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Toll‐like receptor 4 mutation delays the onset of insulin resistance in post‐menopausal mice fed a high fat diet

Previous studies in the VCD‐model of menopause demonstrated that the development and progression of metabolic syndrome was accelerated when mice were fed a high‐fat diet. Fatty acids are able to activate toll‐like receptor 4 (TLR4) signaling and in turn, TLR4 can mediate inflammatory events and insulin resistance in peripheral organs. In this study mice heterozygous for a TLR4 mutation were fed a high‐fat (HF) diet and dosed with VCD, to induce menopause (VCD/HF). Previously, VCD‐treated mice became hyperinsulinemic and insulin resistant after 12 weeks on a high fat diet. In contrast, VCD‐treated mice with a TLR4 mutation took 20 weeks on a high fat diet to become hyperinsulinemic (VCD/HF 2.6±0.29 vs HF 1.8±0.41 and Con 0.6±0.15 ng/ml) and to develop insulin resistance (VCD/HF 25.6±3.1 vs HF 15.5±1.5 and Con 5.3±1.9 mg/dl*uU/ml). Circulating levels of leptin and adiponectin were examined: adiponectin levels were reduced in both VCD/HF and HF mice after 12 weeks on a high fat diet, in contrast leptin levels were significantly higher in VCD‐treated mice after 16 weeks on a high fat diet compared to all other groups (VCD/HF 33.9±10 vs HF 12.8±1.2 and Con 2.9±1.3 ng/ml). This study suggests that loss of TLR4 infers a resistance to the onset of insulin resistance; however hormonal changes that occurred during menopause continued to promote the development of insulin resistance.