were heavier with slightly elevated glucose levels [323].…”