Olivier Douay

High Birth Weight and Early Postnatal Weight Gain Protect Obese Children and Adolescents From Truncal Adiposity and Insulin Resistance Metabolically healthy but obese subjects

OBJECTIVE—Low birth weight (LBW), no early catch-up weight, and subsequent fat accumulation have been associated with increased risks of insulin resistance from childhood onward and later cardiovascular disease. We sought to clarify the effects of high birth weight (HBW) and postnatal weight gain on insulin resistance. RESEARCH DESIGN AND METHODS—A total of 117 obese children aged 10.4 ± 2.4 years were divided into three groups according to fetal growth after exclusion of maternal diabetes. They were comparable for age, sex, puberty, and percent body fat. Customized French birth weight standards, adjusted for maternal characteristics and gestation number, identified subjects with true altered fetal growth: 32 had increased fetal growth according to customized standards (HBWcust), 52 were eutrophic, and 33 had restricted fetal growth according to customized standards (LBWcust). Fat distribution by dual-energy X-ray absorptiometry, insulin sensitivity indexes from an oral glucose tolerance test (OGTT), and leptin, adiponectin, and visfatin levels were compared between groups. RESULTS—The HBWcust subjects had a higher adiponectin level, higher whole-body insulin sensitivity index (WBISI), and lower hepatic insulin resistance index, lower insulin and free fatty acid concentrations during OGTT, and lower trunk fat percent than eutrophic (P < 0.05) and LBWcust subjects (P < 0.05). Besides birth weight, weight gain between 0 and 2 years was a positive predictor (P < 0.05) of WBISI, whereas weight gain after 4 years was a negative predictor (P < 0.05). CONCLUSIONS—HBW and early weight gain may program insulin sensitivity and adipose tissue metabolism and contribute to so-called metabolically healthy obesity.

Dexamethasone treatment specifically increases the basal proton conductance of rat liver mitochondria

We investigated the role that mitochondrial proton leak may play in the glucocorticoid‐induced hypermetabolic state. Sprague–Dawley rats were injected with dexamethasone over a period of 5 days. Liver mitochondria and gastrocnemius subsarcolemmal and intermyofibrillar mitochondria were isolated from dexamethasone‐treated, pair‐fed and control rats. Respiration and membrane potential were measured simultaneously using electrodes sensitive to oxygen and to the potential‐dependent probe triphenylmethylphosphonium, respectively. Five days of dexamethasone injection resulted in a marked increase in the basal proton conductance of liver mitochondria, but not in the muscle mitochondrial populations. This effect would have a modest impact on energy expenditure in rats.

Mitochondrial bioenergetic background confers a survival advantage to HepG2 cells in response to chemotherapy

Cancer cells mainly rely on glycolysis for energetic needs, and mitochondrial ATP production is almost inactive. However, cancer cells require the integrity of mitochondrial functions for their survival, such as the maintenance of the internal membrane potential gradient (ΔΨm). It thus may be predicted that ΔΨm regeneration should depend on cellular capability to produce sufficient ATP by upregulating glycolysis or recruiting oxidative phosphorylation (OXPHOS). To investigate this hypothesis, we compared the response to an anticancer agent chloroethylnitrosourea (CENU) of two transformed cell lines: HepG2 (hepatocarcinoma) with a partially differentiated phenotype and 143B (osteosarcoma) with an undifferentiated one. These cells types differ by their mitochondrial OXPHOS background; the most severely impaired being that of 143B cells. Treatment effects were tested on cell proliferation, O2 consumption/ATP production coupling, ΔΨm maintenance, and global metabolite profiling by NMR spectroscopy. Our results showed an OXPHOS uncoupling and a lowered ΔΨm, leading to an increased energy request to regenerate ΔΨm in both models. However, energy request could not be met by undifferentiated cells 143B, which ATP content decreased after 48 h leading to cell death, while partially differentiated cells (HepG2) could activate their oxidative metabolism and escape chemotherapy. We propose that mitochondrial OXPHOS background confers a survival advantage to more differentiated cells in response to chemotherapy. This suggests that the mitochondrial bioenergetic background of tumors should be considered for anticancer treatment personalization.

Maternal and Cord Blood Ghrelin in the Pregnancies of Smoking Mothers: Possible Markers of Nutrient Availability for the Fetus

Aims: To investigate the role of ghrelin in maternal and fetal metabolism, we determined its value in maternal smoking, a specific cause of reduced placenta function and fetal growth. Methods: In 85 normal term pregnancies, 42 in smoking and 43 in non-smoking mothers, we measured ghrelin in the maternal blood at the onset of labor and in the cord blood of their 85 singletons immediately after birth. We determined the relationships between ghrelin and placental GH (PGH), pituitary GH (pitGH), and IGF-I. Results: The newborns of smoking mothers weighed 0.24 kg less (p < 0.05) than those of non-smoking mothers. Cord blood ghrelin was 71% higher and PGH and cord blood IGF-I were 34% and 32% lower, respectively, in the pregnancies of smoking compared with non-smoking mothers (p < 0.05). Cord blood ghrelin was unrelated to pitGH and cord blood IGF-I. Maternal ghrelin was unchanged in smoking mothers, increased with maternal fasting duration (r = 0.26, p < 0.05), showed no correlation with PGH and negative correlation with cord blood IGF-I (r = –0.42, p < 0.01). Conclusion: The decrease in placental function and fetal growth in smoking mothers is associated with an increase in cord blood ghrelin, and no change in maternal ghrelin. Maternal ghrelin concentration increases with fasting, and is negatively correlated with cord blood IGF-I: it may signal a reduction in the level of nutrients available for placental transfer. No correlation supports a role for ghrelin in PGH or pitGH secretion.