Attenuation of the cardiovascular and metabolic complications of obesity in CD14 knockout mice

Abstract

Aims: Although toll-like receptors (TLR) are known to mediate the metabolic complications of obesity, the mechanisms underlying its activation remain largely unknown. The present study analyzed a model of dietinduced obesity in mice lacking the TLR4/TLR2 co-receptor CD14. Main methods: Six-week-old male mice lacking CD14 (n = 16) were allocated to either a control diet or a highfat high-simple carbohydrate diet (5.4 kcal/g; 35% fat; 35% sucrose), and compared with C57BL/6 (WT; n = 15) controls. After 12 weeks, body composition, basal sympathetic activity, non-invasive blood pressure and glucose tolerance were evaluated. Hepatic and adipose tissues were collected for mRNA quantification, histology and LPS incubation. Key findings: In both WT and CD14 knockout mice, obesity was accompanied by TLR2 and TLR4 upregulation. However, obese mice lacking CD14 presented decreased lipid and macrophage content in hepatic and adipose tissues, lower urinary levels of noradrenaline, decreased systolic blood pressure, reduced fasting plasma glucose and blunted glucose intolerance, compared with obese WT group. In the presence of exogenous sCD14, adipose tissue incubation with LPS-induced TLR2 and TNF-α upregulation in both WT and CD14 knockout obese mice. Significance: In our model of diet-induced obesity, mice lacking CD14 showed lower adiposity and hepatic steatosis, improved glucose homeostasis, blunted sympathetic overactivity and reduced blood pressure elevation. This was observed in the presence of preserved TLR4 and TLR2 gene expression, and intact TLR4 signaling pathways. These results suggest that CD14-mediated TLR activation might contribute to the cardiovascular and metabolic complications of obesity.

Metabolic endotoxemia: a molecular link between obesity and cardiovascular risk

“…To clarify the mechanisms of ME-induced innate immunity activation, mice lacking TLR4 co-receptor CD14 were studied. We have shown that CD14 KO mice when exposed to a high-fat highsimple carbohydrate diet show attenuation in CV and metabolic complications of obesity compared with wildtype mice (Roncon-Albuquerque et al 2008). Moreover, when chronically injected with LPS, CD14 KO mice do not show body weight gain and increased visceral and subcutaneous adipose depots, as observed in wildtype animals (Cani et al 2007a).…”

Novel mechanisms of Na+ retention in obesity: phosphorylation of NKCC2 and regulation of SPAK/OSR1 by AMPK

“…Leptin and insulin affect Na ϩ excretion (2, 52) and thus potentially affect the analysis of Na ϩ transporters. Several studies have found that C57BL/6 mice develop obesity-related hypertension after high fat feeding (35-60% energy from fat) from as early as 8 wk (37,45,54) as well as impaired renal salt handling and salt sensitivity (7). C57BL/6 mice fed a HFD develop progressive insulin resistance and provide a good model for studying obesity-related hyperinsulinemia (55).…”

Effect of Obesity on Circulating Adipokines and Their Expression in Omental Adipose Tissue of Female Bariatric Surgery Patients

“…In knockout mice lacking CD14 there is less diet-induced obesity and macrophage accumulation in adipose tissue (Cani et al, 2007;Roncon-Albuquerque et al, 2008). CD 14 is a co-receptor with toll-like receptor 4 [TLR4] for activation of macrophages by lipopolysaccharide and by free fatty acids, which Fessler et al (2009) have postulated to be the link between obesity and inflammation.…”