Peroxisome proliferator-activated receptor-α (PPARα), PPARδ and PPARγ are transcription factors that regulate gene expression following ligand activation. PPARα increases cellular fatty acid uptake, esterification and trafficking and regulates lipoprotein metabolism genes. PPARδ stimulates lipid and glucose utilization by increasing mitochondrial function and fatty acid desaturation pathways. By contrast, PPARγ promotes fatty acid uptake, triglyceride formation and storage in lipid droplets, thereby improving insulin sensitivity and glucose metabolism. PPARs also exert anti-atherogenic and anti-inflammatory effects on the vascular wall and immune cells. Clinically, PPARγ activation by glitazones and PPARα activation by fibrates improve insulin resistance and dyslipidaemia, respectively. PPARs are also physiological master switches in the heart, steering cardiac energy metabolism in cardiomyocytes, thereby affecting pathological heart failure and diabetic cardiomyopathy. Novel PPAR agonists in clinical development are providing new opportunities in the management of metabolic and cardiovascular diseases.

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the gut microbiota participates in the control of energy homeostasis partly through fermentation of dietary fibers hence producing short-chain fatty acids (SCFAs), which in turn promote the secretion of the incretin Glucagon-Like Peptide-1 (GLP-1) by binding to the SCFA receptors FFAR2 and FFAR3 on enteroendocrine L-cells. We have previously shown that activation of the nuclear farnesoid X Receptor (FXR) decreases the L-cell response to glucose. Here, we investigated whether FXR also regulates the SCFA-induced GLP-1 secretion. GLP-1 secretion in response to SCFAs was evaluated ex vivo in murine colonic biopsies and in colonoids of wild-type (WT) and FXR knockout (KO) mice, in vitro in GLUtag and NCI-H716 L-cells activated with the synthetic FXR agonist GW4064 and in vivo in Wt and fXR Ko mice after prebiotic supplementation. SCFA-induced GLP-1 secretion was blunted in colonic biopsies from GW4064-treated mice and enhanced in FXR KO colonoids. In vitro FXR activation inhibited GLP-1 secretion in response to SCFAs and FFAR2 synthetic ligands, mainly by decreasing FFAR2 expression and downstream Gαq-signaling. FXR KO mice displayed elevated colonic FFAR2 mRNA levels and increased plasma GLP-1 levels upon local supply of SCFAs with prebiotic supplementation. Our results demonstrate that FXR activation decreases L-cell GLP-1 secretion in response to inulin-derived SCFA by reducing FFAR2 expression and signaling. Inactivation of intestinal FXR using bile acid sequestrants or synthetic antagonists in combination with prebiotic supplementation may be a promising therapeutic approach to boost the incretin axis in type 2 diabetes.

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Analysis of heart rate variability (HRV) is a recognized tool in the assessment of autonomic nervous system (ANS) activity. Indeed, both time and spectral analysis techniques enable us to obtain indexes that are related to the way the ANS regulates the heart rate. However, these techniques are limited in terms of the lack of thresholds of the numerical indexes, which is primarily due to high inter-subject variability. We proposed a new fetal HRV analysis method related to the parasympathetic activity of the ANS. The aim of this study was to evaluate the performance of our method compared to commonly used HRV analysis, with regard to i) the ability to detect changes in ANS activity and ii) inter-subject variability. This study was performed in seven sheep fetuses. In order to evaluate the sensitivity and specificity of our index in evaluating parasympathetic activity, we directly administered 2.5 mg intravenous atropine, to inhibit parasympathetic tone, and 5 mg propranolol to block sympathetic activity. Our index, as well as time analysis (root mean square of the successive differences; RMSSD) and spectral analysis (high frequency (HF) and low frequency (LF) spectral components obtained via fast Fourier transform), were measured before and after injection. Inter-subject variability was estimated by the coefficient of variance (%CV). In order to evaluate the ability of HRV parameters to detect fetal parasympathetic decrease, we also estimated the effect size for each HRV parameter before and after injections. As expected, our index, the HF spectral component, and the RMSSD were reduced after the atropine injection. Moreover, our index presented a higher effect size. The %CV was far lower for our index than for RMSSD, HF, and LF. Although LF decreased after propranolol administration, fetal stress index, RMSSD, and HF were not significantly different, confirming the fact that those indexes are specific to the parasympathetic nervous system. In conclusion, our method appeared to be effective in detecting parasympathetic inhibition. Moreover, inter-subject variability was much lower, and effect size higher, with our method compared to other HRV analysis methods.

ObjectiveAccording to the Developmental Origin of Health and Disease (DOHaD) concept, maternal obesity and accelerated growth in neonates predispose offspring to white adipose tissue (WAT) accumulation. In rodents, adipogenesis mainly develops during lactation. The mechanisms underlying the phenomenon known as developmental programming remain elusive. We previously reported that adult rat offspring from high-fat diet-fed dams (called HF) exhibited hypertrophic adipocyte, hyperleptinemia and increased leptin mRNA levels in a depot-specific manner. We hypothesized that leptin upregulation occurs via epigenetic malprogramming, which takes place early during development of WAT.MethodsAs a first step, we identified in silico two potential enhancers located upstream and downstream of the leptin transcription start site that exhibit strong dynamic epigenomic remodeling during adipocyte differentiation. We then focused on epigenetic modifications (methylation, hydroxymethylation, and histone modifications) of the promoter and the two potential enhancers regulating leptin gene expression in perirenal (pWAT) and inguinal (iWAT) fat pads of HF offspring during lactation (postnatal days 12 (PND12) and 21 (PND21)) and in adulthood.ResultsPND12 is an active period for epigenomic remodeling in both deposits especially in the upstream enhancer, consistent with leptin gene induction during adipogenesis. Unlike iWAT, some of these epigenetic marks were still observable in pWAT of weaned HF offspring. Retained marks were only visible in pWAT of 9-month-old HF rats that showed a persistent “expandable” phenotype.ConclusionsConsistent with the DOHaD hypothesis, persistent epigenetic remodeling occurs at regulatory regions especially within intergenic sequences, linked to higher leptin gene expression in adult HF offspring in a depot-specific manner.

The adequate control of glucose homeostasis during both gestation and early postnatal life is crucial for the development of the fetoplacental unit and adaptive physiological responses at birth. Growing evidences indicate that apelin and its receptor, APJ, which are expressed across a wide range of tissues, exert important roles in glucose homeostasis in adults. However, little is known about the function of the apelinergic system during gestation. In this study, we evaluated the activity of this system in rats, the role of apelin in fetal and neonatal glucose homeostasis, and its modulation by maternal food restriction. We found that 1) the apelinergic system was expressed at the fetoplacental interface and in numerous fetal tissues, 2) ex vivo, the placenta released high amounts of apelin in late gestation, 3) intravenous apelin injection in mothers increased the transplacental transport of glucose, and 4) intraperitoneal apelin administration in neonates increased glucose uptake in lung and muscle. Maternal food restriction drastically reduced apelinemia in both mothers and growth-restricted fetuses and altered the expression of the apelinergic system at the fetoplacental interface. Together, our data demonstrate that apelin controls fetal and neonatal glucose homeostasis and is altered by fetal growth restriction induced by maternal undernutrition.

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