Abstract
Toll-like receptor 2 (TLR2), which recognizes several lipopeptides and transduces inflammatory signaling, promotes the pathogenesis of diet-induced dyslipidemia and obesity. TLR2-deficient mice were shown to have improved insulin sensitivity and reduced diet-induced metabolic syndrome. Previous studies demonstrated that prenatal lipopolysaccharide (LPS) exposure causes dyslipidemia accompanied by increased body weight and insulin resistance in offspring. To determine whether TLRs are involved in this complex abnormal phenotype, we analyzed TLR2 and TLR4 expression levels in adipose tissues from offspring with prenatal LPS-exposure (offspring-pLPS) and compared these levels to those of control offspring with prenatal saline-exposure (offspring-pSaline). TLR2 expression was specifically upregulated in the adipose tissue of offspring-pLPS mice. However, unexpectedly, TLR2-deficient offspring-pLPS mice not only presented with an abnormal phenotype comparable to that of wild-type offspring-pLPS mice but also exhibited significantly more severe hyperlipidemia. Our further analyses revealed a dramatic upregulation of TLR4 expression and overactivation of the TLR4/Myd88 signaling pathway in TLR2-deficient offspring-pLPS adipose tissue. Our finding suggests a compensatory genetic interaction between TLR2 and TLR4 in the context of prenatal inflammatory stimulation, and this interaction likely contributes to the prenatal inflammation-induced hyperlipidemia and lipid overload-induced obesity, thus providing a potential mechanism for the fetal origin of adult metabolic diseases.
Highlights
Obesity is associated with an increased risk of coronary heart disease and diabetes, partly due to its strong association with hyperlipidemia
We found a similar trend in glucose and insulin resistance, as indicated by Intraperitoneal Glucose Tolerance Test (IPGTT), Intraperitoneal Insulin Tolerance Test (IPITT) and protein expression of phosphorylated IRS-1Ser307 and AKTSer473, in offspring-pLPS mice of both wild-type and Toll-like receptor 2 (TLR2)-deficient genotypes when compared to the offspring-pSaline mice of both wild-type and TLR2-deficient genotypes (Figures 2F–H)
Since the phosphorylation of Myd88 at Tyr257 is likely involved in the recruitment of PI3 kinase p85 subunit to Myd88 for further inflammatory signal transduction, our results suggest that this process might not be affected by the genetic compensation of TLR4 alone, our results highlight the potential hypersensitivity in TLR2-deficient offspring-pLPS to additional inflammatory stimulation (Gelman et al, 2006; Heun et al, 2019)
Summary
Obesity is associated with an increased risk of coronary heart disease and diabetes, partly due to its strong association with hyperlipidemia. Increasing evidence and epidemiological studies support the notion that adverse intrauterine exposure to inflammation is associated with chronic diseases in adult offspring (Gluckman and Hanson, 2004; McEvoy et al, 2014; Palinski, 2014; Postma et al, 2015), including obesity (Kubo et al, 2014; Fleisch et al, 2015). Pyrrolidine dithiocarbamate (PDTC, a selective NF-κB inhibitor) intervention during middle gestation could successfully remediate obesity, hyperlipidemia and hypertension induced by prenatal LPS exposure (Hao et al, 2010), which was consistent with the notion in epidemiological studies that prenatal inflammatory exposure is likely associated with chronic diseases in offspring (Palinski, 2014)
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