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Triphenyl phosphate causes a sexually dimorphic metabolism dysfunction associated with disordered adiponectin
Cui Wang1, Yifei Le1, Dezhao Lu1
1College of Life Science, Zhejiang Chinese Medical University, Hangzhou 310053, China.
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.
Insights
Triphenyl phosphate (TPhP) disrupts metabolism differently in males and females. TPhP impairs female metabolic health via the adiponectin pathway, while males show stimulated responses, highlighting sexual dimorphism in TPhP
Area of Science:
- Environmental toxicology
- Endocrinology
- Metabolic disorders
Background:
- Triphenyl phosphate (TPhP) exposure is linked to metabolic dysfunction.
- The sex-specific mechanisms underlying TPhP's metabolic disruption remain largely unknown.
Purpose of the Study:
- To investigate the sexual dimorphism in TPhP-induced metabolic disruption.
- To elucidate the role of the adiponectin/AdipoR pathway in mediating these effects.
Main Methods:
- Oral administration of TPhP to assess metabolic parameters.
- Analysis of serum adiponectin levels and HOMA-IR (Homeostatic Model Assessment for Insulin Resistance).
- Examination of hepatic AdipoR1/R2, pAKT, PPARα, and pAMPK signaling pathways.
Main Results:
- TPhP inhibited adiponectin and increased HOMA-IR in females, with attenuated hepatic AdipoR1/R2, pAKT, and PPARα signaling, leading to glucose intolerance and hepatic lipid accumulation.
- TPhP stimulated adiponectin and upregulated AdipoR1/R2 and downstream signaling (pAMPK, PPARα) in males, maintaining normal glucose and hepatic triacylglyceride levels.
- Skeletal muscle AdipoR1/R2 and related gene expression showed no sex-specific response to TPhP.
Conclusions:
- TPhP-induced hepatic nutrient metabolism disruption is mediated by the adiponectin/AdipoR pathway in a sex-dependent manner during puberty.
- Females are more susceptible to TPhP's adverse metabolic effects due to pathway inhibition, while males exhibit a compensatory response.
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