Activation of Noncanonical Wnt Signaling Through WNT5A in Visceral Adipose Tissue of Obese Subjects Is Related to Inflammation

Abstract

Activation of noncanonical Wnt signaling through the up-regulation of WNT5A and down-regulation of SFRP5 may promote a proinflammatory state in visceral adipose tissue contributing to the development of obesity-associated comorbidities.

Obesity-Induced Changes in Adipose Tissue Microenvironment and Their Impact on Cardiovascular Disease

“…Several studies have shown that circulating levels of Sfrp5 are reduced in obese individuals, particularly in those exhibiting clear evidence of metabolic dysfunction, such as impaired glucose tolerance and insulin resistance 346, 348–350 . Consistently, human Sfrp5 transcript levels in visceral adipose tissue decrease with obesity 351 . In marked contrast, one study found a positive association between increased serum Sfrp5 levels and high HOMA-IR, an index of insulin resistance, in humans 352 .…”

Wnt signaling in cardiovascular disease: opportunities and challenges

“…While this autosomal dominant variant does impair LDL cholesterol clearance, it also hampers canonical Wnt signaling required for TCF7L2-dependent transcriptional support of insulin receptor expression in peripheral tissues [63]. As a proof-of principle, Mani’s group went on to show that augmenting canonical Wnt signaling programs in LRP6 (611C/611C) homozygous mutant mice with recombinant Wnt3a injections reversed the combined dyslipidemia [64]. These studies revealed that hepatic de novo lipogenesis and apoB-containing lipoprotein secretion is held in check by canonical Wnt signals via LRP6 [64].…”

“…As a proof-of principle, Mani’s group went on to show that augmenting canonical Wnt signaling programs in LRP6 (611C/611C) homozygous mutant mice with recombinant Wnt3a injections reversed the combined dyslipidemia [64]. These studies revealed that hepatic de novo lipogenesis and apoB-containing lipoprotein secretion is held in check by canonical Wnt signals via LRP6 [64]. Since the insulin resistance and dyslipidemia of metabolic syndrome are clear contributors to cardiovascular disease risk [65], LRP6-dependent Wnt signaling tone globally mitigates cardiometabolic risk [28].…”

“…Similarly, SFRP5 inhibits myocardial inflammation and injury in a preclinical ischemia/reperfusion model[106]. Importantly, while SFRP family members can inhibit both canonical and noncanonical signaling, it appears that SFRP5 preferentially inhibits noncanonical signaling in proinflammatory cellular contexts [64, 107]. Of note, however, SFRP2 exhibits a more nuanced cardiovascular response, promoting myocardial stem cell survival and repair with ischemia[108], likely by shaping canonical [109] and planar cell polarity[110] signals that mitigate fibrosis[109, 111].…”

Development of a vascularized, induced pluripotent stem cell-derived liver-tissue mimic for therapeutic applications.

“…Wnt5a utilizes multiple receptors but is generally categorized as a non-canonical Wnt 379,398 . To determine if the same effect on hSVF EC networking could be produced by a different Wnt, we repeated the above experiment using the prototypical canonical Wnt, Wnt3a at the same concentrations as those used for the rhWnt5a in vitro experiment ( Figure 18A).…”