Noncanonical Wnt Signaling Promotes Obesity-Induced Adipose Tissue Inflammation and Metabolic Dysfunction Independent of Adipose Tissue Expansion

Abstract

Adipose tissue dysfunction plays a pivotal role in the development of insulin resistance in obese individuals. Cell culture studies and gain-of-function mouse models suggest that canonical Wnt proteins modulate adipose tissue expansion. However, no genetic evidence supports a role for endogenous Wnt proteins in adipose tissue dysfunction, and the role of noncanonical Wnt signaling remains largely unexplored. Here we provide evidence from human, mouse, and cell culture studies showing that Wnt5a-mediated, noncanonical Wnt signaling contributes to obesity-associated metabolic dysfunction by increasing adipose tissue inflammation. Wnt5a expression is significantly upregulated in human visceral fat compared with subcutaneous fat in obese individuals. In obese mice, Wnt5a ablation ameliorates insulin resistance, in parallel with reductions in adipose tissue inflammation. Conversely, Wnt5a overexpression in myeloid cells augments adipose tissue inflammation and leads to greater impairments in glucose homeostasis. Wnt5a ablation or overexpression did not affect fat mass or adipocyte size. Mechanistically, Wnt5a promotes the expression of proinflammatory cytokines by macrophages in a Jun NH2-terminal kinase–dependent manner, leading to defective insulin signaling in adipocytes. Exogenous interleukin-6 administration restores insulin resistance in obese Wnt5a-deficient mice, suggesting a central role for this cytokine in Wnt5a-mediated metabolic dysfunction. Taken together, these results demonstrate that noncanonical Wnt signaling contributes to obesity-induced insulin resistance independent of adipose tissue expansion.

Secreted Frizzled-related Protein 5 Diminishes Cardiac Inflammation and Protects the Heart from Ischemia/Reperfusion Injury

“…JNK, a component of planar cell polarity, is activated by noncanonical Wnt signaling in multiple systems (28,44,45) including cardiac myocytes (Ref. 46 and data not shown).…”

“…Sfrp5/Wnt5a-mediated Modulation of Macrophage Signaling-Accumulating evidence suggests that Wnt5a can function as an immune system modulator that acts in an autocrine manner (45,(47)(48)(49)(50). Thus, we evaluated the effects of Wnt5a and Sfrp5 on murine BMDMs in vitro.…”

“…In this regard, we identified Sfrp5 as an anti-inflammatory adipokine that antagonizes the pro-inflammatory activity of Wnt5a, a regulator of non-canonical Wnt signaling (28). Utilizing genetic models, it was shown that Sfrp5/Wnt5a signaling is a regulator of adipose tissue inflammation and systemic metabolic health (28,45). Here we show that genetic ablation of Sfrp5, a condition that is mimicked by severe metabolic dysfunction, is sufficient to promote adverse effects on the ischemic heart that are associated with elevated inflammation in the injured myocardium.…”

Retention of sedentary obese visceral white adipose tissue phenotype with intermittent physical activity despite reduced adiposity

“…However, the mechanisms that link obesity and insulin resistance remain poorly understood. Visceral white adipose tissue (AT) dysfunction is a characteristic feature of obesity-related insulin resistance, and evidence implicates AT inflammation as a causal link between obesity and insulin resistance (10). Obesity is associated with infiltration of immune cells into AT, thus contributing to AT inflammation and secretion of inflammatory cytokines (13).…”

Androgen Deprivation Therapy (ADT), Metabolic Syndrome and Metastatic Prostate Cancer: In Vivo and In Vitro Assessments of Effects of Metformin

“…Men treated with non-specific HIF-1-alpha inhibitors (digoxin, metformin and angiotensin 2 receptor blockers) have exhibited reduced incidence of metastatic disease and increased time to cancer progression [131]. Furthermore, inflammatory mediators such as interleukin -6 have been shown to contribute towards insulin mediated cancer growth and Wnt5a mediated metabolic dysfunction in both in vitro and in vivo experiments [132,133].…”