Abstract
BackgroundObesity is considered as a systemic chronic low grade inflammation characterized by increased serum pro-inflammatory proteins and accumulation of macrophages within white adipose tissue (WAT) of obese patients. C5L2, a 7-transmembrane receptor, serves a dual function, binding the lipogenic hormone acylation stimulating protein (ASP), and C5a, involved in innate immunity.AimWe evaluated the impact of C5L2 on macrophage infiltration in WAT of wildtype (Ctl) and C5L2 knock-out (C5L2−/−) mice over 6, 12 and 24 weeks on a chow diet and moderate diet-induced obesity (DIO) conditions.ResultsIn Ctl mice, WAT C5L2 and C5a receptor mRNA increased (up to 10-fold) both over time and with DIO. By contrast, in C5L2−/−, there was no change in C5aR in WAT. C5L2−/− mice displayed higher macrophage content in WAT, varying by time, fat depot and diet, associated with altered systemic and WAT cytokine patterns compared to Ctl mice. However, in all cases, the M1 (pro-) vs M2 (anti-inflammatory) macrophage proportion was unchanged but C5L2−/− adipose tissue secretome appeared to be more chemoattractant. Moreover, C5L2−/− mice have increased food intake, increased WAT, and altered WAT lipid gene expression, which is reflected systemically. Furthermore, C5L2−/− mice have altered glucose/insulin metabolism, adiponectin and insulin signalling gene expression in WAT, which could contribute to development of insulin resistance.ConclusionDisruption of C5L2 increases macrophage presence in WAT, contributing to obesity-associated pathologies, and further supports a dual role of complement in WAT. Understanding this effect of the complement system pathway could contribute to targeting treatment of obesity and its comorbidities.
Highlights
Obesity is associated with ‘metaflammation’, characterized by a systemic chronic low grade inflammation, differing from classic acute inflammation [1,2]
Macrophage accumulation is strongly correlated with adipocyte hypertrophy [8], which leads to altered adipokine secretion [9], local hypoxia [10] and adipocyte death [11]
Classical chemoattractant receptor and complement protein are modulated over time and according to dietary conditions To evaluate the immune impact of total body C5L2 deletion in white adipose tissue (WAT), we first evaluated the related chemokine receptors (C5L2, C5aR and C3a receptor (C3aR)) and complement proteins which bind these receptors in WAT using two different diet conditions: a typical standard low fat complex carbohydrate chow diet, and a moderate fat-sucrose diet-induced obesity (DIO) diet with statistical emphasis on the genotype 6 time effects
Summary
Obesity is associated with ‘metaflammation’, characterized by a systemic chronic low grade inflammation, differing from classic acute inflammation [1,2]. Metaflammation differs by its multi-organ target and chronic low-level activation of the innate immune response, as seen in obesity, which affects metabolic homeostasis over time [2]. This inflammation is assumed to lead to insulin resistance which could induce type 2 diabetes [6] and is considered a precursor for other obesity-associated pathologies. Obesity is considered as a systemic chronic low grade inflammation characterized by increased serum proinflammatory proteins and accumulation of macrophages within white adipose tissue (WAT) of obese patients. C5L2, a 7transmembrane receptor, serves a dual function, binding the lipogenic hormone acylation stimulating protein (ASP), and C5a, involved in innate immunity
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