Increased Leptin Response and Inhibition of Apoptosis in Thymocytes of Young Rats Offspring from Protein Deprived Dams during Lactation

Abstract

We investigated the consequences of mild maternal malnutrition in rat dams, in terms of thymocyte responses and the putative role of leptin. The young progeny of dams submitted to protein deprivation (PD) during lactation showed at 30 days of age lower body and thymus weights, significant alterations in CD4/CD8-defined T cell subsets without modifications in total thymocyte number as well as in proliferative response. Despite, the rats from PD group did not present alterations in leptin circulating levels, the expression of leptin receptor ObRb was enhanced in their thymocytes. This change was accompanied by an increase in leptin signaling response of thymocytes from PD rats, with an increase in JAK2 and STAT3 phosphorylation after leptin stimulation. Thymocytes from PD rats also presented a decreased rate of spontaneous apoptosis when compared to controls. Accordingly, higher expression of anti-apoptotic protein Bcl-2, and lower of pro-apoptotic protein Bax, with no change of pro-apoptotic Bad, and higher pro-caspase 3 content were detected in PD thymocytes. Moreover, thymocytes from PD group exhibited a constitutive higher nuclear content of p65 NF-kB associated to a lower IkB content in the cytoplasm. Finally, although there was no change in ob gene expression in PD thymocytes, a higher mRNA expression for the Ob gene was observed in the thymic microenvironment from PD animals. Taken together, the results show that mild maternal protein deprivation during lactation affects thymic homeostasis, enhancing leptin activity, which in turn protects thymocytes from apoptosis in the young progeny, with possible consequences upon the immune response of these animals in adult life.

Protein malnutrition promotes dysregulation of molecules involved in T cell migration in the thymus of mice infected with Leishmania infantum

“…Interestingly, the anti-apoptotic gene Bcl -2 was upregulated by the protein restricted diet at 14 dpi. This is in accordance with other malnourishment models where BCL-2 protein was overexpressed in thymocytes of protein deprived mice, thereby protecting them from apoptotic stimuli30. In fact, Bcl -2 is a molecule induced by CXCR4 signalling31 and we observed here that increased expression of Bcl -2 correlates with increased expression of Cxcr4 .…”

Hormonal control of T-cell development in health and disease

“…75 The db/db mouse line, which lacks the leptin receptor, develops type 2 diabetes mellitus and obesity. In our own research, we have shown that db/db mice also undergo a precocious thymic involution, with severe loss of thymocytes and accumulation of adipocytes within the organ.…”

“…78 Accordingly, intrathymic leptin mRNA is selectively increased in microenvironmental cells in the young rats from protein-deprived dams, which in turn protects thymocytes from apoptosis. 75 The function of both leptin and ghrelin support thymopoiesis. In addition to changing the TCR repertoire, both hormones partially reverse age-associated thymic involution, albeit by distinct mechanisms.…”

Leptin Inhibits the Apoptosis of Endometrial Carcinoma Cells Through Activation of the Nuclear Factor κB–inducing Kinase/IκB Kinase Pathway

“…Inhibitor of JB (IJB) retains NF-JB dimers in the cytoplasm, 12 and its degradation through IKK phosphorylation subsequently releases NF-JB dimers into the nucleus where they regulate the transcription of diverse genes, including cytokines, cell adhesion molecules, growth factors, and proapoptotic and antiapoptotic proteins. 12 Leptin binding to Ob-R is reported to inhibit cell apoptosis, 13 but its contributory role in the molecular mechanisms of cancer is yet to be elucidated.…”