Depot-specific differences in angiogenic capacity of adipose tissue in differential susceptibility to diet-induced obesity

Abstract

ObjectiveAdipose tissue (AT) expansion requires AT remodeling, which depends on AT angiogenesis. Modulation of AT angiogenesis could have therapeutic promise for the treatment of obesity. However, it is unclear how the capacity of angiogenesis in each adipose depot is affected by over-nutrition. Therefore, we investigated the angiogenic capacity (AC) of subcutaneous and visceral fats in lean and obese mice.MethodsWe compared the AC of epididymal fat (EF) and inguinal fat (IF) using an angiogenesis assay in diet-induced obese (DIO) mice and diet-resistant (DR) mice fed a high-fat diet (HFD). Furthermore, we compared the expression levels of genes related to angiogenesis, macrophage recruitment, and inflammation using RT-qPCR in the EF and IF of lean mice fed a low-fat diet (LFD), DIO mice, and DR mice fed a HFD.ResultsDIO mice showed a significant increase in the AC of EF only at 22 weeks of age compared to DR mice. The expression levels of genes related to angiogenesis, macrophage recruitment, and inflammation were significantly higher in the EF of DIO mice than in those of LFD mice and DR mice, while expression levels of genes related to macrophages and their recruitment were higher in the IF of DIO mice than in those of LFD and DR mice. Expression of genes related to angiogenesis (including Hif1a, Vegfa, Fgf1, Kdr, and Pecam1), macrophage recruitment, and inflammation (including Emr1, Ccr2, Itgax, Ccl2, Tnf, and Il1b) correlated more strongly with body weight in the EF of HFD-fed obese mice compared to that of IF.ConclusionsThese results suggest depot-specific differences in AT angiogenesis and a potential role in the susceptibility to diet-induced obesity.

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

“…Serial angiogenic processes during tissue remodeling are regulated by macrophages 5,31 . Diet-induced body weight gain positively correlates with CD11c expression in eWAT, which has a higher angiogenic capacity than inguinal WAT 32 . However, whether ATMs contribute to adipose angiogenesis during obesity remains unclear.…”

Acute endurance exercise increases Vegfa mRNA expression in adipose tissue of rats during the early stages of weight gain

“…VEGF-A binding to VEGF-receptors on endothelial cells signals their proliferation and migration, as well as vasodilation and vascular permeability (Cao 2007), with the most potent and essential signaling thought to occur through tyrosine phosphorylation of the VEGFR2 (Olsson et al 2006). The regulation of Vegf-a expression in adipose tissue is not well studied, but some work has found depot differences in angiogenic gene expression and angiogenic capacity in obesity (Gealekman et al 2011; Song et al 2016). There are very limited available data on the effects of exercise on VEGF in adipose tissue.…”

“…Furthermore, histology as well as ex vivo analyses have demonstrated a greater angiogenic capacity of human visceral adipose versus human subcutaneous adipose tissue (Gealekman et al 2011; Song et al 2016). Therefore, an important secondary research question to extend applicability of the experiments here was whether a depot × exercise interaction existed in the angiogenic response to exercise.…”

“…Data concerning the regulation of the adipose tissue angiogenic response to acute exercise are mixed, with no consensus on the VEGF response to exercise in adipose tissue (Czarkowska-Paczek et al 2011; Disanzo and You 2014; Van Pelt et al 2017). Differences in ex vivo angiogenic capacity have been observed between depots (subcutaneous vs. visceral), and in response to weight gain and obesity in rodent and human fat (Gealekman et al 2011; Song et al 2016; Villaret et al 2010). The aim of this experiment was to assess changes in adipose tissue expression of key angiogenic genes in response to a single session of exercise during early diet-induced weight gain in rats.…”

Putative positive role of inflammatory genes in fat deposition supported by altered gene expression in purified human adipocytes and preadipocytes from lean and obese adipose tissues

“…Various ECM proteins, including MMP2, ADAM, TIMP, CTSK, and CTSS, are altered in obese AT [9][10][11][12]. Angiogenic genes such as VEGF and ANGPT2 are upregulated in response to activated HIF1A (i.e., hypoxia-related transcription factor) [13,14]. LEP and ADIPOQ are another genes that have potential adipokine functions involved in AT remodeling [8,15].…”