Leptin and its role in endometriosis

We’ve heard about leptin and its role in weight gain/loss, but did you know leptin does more than that?

“Subsequent work has confirmed that leptin has a pleiotrophic role on the immune response and can rightly be considered, both structurally and functionally, as a proinflammatory cytokine (Lord, 2006, p. 151).” (Note: Pleiotrophic means one gene that influence many, so leptin can influence lots of different things.) Also, in a very small study, leptin was tied to greater fatigue in CFS patients: “Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology (Stringer et al., 2013, p.1).   

So, leptin can be proinflammatory and influence many different responses in the body (including energy/fatigue and immune response). The following studies demonstrate that leptin (similar to the effects of estrogen) can cause endometriosis lesions to proliferate (to get bigger and bulkier).

This study explores leptin’s role in endometriosis and its effect on inflammation and angiogenesis (creating new blood vessels). It also found that leptin had a different effect on cells in the uterus versus endometriosis lesions (highlighting that endometriosis cells have distinct differences from the lining of the uterus).

• Wu, M. H., Chuang, P. C., Chen, H. M., Lin, C. C., & Tsai, S. J. (2002). Increased leptin expression in endometriosis cells is associated with endometrial stromal cell proliferation and leptin gene up-regulation. Molecular human reproduction, 8(5), 456-464. Retrieved from https://academic.oup.com/molehr/article/8/5/456/1030708
  
  “Leptin has been reported to exert immunoregulatory, proinflammatory, mitogenic and angiogenic effects in several tissues (Gainsford et al., 1996; Wolf et al., 1999; Caprio et al., 2001). This makes it a potential candidate for contributing to the progress of endometriosis. A recent report even demonstrated that leptin levels in peritoneal fluid and serum of patients with pelvic endometriosis are increased (Matarese et al., 2000). However, the cellular origin and mechanism by which leptin modulates the formation of endometriosis is not clear. We herein present evidence showing that leptin and its receptor are differentially expressed in endometriosis and are involved in the proliferation of endometrial stromal cells….
  
  “…leptin stimulated a significant increase in eutopic as well as ectopic endometrial stromal cell proliferation. However, this mitogenic effect of leptin was somewhat different in eutopic endometrial stromal cells compared with ectopic endometriotic stromal cells. In eutopic endometrial stromal cells, leptin caused a greater extent of cell proliferation and at much lower doses (Figure 8A). In stromal cells obtained from ectopic endometriotic implants, only high doses of leptin (3 and 10 ng/ml) induced cell proliferation and the induction was less pronounced (Figure 8B)…. 
  
  “…we showed that both leptin transcripts and protein are highly expressed in ectopic endometriotic lesions. In eutopic endometrium, leptin was not detected in a half of the samples and only extremely low amounts of leptin were detected in the other half of the endometria. In concordance with our finding, contradictory reports have shown either positive or negative leptin expression in normal human endometrium (Alfer et al., 2000; Gonzalez et al., 2000a; Kitawaki et al., 2000). The reasons for differences in leptin transcript expression in eutopic endometrium are not known. Nevertheless, leptin was highly expressed in ectopic endometriotic lesions. The elevation of leptin in ectopic endometriosis was not due to differences in the stages of menstrual cycles or body mass as evidenced by marked increase of leptin in ectopic endometriotic tissues as compared to the eutopic endometrium collected from the same patients (n = 4). In addition, the mean BMI was not different between eutopic and endometriosis groups. Thus, elevated expression of leptin in ectopic endometriotic tissues may reflect the distinct biochemical nature of endometriotic lesions. Our result showing that leptin is markedly expressed in ectopic endometriotic lesions supports previous reports that the peritoneal fluid concentration of leptin was increased in women with endometriosis (Matarese et al., 2000; De Placido et al., 2001).…One of the examples is the acquisition of estrogen-producing ability in ectopic endometriotic implants (Noble et al., 1996; Bulun et al., 1999, 2000). Our recent data have also indicated that ectopic endometriotic cells of early endometriosis express high quantities of steroidogenic acute regulatory protein and produce high levels of progesterone (Tsai et al., 2001c). As a consequence, the ectopic endometriotic tissues become independent of the survival factors generated from gonads, and proliferate continuously throughout the cycle….In summary, differential expression of leptin and its receptor in eutopic and ectopic endometrium suggests that leptin may have a critical role in endometriosis development. Elevated leptin expression by endometriosis lesions appears to enhance the proliferation of ectopic endometriotic stromal cells. Our findings may open a new field of investigation into the actions of leptin in the pathogenesis of endometriosis and provide a reasonable rationale for developing a therapeutic regime for endometriosis by targeting leptin and its action.”

