Abstract
The accumulation of visceral adiposity is strongly associated with systemic inflammation and increased cardiometabolic risk. WNT5A, a non-canonical WNT ligand, has been shown to promote adipose tissue inflammation and insulin resistance in animal studies. Among other non-canonical pathways, WNT5A activates planar cell polarity (PCP) signaling. The current study investigated the potential contribution of non-canonical WNT5A/PCP signaling to visceral adipose tissue (VAT) inflammation and associated metabolic dysfunction in individuals with obesity. VAT and subcutaneous adipose tissue (SAT) samples obtained from subjects undergoing bariatric surgery were analyzed by qRT-PCR for expression of WNT/PCP genes. In vitro experiments were conducted with preadipocytes isolated from VAT and SAT biopsies. The expression of 23 out of 33 PCP genes was enriched in VAT compared to SAT. Strong positive expression correlations of individual PCP genes were observed in VAT. WNT5A expression in VAT, but not in SAT, correlated with indexes of JNK signaling activity, IL6, waist-to-hip ratio and hsCRP. In vitro, WNT5A promoted the expression of IL6 in human preadipocytes. In conclusion, elevated non-canonical WNT5A signaling in VAT contributes to the exacerbated IL-6 production in this depot and the low-grade systemic inflammation typically associated with visceral adiposity.
Highlights
Obesity, defined as a body mass index (BMI) ≥30 kg/m2, is a major risk factor for systemic metabolic dysfunction and cardiovascular disease (CVD)
The present study provides evidence supporting that WNT5A/planar cell polarity (PCP) signaling is overactivated in VAT compared to SAT and contributes to the increased local and systemic inflammation associated with visceral adiposity
WNT5A and downstream signaling in obesity-associated adipose tissue dysfunction in humans, we used quantitative real-time PCR to evaluate transcript expression of 33 genes involved in Wingless-type MMTV integration site family (WNT)/PCP signaling in visceral and subcutaneous fat obtained from 44 individuals at the time of bariatric surgery
Summary
Obesity, defined as a body mass index (BMI) ≥30 kg/m2, is a major risk factor for systemic metabolic dysfunction and cardiovascular disease (CVD). It is widely accepted that accumulation of intra-abdominal visceral fat is a major contributor to systemic metabolic dysfunction and cardiovascular risk. In this regard, an increasing body of evidence supports the notion that visceral (VAT) and subcutaneous (SAT) adipose tissue exhibit different intrinsic properties, which make VAT a more pathogenic depot[2]. While the role of canonical WNT signaling in the regulation of adipose tissue expansion is generally accepted[12], the potential effects of non-canonical WNT signaling activation in this tissue and its contribution to fat depot heterogeneity in humans remain poorly defined. The present study provides evidence supporting that WNT5A/PCP signaling is overactivated in VAT compared to SAT and contributes to the increased local and systemic inflammation associated with visceral adiposity
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