Oxytocin (Oxt) is a hormone produced by the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus, known to mediate the central anorexigenic effects of the adipokine leptin (Lep), as well as to promote adipose tissue (AT) lipolysis in periphery. Here, we sought to address whether Oxt neurons could directly respond to Lep and if any such regulatory cascade would increase Oxt levels in plasma. Adult C57BL/6J mice were intraperitoneally injected with recombinant leptin (0.5 mg/kg) or saline. We found that Lep induced c-Fos, but not p-Stat3, activation mainly in Oxt neurons of the SON. Furthermore, Lep administration resulted in increased Oxt plasma levels time-dependently and with a sex-dimorphic pattern and in increased Oxt receptor (Oxtr) protein levels in AT. However, Lep receptor (Lepr) is not expressed by Oxt neurons and Lep perfusion failed to induce Ca2+ signalling in SON neurons, ex-vivo. At the same time, we revealed that melanocortin 4 receptor (Mc4r) is not expressed by Oxt neurons, although pro-opiomelanocortin (POMC) neurons, which are known to express Lepr, abundantly innervated Oxt neurons in the SON. Therefore, we have characterized a Lep-dependent Oxt secretory pathway driven in SON neurons. As Oxt system is shaped during post-natal development and may affect vulnerability to obesity in adulthood, we exposed mice to “early life stress” protocol (ELS) (from postnatal day 2-P2 to P9) and adult mice to 12-weeks of high fat diet (HFD) to assess Oxt circulating levels. We found that endogenous Oxt system is not significantly altered by ELS in mice at P21 but is affected by HFD in adulthood. In conclusion, our study points to the existence of a novel neuroendocrine pathway underlying the crosstalk between Lep and Oxt and possibly implicated in the regulation of the energy balance, hence of critical relevance for the study of obesity.
L'ossitocina (Oxt) è un ormone prodotto dai nuclei paraventricolari (PVN) e supraottici (SON) del l'ipotalamo, noti per mediare gli effetti anoressegici centrali della leptina adipochina (Lep), nonché per promuovere la lipolisi del tessuto adiposo (AT) nella periferia. Qui, abbiamo cercato di esaminare se i neuroni Oxt potrebbero rispondere direttamente a Lep e se una tale cascata regolatrice aumenterebbe i livelli di Oxt nel plasma. Topi adulti C57BL/6J sono stati iniettati intraperitonealmente con leptina ricombinante (0,5 mg/ kg) o salina. Abbiamo trovato che Lep indotto c-Fos, ma non p-Stat3, attivazione principalmente in neuroni Oxt del SON. Inoltre, la somministrazione di Lep ha portato ad un aumento dei livelli plasmatici di Oxt in funzione del tempo e con uno schema sesso-dimorfico e ad un aumento dei livelli proteici del recettore Oxt (Oxtr) nell'AT. Tuttavia, il recettore di Lep (Lepr) non è espresso dai neuroni di Oxt e la perfusione di Lep ha mancato di indurre la segnalazione di Ca2+ nei neuroni di SON, ex vivo. Allo stesso tempo, abbiamo rivelato che melanocortin 4 recettore (Mc4r) non è espressa da neuroni Oxt, anche se pro-opiomelanocortin (POMC) i neuroni, che sono noti per esprimere Lepr, abbondantemente innervato neuroni Oxt nel figlio. Pertanto, abbiamo caratterizzato un Lep-dipendente Oxt via secretoria guidata in neuroni SON. Poiché il sistema Oxt si forma durante lo sviluppo post-natale e può influenzare la vulnerabilità all'obesità in età adulta, abbiamo esposto i topi al protocollo di "stress precoce della vita" (ELS) (dal giorno postnatale 2-P2 a P9) e ai topi adulti a 12 settimane di dieta ad alto contenuto di grassi (HFD) per valutare i livelli di circolazione Oxt. Abbiamo scoperto che il sistema Oxt endogeno non è significativamente alterato da ELS nei topi a P21, ma è influenzato da HFD in età adulta. In conclusione, il nostro studio indica l'esistenza di una nuova via neuroendocrina che sottende la coincidenza tra Lep e Oxt e che potrebbe essere coinvolta nella regolazione del bilancio energetico, quindi di importanza critica per lo studio dell'obesità.
OXYTOCIN AND LEPTIN CROSSTALK IN THE REGULATION OF THE ENERGY BALANCE
GALLI, CHIARA
2025
Abstract
Oxytocin (Oxt) is a hormone produced by the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus, known to mediate the central anorexigenic effects of the adipokine leptin (Lep), as well as to promote adipose tissue (AT) lipolysis in periphery. Here, we sought to address whether Oxt neurons could directly respond to Lep and if any such regulatory cascade would increase Oxt levels in plasma. Adult C57BL/6J mice were intraperitoneally injected with recombinant leptin (0.5 mg/kg) or saline. We found that Lep induced c-Fos, but not p-Stat3, activation mainly in Oxt neurons of the SON. Furthermore, Lep administration resulted in increased Oxt plasma levels time-dependently and with a sex-dimorphic pattern and in increased Oxt receptor (Oxtr) protein levels in AT. However, Lep receptor (Lepr) is not expressed by Oxt neurons and Lep perfusion failed to induce Ca2+ signalling in SON neurons, ex-vivo. At the same time, we revealed that melanocortin 4 receptor (Mc4r) is not expressed by Oxt neurons, although pro-opiomelanocortin (POMC) neurons, which are known to express Lepr, abundantly innervated Oxt neurons in the SON. Therefore, we have characterized a Lep-dependent Oxt secretory pathway driven in SON neurons. As Oxt system is shaped during post-natal development and may affect vulnerability to obesity in adulthood, we exposed mice to “early life stress” protocol (ELS) (from postnatal day 2-P2 to P9) and adult mice to 12-weeks of high fat diet (HFD) to assess Oxt circulating levels. We found that endogenous Oxt system is not significantly altered by ELS in mice at P21 but is affected by HFD in adulthood. In conclusion, our study points to the existence of a novel neuroendocrine pathway underlying the crosstalk between Lep and Oxt and possibly implicated in the regulation of the energy balance, hence of critical relevance for the study of obesity.File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.14242/202951
URN:NBN:IT:UNIVPM-202951