Pastorino, Monica (2025) New insights on the hypothalamic orexigenic neuropeptides: the dysfunctional role of the pesticide Chlorpyrifos. [Tesi di dottorato]

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Abstract

Obesity has become a major public health problem worldwide. The hypothalamus plays a crucial role in sensing and controlling energy status. Therefore, identifying factors affecting hypothalamic pathways is pivotal to understanding obesity. Environmental toxicants are now emerging as factors linked to the development of obesity. In particular, it has been reported that Chlorpyrifos (CPF), a specific worldwide pesticide, promotes increased body mass and adiposity and worsens glucose tolerance and insulin sensitivity in obese mice. My PhD project aims to assess whether CPF might affect the regulation of hypothalamic pathways and establish the molecular mechanisms through which CPF might exert its dysfunctional effects. Hypothalami from CD-1 mice chronically treated with CPF (10mg/kg/day) from their conception to 6 months of age and from untreated mice and the hypothalamic mhypoE-N46 cells untreated and treated with CPF (1 pM) have been used as experimental models. Real-time qPCR has been assayed for gene expression analysis. Speedvac vacuum concentrator and Elisa assay have been used to evaluate neuropeptides secretion; Western Blot analysis has been used for protein levels measurements. Moreover, ER- selective antagonists were used for treatments. Neuropeptide Y (Npy) and Agouti-related protein (AgRP) mRNA levels are significantly increased in CPF-treated mice compared to untreated mice as well as in the mhypoE-N46 cells upon acute (1, 2 e 4h) and chronic (Day 6) exposures to CPF. Noteworthy, the mRNA expression of the Estrogen Receptor Beta (ERβ), a putative interactor for CPF, is significantly increased both in the CPF-treated mice and in the mhypoE-N46 cells acutely/chronically exposed to CPF. Notably, the ERβ protein levels also increase in an in vitro chronic CPF exposure compared to controls. Finally, the acute treatment with ER-selective antagonists strengthens the hypothesis of the specific ERβ functional role in regulating orexigenic neuropeptides under CPF acute exposure conditions. Taken together, these data support the hypothesis that CPF may exert dysfunctional effects on the regulation of the orexigenic pathway by affecting the expression of the neuropeptides Npy and AgRP through ERβ modulation. Future experiments will also address whether ERβ is involved in these dysfunctional processes.

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