Hypoxia Inhibits Leptin Production by Cultured Rat Adipocytes
Article first published online: 6 SEP 2012
2002 North American Association for the Study of Obesity (NAASO)
Volume 10, Issue 2, page 128, February 2002
How to Cite
Yasumasu, T., Takahara, K. and Nakashima, Y. (2002), Hypoxia Inhibits Leptin Production by Cultured Rat Adipocytes. Obesity Research, 10: 128. doi: 10.1038/oby.2002.20
- Issue published online: 6 SEP 2012
- Article first published online: 6 SEP 2012
Leptin is a key mediator in the neuroendocrine regulation of energy homeostasis and appetite. An in vivo study that raised leptin concentrations at high altitudes associated with loss of appetite (1) led us to speculate that low oxygen (hypoxia) might be the key stimulus for leptin secretion from adipocytes. Because leptin has angiogenic effects as well as vascular endothelial growth factor (2) and leptin secretion from non-adipocytes, human trophoblastic cells (3) are increased in culture under hypoxic conditions (4).
We investigated the effect of hypoxia on leptin production and on lipogenic activity and glucose uptake in primary cultures of rat adipocytes. To determine the effects of hypoxia on leptin secretion, adipocytes were exposed to 10% or 20% O2 atmosphere for 48 hours and the levels of leptin released from adipocytes were determined by radioimmunoassay. Hypoxia suppressed the secretion of leptin by ∼50% compared with adipocytes exposed to normoxia (3.8 ± 0.8 vs. 8.4 ± 1.4 ng/mL per milligram protein, mean ± SEM, five experiments, p < 0.05). To examine the effects of hypoxia on lipogenesis and glucose uptake, adipocytes were exposed to either 10% or 20% O2 atmosphere for 48 hours and glycero-3-phosphate dehydrogenase activity of lipogenic enzyme, triglyceride content, and glucose uptake were measured spectrophotometrically, by H2O2 colorimetric assay and enzymatically, respectively. Hypoxia resulted in a significant reduction of glycero-3-phosphate dehydrogenase activity (10% O2: 1.4 ± 0.5; 20% O2: 4.6 ± 0.9 U/mg protein, five experiments, p < 0.05) and accumulation of triglyceride (10% O2: 39.0 ± 10.7; 20% O2: 106.4 ± 22.1 mg/dL per milligram protein, five experiments, p < 0.05). However, hypoxia did not significantly affect the amount of glucose uptake by adipocytes (10% O2: 392.7 ± 69.8; 20% O2: 655.6 ± 128.9 mg/dL per milligram protein, five experiments, p = 0.11).
Our results show that hypoxia does not stimulate leptin secretion from adipocytes; it rather decreased leptin secretion from adipocytes associated with a concomitant reduction in lipogenic response of adipocytes in vitro. These results indicate that the high leptin levels circulating in individuals with anorexia at high altitude are not simply attributable to the direct effect of hypoxia on secretion of leptin in adipocytes. The comprehensible mechanisms are at least three factors: increased production of leptin in adipocytes indirectly stimulated by the other hormones or cytokines induced by hypoxia; delayed clearance of leptin from circulation due to binding its soluble receptor, which increases its half-life; and changed tissue distribution of leptin/leptin shift to circulation from other tissues (5, 6). But according to our results, the first factor is improbable unless the hormones or cytokines, which have a potent effect to stimulate the leptin release from adipocytes to overcome the inhibitory effect of hypoxia on the leptin release, are up-regulated by hypoxia.
Our results also indicated that glucose uptake by adipocytes under hypoxia tended to be lower than under normoxia, similar to leptin release from adipocytes, but this difference in glucose metabolism under these two conditions was not statistically significant. In contrast, the lipogenic activity of adipocytes was significantly reduced concomitant with the low level of leptin secretion by rat adipocytes cultured under hypoxic conditions. Even under hypoxic conditions, leptin levels in the medium can be a more sensitive marker of lipid accumulation than glucose metabolism in adipocytes.