👤 Alain Berdeaux

The melanocortin 4 receptor (MC4R) plays an important role in the regulation of appetite and energy expenditure in humans and rodents. Impairment of MC4R signaling causes severe obesity. MC4R mainly couples to the G-protein G Show less

Understanding the molecular mechanisms underlying the changes observed during aging is a prerequisite to design strategies to prevent age-related diseases. Aging is associated with metabolic changes, including alteration in the brain lipid metabolism. These alterations may contribute to the development of pathophysiological conditions. Modifications in the gut microbiota composition are also observed during aging. As communication axes exist between the gut microbiota and the brain and knowing that microbiota influences the host metabolism, we speculated on whether age-associated modifications in the gut microbiota could be involved in the lipid changes observed in aging brain. For that purpose, germ-free mice were colonized by the fecal microbiota of young or old donor mice. Lipid classes and fatty acid profiles were determined in the brain (cortex), plasma and liver by thin-layer chromatography on silica gel-coated quartz rods and gas chromatography. Gut colonization by microbiota of old mice resulted in a significant increase in total monounsaturated fatty acids (MUFA) and a significant decrease in the relative amounts of cholesterol and total polyunsaturated fatty acids (PUFA) in the cortex. Among the eight most represented fatty acids in the cortex, the relative abundances of five (C18:1n-9, C22:6n-3, C20:4n-6, C18:1n-7, and C20:1n-9) were significantly altered in mice inoculated with an aged microbiota. Liquid chromatography analyses revealed that the relative abundance of major species among phosphatidyl and plasmenylcholine (PC 16:0/18:1), phosphatidyl and plasmenylethanolamine (PE 18:0/22:6), lysophosphatidylethanolamine (LPE 22:6) and sphingomyelins (SM d18:1/18:0) were significantly altered in the cortex of mice colonized by the microbiota obtained from aged donors. Transplantation of microbiota from old mice also modified the lipid class and fatty acid content in the liver. Finally, we found that the expression of several genes involved in MUFA and PUFA synthesis ( Show less

Obesity is a major health issue that impedes the ability of preconditioning and postconditioning to protect the myocardium against infarction secondary to dysregulation of kinase signaling pathways. Moreover, exercise decreases cardiovascular mortality in obese patients but the mechanism remains to be established. Wild-type (WT) and obese (ob/ob) mice were assigned to sedentary conditions or regular treadmill exercise (1h/day, 5 days/7, 4 weeks, 4° slope, 10-30 cm/s) and underwent 30 min of coronary artery occlusion followed by 24h of reperfusion for infarct size measurement. In WT, exercise reduced infarct size by 60% and increased phosphorylation of kinases such as Akt, ERK 1/2, p70S6K, AMPK and GSK3β. Importantly, the level of corresponding phosphatases PTEN, MKP-3 and PP2C was decreased. Calcium concentration inducing the opening of mitochondrial permeability transition pore (mPTP) was increased by exercise. In ob/ob, regular exercise induced a robust cardioprotection by reducing infarct size (-67%), increasing kinase phosphorylation, decreasing phosphatase levels and improving the resistance to mPTP opening. However exercise did not modify hyperglycemia, hypercholesterolemia, hyperinsulinemia, fat mass and body weight in obese mice. In conclusion, regular exercise induces cardioprotection against myocardial infarction despite obesity and restores pro-survival signaling pathways with simultaneous increase in kinase phosphorylations, decreased levels of phosphatases and increased resistance of mPTP opening, independently from improvement in associated co-morbidities. Show less

Ischemic postconditioning (IPCD) significantly reduces infarct size in healthy animals and protects the human heart. Because obesity is a major risk factor of cardiovascular diseases, the effects of IPCD were investigated in 8- to 10-wk-old leptin-deficient obese (ob/ob) mice and compared with wild-type C57BL/6J (WT) mice. All animals underwent 30 min of coronary artery occlusion followed by 24 h of reperfusion associated or not with IPCD (6 cycles of 10-s occlusion, 10-s reperfusion). Additional mice were killed at 10 min of reperfusion for Western blotting. IPCD reduced infarct size by 58% in WT mice (33+/-1% vs. 14+/-3% for control and IPCD, respectively, P<0.05) but failed to induce cardioprotection in ob/ob mice (53+/-4% vs. 56+/-5% for control and IPCD, respectively). In WT mice, IPCD significantly increased the phosphorylation of Akt (+77%), ERK1/2 (+41%), and their common target p70S6K1 (+153% at Thr389 and +57% at Thr421/Ser424). In addition, the phosphorylated AMP-activated protein kinase (AMPK)-to-total AMPK ratio was also increased by IPCD in WT mice (+64%, P<0.05). This was accompanied by decreases in phosphatase and tensin homolog deleted on chromosome 10 (PTEN), MAP kinase phosphatase (MKP)-3, and protein phosphatase (PP)2C levels. In contrast, IPCD failed to increase the phosphorylation state of all these kinases in ob/ob mice, and the level of the three phosphatases was significantly increased. Thus, although IPCD reduces myocardial infarct size in healthy animals, its cardioprotective effect vanishes with obesity. The lack of enhanced phosphorylation by IPCD of Akt, ERK1/2, p70S6K1, and AMPK might partly explain the loss of cardioprotection in this experimental model of obese mice. Show less