Hypoxia Inhibits Leptin Production by Cultured Rat Adipocytes

Abstract

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% O 2 atmosphere for 48 hours and the levels of leptin released from adipocytes were determined by radioimmunoassay. Hypoxia suppressed the secretion of leptin by ϳ50% compared with adipocytes exposed to normoxia (3.8 Ϯ 0.8 vs. 8.4 Ϯ 1.4 ng/mL per milligram protein, mean Ϯ SEM, five experiments, p Ͻ 0.05). To examine the effects of hypoxia on lipogenesis and glucose uptake, adipocytes were exposed to either 10% or 20% O 2 atmosphere for 48 hours and glycero-3-phosphate dehydrogenase activity of lipogenic enzyme, triglyceride content, and glucose uptake were measured spectrophotometrically, by H 2 O 2 colorimetric assay and enzymatically, respectively. Hypoxia resulted in a significant reduction of glycero-3-phosphate dehydrogenase activity (10% O 2 : 1.4 Ϯ 0.5; 20% O 2 : 4.6 Ϯ 0.9 U/mg protein, five experiments, p Ͻ 0.05) and accumulation of triglyceride (10% O 2 : 39.0 Ϯ 10.7; 20% O 2 : 106.4 Ϯ 22.1 mg/dL per milligram protein, five experiments, p Ͻ 0.05). However, hypoxia did not significantly affect the amount of glucose uptake by adipocytes (10% O 2 : 392.7 Ϯ 69.8; 20% O 2 : 655.6 Ϯ 128.9 mg/dL per milligram protein, five experiments, p ϭ 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 upregulated by hypoxia.Our results also indicated that glucose uptake by adipocy...

Ghrelin and leptin levels of sojourners and acclimatized lowlanders at high altitude

“…Yasumasu et al (2002) have reported about 50% decreased leptin secretion in case of in vitro cultured adipocytes exposed to low oxygen concentration. There are two studies on human subjects in which decrease in leptin levels are reported at HA (Vats et al 2004, Zaccaria et al 2004).…”

Effect of chronic hypoxia on leptin, insulin, adiponectin, and ghrelin

“…A higher leptin per body weight content was observed in our hypoxic group at 8 weeks, suggesting that, most probably, the origin of the high leptin is not only from the adipocytes. Although clinically leptin serves as a useful marker of adiposity, reflecting the total lipid content in humans [33], Yasumasu et al [34] showed that hypoxia does not stimulate leptin secretion from adipocytes; leptin secretion during this condition comes from non-adipocytes.…”

Inhibition of Lipolysis Ameliorates Diabetic Phenotype in a Mouse Model of Obstructive Sleep Apnea

“…Leptin was previously shown to stimulate lipolysis and oppose the antilipolytic action of adenosine (48). Furthermore, sustained hypoxia and IH increased plasma leptin levels and gene expression (6,49), even though contradictory findings have also been reported (50,51). However, it seems unlikely that leptin is the causal mechanism linking IH exposure with increased lipolysis and whole-body metabolic impairments; this is because plasma leptin levels, as well as leptin and leptin receptor gene expression, in adipose tissue remained unaffected in our study, whereas lipolysis was strongly augmented.…”

“…Sensitivity of the lipolytic pathway to isoprenaline stimulation, assessed as half-maximal effective concentration (EC 50[iso] ), was unaffected by either IH exposure or acipimox treatment (EC 50[iso] = 1.1 6 0.4, 0.6 6 0.4, 1.3 6 0.5, and 1.5 6 0.5 nmol/L for control, IHexposed, acipimox-treated control, and acipimox-treated IH-exposed groups, respectively; two-way ANOVA, P . 0.05).…”

“…Blood glucose was determined using a glucometer (Accu-Check Aviva; Roche, Indianapolis, IN) at 0, 10, 20, 30, 60, 90, and 120 minutes after intraperitoneal injection of 1 g/kg glucose (n = 10 per group) or at 0, 10,20,30,40,50,60,90, and 120 minutes after intraperitoneal injection of 0.5 IU/kg insulin (ITT; n = 10 per group).…”