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  • Leptin synthesized in adipocytes is a regulator of fat metab

    2019-05-16

    Leptin, synthesized in adipocytes, is a regulator of fat metabolism and reproduction [7]. The levels of leptin correlate with body fat mass and show a wide variation in individuals. In the bone marrow microenvironment, the leptin secreting adipocytes occupy a significant part [8]. Leptin stimulates hematopoietic stem Epinastine HCl in vitro, regulates differentiation within the myeloid and erythroid cell lineage, and is involved in the growth of hematopoietic malignancies [9]. An increase of leptin in IM treated CML adult patients in molecular remission has recently been observed [10]. Here we evaluated the serum leptin concentrations in young CML patients during IM assumption. Our data indicate that, regardless of BMI and percentage of fat mass (FM), long term IM treatment may induce modification of leptin secretion.
    Subjects and methods
    Results Table 1 shows the demographic, anthropometric, serum leptin and FM characteristics of the patients during follow-up. Leptin concentrations were outside the reference values in all patients. In particular, leptin was higher than normal in 8 patients and lower in one (case 5). All the subjects were within the normal BMI range (18.5–24.26kg/m2). The FM% was higher than normal in 3 cases. However, on the whole, no apparent relationship was found between the FM% and leptin levels. The patient who interrupted IM after 3.4 years of assumption (case 2) recovered the leptin normal value after drug discontinuation. The three patients who started the IM intermittent treatment (cases 1, 5, and 6), showed a trend toward an improvement of leptin values.
    Discussion Among the patients under IM in our series, 8 out of 9 had levels of leptin higher than the highest reference range while in one it was lower. In agreement with the reported lack of association between anthropometric measures, including BMI, and CML, [11] all our patients had a normal BMI, indicating that the variation of leptin was not ascribable to an excess of body weight. However, being BMI an inaccurate measure of fatness, we measured the FM% by DEXA. 3 subjects had a FM% higher than normal. In these cases, we cannot rule out an influence of FM excess on leptin values. In the remaining patients, the FM% was within the normal range, suggesting that the modification of leptin may be associated with IM use. As a matter of fact, the highest leptin concentration was measured in a patient with FM% in the lower normal limit. These results are in line with previous findings [10] showing that, under IM, all CML patients in molecular remission had a significant increase in leptin compared to baseline. A possible causal relationship between IM intake and leptin modification is further reinforced by the results obtained here after IM withdrawal. Infact, one patient who stopped IM and underwent SCT, recovered the leptin normal value. Furthermore, three patients showed a trend toward a normalization of leptin when scheduled to intermittent IM therapy. An interaction between IM and leptin is made plausible by the sharing of some intracellular signaling pathways and by the interplay with common hematopoietic growth factors. Noteworthy, IM modulates the activity of MEK/MAPK, STAT and other intracellular signals [12] and leptin regulates, and is reciprocally regulated, by the same pathways[13]. Moreover, previous clinical data showed that IM may cause long-term endocrine and metabolic side-effects [1–6]. The receptor for leptin is expressed in hematopoietic stem/progenitor cells. In bone marrow, leptin is secreted from local adipocytes, which occupy most of the marrow cavity in humans, and stimulates myeloid and erythroid development. Therefore, leptin and leptin receptors might play an important role in the control of the expansion and differentiation of primitive hematopoietic cells through paracrine interaction in the bone marrow [8,14,15]. The fat cell content of the bone marrow may thus reflect the requirement for leptin in hematopoietic development. Leptin receptors are also expressed in leukemic cells from patients affected by CML, acute myeloblastic leukemia and acute lymphoblastic leukemia. Particularly, in CML higher expression of leptin receptors has been observed during blast crisis than in the chronic phase [16]. Moreover, leptin alone and in combination with other cytokines, shows anti-apoptotic and proliferative effects on leukemia cells, suggesting that leptin may play an active role in the pathophysiology of leukemia [16]. All together, these data reinforce the view that IM may influence either directly or indirectly leptin.