In the following study, the authors further investigate the role of leptin in endometriosis through its inflammatory and angiogenic properties:

• Nácul, A. P., Lecke, S. B., Edelweiss, M. I., Morsch, D. M., & Spritzer, P. M. (2013). Gene expression of leptin and long leptin receptor isoform in endometriosis: a case-control study. Obstetrics and gynecology international, 2013. Retrieved from http://www.hindawi.com/journals/ogi/2013/879618/ 

“It (Leptin) may also play a role in endometriosis through its inflammatory and angiogenic properties…. Moreover, the possibility of an association between PF leptin levels and severity of endometriosis is also controversial, with some studies suggesting a negative correlation [2, 6, 8] and others showing a positive correlation with more severe forms of peritoneal endometriosis [5, 7, 13, 15]….Conclusions: The present data suggest that serum leptin/BMI ratio is associated with the presence of endometriosis. Nevertheless, the clinical applicability of the leptin/BMI ratio for prediction of endometriosis still requires confirmation. Moreover, the increased expression of leptin and OB-RL in ectopic endometrium suggests a modulatory interaction between leptin and its active receptor and a role of leptin, an inflammatory and angiogenic cytokine, in the initiation or development of endometrial implants.” 

In this study, the authors elaborate on the increased leptin expression in endometriosis cells causing them to proliferate:

• Wu, M. H., Chuang, P. C., Chen, H. M., Lin, C. C., & Tsai, S. J. (2002). Increased leptin expression in endometriosis cells is associated with endometrial stromal cell proliferation and leptin gene up-regulation. Molecular human reproduction, 8(5), 456-464. Retrieved from https://pubmed.ncbi.nlm.nih.gov/11994543/ 

“Increased leptin expression in endometriosis cells is associated with endometrial stromal cell proliferation and leptin gene up-regulation. Abstract: Endometriosis is a polygenic disease with complex, multifactorial aetiologies affecting approximately 10% of women of reproductive age. Leptin is the product of the ob gene, which is related to reproductive function and immunological alteration. The angiogenic and mitogenic action of leptin may influence the formation of endometriosis. This study was aimed at determining whether leptin and leptin receptor expression differs in eutopic and ectopic endometria collected from laparoscopy and at investigating the pathophysiological role of leptin in the development of endometriosis. Leptin mRNA was undetectable in seven out of 14 eutopic endometria and only a minute amount was detected in the remaining samples. In contrast, there was a marked increase in leptin mRNA and protein expression in ectopic endometriotic lesions of patients with endometriosis (P < 0.05). Receptors for leptin were immunologically stained in eutopic endometrium as well as in ectopic endometriotic implants. However, the levels of mRNA for the long and total forms of leptin receptors were suppressed in association with the severity of endometriosis (P < 0.05). Administration of leptin stimulated its own mRNA expression in ectopic endometriotic stromal cells but decreased steady-state concentrations of mRNA encoding for leptin receptor (n = 6). In addition, leptin significantly enhanced both eutopic and ectopic endometrial stromal cell proliferation (P < 0.05). In conclusion, the differential distribution of mRNA for leptin and its receptor suggests an important autocrine and paracrine role for leptin in human endometriosis. The mitogenic and auto-augmentation effects of leptin may further contribute to the pathogenesis of endometriosis.”   

The following study discusses leptin stimulating the increased growth of endometriosis cells:

• Oh, H. K., Choi, Y. S., Yang, Y. I., Kim, J. H., Leung, P. C., & Choi, J. H. (2012). Leptin receptor is induced in endometriosis and leptin stimulates the growth of endometriotic epithelial cells through the JAK2/STAT3 and ERK pathways. MHR: Basic science of reproductive medicine, 19(3), 160-168. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/23184927

“Leptin receptor is induced in endometriosis and leptin stimulates the growth of endometriotic epithelial cells through the JAK2/STAT3 and ERK pathways. Leptin acts as a potential growth stimulator in several normal and neoplastic cells. Recent studies have shown the presence of increased levels of leptin in the peritoneal fluid of patients with endometriosis, implicating leptin in the pathogenesis of endometriosis. However, the specific function of leptin in the induction of mitogenesis in endometriosis is not known. This study investigated the expression of the leptin receptor (ObR) in endometrioma tissues and immortalized endometriotic cells, and the effect of leptin on cell growth. ObR expression was higher in endometriomas than in the normal endometrium, and it was detected in 74% of epithelial and 30% of stromal endometrioma tissues. In addition, human endometriotic epithelial cells (11Z and 12Z) showed a high level of ObR when compared with endometrial cells and endometriotic stromal cells (22B). Furthermore, leptin treatment stimulated the growth of 11Z and 12Z cells, but not that of 22B cells. Knockdown of the ObR in 11Z and 12Z cells impaired the ability of leptin to induce cell growth. Leptin induced the activation of Janus Kinases 2 (JAK2), signal transducers and activators of transcription 3 (STAT3) and extracellular signal-regulated kinase (ERK) in endometriotic epithelial cells. Moreover, pretreatment with the JAK2/STAT3 inhibitor AG490 and the ERK inhibitor PD98059 significantly inhibited leptin-induced cell growth. The present results show that the ObR is induced in endometriosis, and that leptin stimulates the growth of endometriotic epithelial cells through the JAK2/STAT3 and ERK pathways.”   

References

Lord, G. M. (2006). Leptin as a proinflammatory cytokine. In Obesity and the Kidney (Vol. 151, pp. 151-164). Karger Publishers. Retrieved from https://pubmed.ncbi.nlm.nih.gov/16929139/

Stringer, E. A., Baker, K. S., Carroll, I. R., Montoya, J. G., Chu, L., Maecker, H. T., & Younger, J. W. (2013). Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology. Journal of translational medicine, 11(1), 93. Retrieved from http://www.translational-medicine.com/content/11/1/93