Transgenic mice with ectopic expression of constitutively active TLR4 in adipose tissues do not show impaired insulin sensitivity

Abstract

IntroductionChronic low‐grade inflammation is associated with obesity and diabetes. However, what causes and mediates chronic inflammation in metabolic disorders is not well understood. Toll‐like receptor 4 (TLR4) mediates both infection‐induced and sterile inflammation by recognizing pathogen‐associated molecular patterns and endogenous molecules, respectively. Saturated fatty acids can activate TLR4, and TLR4‐deficient mice were protected from high fat diet (HFD)‐induced obesity and insulin resistance, suggesting that TLR4‐mediated inflammation may cause metabolic dysfunction, such as obesity and insulin resistance.MethodsWe generated two transgenic (TG) mouse lines expressing a constitutively active TLR4 in adipose tissue and determined whether these TG mice would show increased insulin resistance.ResultsTG mice fed a high fat or a normal chow diet did not exhibit increased insulin resistance compared to their wild‐type controls despite increased localized inflammation in white adipose tissue. Furthermore, females of one TG line fed a normal chow diet had improved insulin sensitivity with reduction in both adiposity and body weight when compared with wild‐type littermates. There were significant differences between female and male mice in metabolic biomarkers and mRNA expression in proinflammatory genes and negative regulators of TLR4 signaling, regardless of genotype and diet.ConclusionsTogether, these results suggest that constitutively active TLR4‐induced inflammation in white adipose tissue is not sufficient to induce systemic insulin resistance, and that high fat diet‐induced insulin resistance may require other signals in addition to TLR4‐mediated inflammation.

Mechanisms of Iron Deficiency in Obese Children

“…Lipopolysaccharide also induces secretion of hepcidin from intestinal myeloid type 2 conventional dendritic cells, which limits iron release from intestinal phagocytes [65]. TLR4 also activates NF-κB and promotes the expression of downstream inflammatory factors, for example, IL-6 and TNF-α, which increase hepcidin expression [66,67].…”

Sweet triterpenoid glycoside from Cyclocarya paliurus ameliorates obesity-induced insulin resistance through inhibiting the TLR4/NF-κB/NLRP3 inflammatory pathway

“…On the one hand, a large number of fat factors and saturated fatty acids generated in patients of obesity-induced IR can boost TLR4, and promote NF-κB activation, increase the expressions of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), etc. proinflammatory cytokines in WAT/BAT promote the formation of WAT, and affect glucose uptake and fatty acid metabolism ( Benomar et al, 2016 ; Kumari et al, 2016 ; Ono-Moore et al, 2017 ); On the other hand may activate NLRP3 inflammasome, and its activation lead to activation of caspase-1 and releases of IL-1β and IL-18. All of these indicated that the related protein expressions of NLRP3 inflammasome were significantly elevated in adipose tissue from obese, dyslipidemic, and diabetic patients and positively correlated with the severity of IR ( Jourdan et al, 2013 ; Zhang et al, 2021 ).…”