BCL-2 or BCL-xL inhibit BAX and BAK activation through a direct interaction involving the so called BH domains. In this model, BAX activation is favored by the pro-apoptotic BH3-only proteins. These proteins can act both as direct activators of BAX as BID, BIM or PUMA, or as de-repressors as BAD, NOXA that interact with anti-apoptotic members of the BCL-2 family. In this work we could demonstrate that leptin treatment decreases BID protein. All these results consolidate the anti-apoptotic role of leptin in placental cells. It was demonstrated that the human BAX gene promoter contains typical p53-binding sites and is transcriptionally upregulated by p53. The p53 tumor suppressor protein is a key component of cellular mechanisms that are activated by cellular stresses. Therefore, we investigated whether this key cell cycle-signaling protein was involved in the effect of leptin. We determined p53 expression in the presence or absence of leptin in a model of serum deprivation condition, both in Swan-71 and human placental explants. A significant decrease of p53 was observed in both models demonstrating that leptin regulates p53 level under stress. Under normal conditions, p53 is a short-lived protein that is highly regulated and maintained at low or undetectable levels. After stress, such us serum deprivation, p53 is activated mostly at the post-translational level by a complex series of modifications that include the phosphorylation and acetylation of specific residues in the amino-terminal and carboxyterminal domains. In addition to post-translational modifications, protein–protein interactions and subcellular relocalization also have a role in the activation of p53. The activation of p53 leads to the transcription of several genes whose products trigger different biological outcomes. MDM2 is known to negatively regulate p53 by mediating its ubiquitination and subsequent degradation in the proteasome. Little is known about leptin effect on MDM2 levels, but we speculate that leptin might regulate MDM2 expression, triggering the degradation of p53. Our data demonstrated that leptin not only decreases p53 protein level but also p53 mRNA level, measured by qRT-PCR. These results will be further explore, studying the mechanisms by which leptin regulates p53 expression. Not all of the pathways involved in the processes regulated by p53 are known but phosphorylation of p53 at Ser-46 was shown to be involved in the regulation of apoptosis after DNA damage. Moreover, there is evidence that Ser-46 of p53 is phosphorylated in response to DNA damage in vivo, and it plays a pivotal role for apoptotic signaling by p53 through regulating the transcriptional activation of an apoptosis-inducing gene, p53AIP1. We decided to study the effect of leptin on this post-translational modification. Our data demonstrated that leptin significantly diminishes Ser-46 of p53 under stress condition.