Triphenyl phosphate causes a sexually dimorphic metabolism dysfunction associated with disordered adiponectin receptors in pubertal mice

Abstract

The potential for triphenyl phosphate (TPhP) caused metabolic dysfunction has been documented. However, the relative mechanism of sexual dimorphic disruption on metabolism induced by TPhP remains unclear. Herein, we observed the insulin-sensitizing hormone (adiponectin) was inhibited in female serum while stimulated in males after oral administration of TPhP. Correspondingly, we found a high index of HOMA-IR in females. The primary receptors of adiponectin (AdipoR1 and AdipoR2) and the downstream: phosphorylation of AKT (pAKT) and PPAR⍺ signaling was attenuated in female liver. The disordered adiponectin/AdipoR signaling reduced hepatic glucose glycolysis and induced gluconeogenesis and finally led to the glucose intolerance in females. Also, the aberrant fatty acid β-oxidation and hepatic triacylglyceride (TG) deposition were found in female liver. Comparably, TPhP upregulated the AdipoR 1/2 and induced the downstream (pAMPK and PPAR⍺ signaling) in males. Thus, the serum glucose and hepatic TG level remained normal. However, modulation on AdipoR1/R2 and the genes related to glucose and lipid disposal in skeletal muscle has no gender-specific effect. Our research firstly revealed TPhP-induced hepatic nutrient metabolism was partially mediated by the adiponectin/AdipoR pathway in sexual-dependent manner during pubertal.

Keywords: AdipoRs; Adiponectin; Insulin resistance; Pubertal exposure; Triphenyl phosphate.