Fecal g. Streptococcus and g. Eubacterium_coprostanoligenes_group combined with sphingosine to modulate the serum dyslipidemia in high-fat diet mice.

Dyslipidemia and diabetes mellitus: Role of lipoprotein species and interrelated pathways of lipid metabolism in diabetes mellitus.

AIMS SAR247799 is a G-protein-biased sphingosine-1 phosphate receptor-1 (S1P1 ) agonist designed to activate endothelial S1P1 and provide endothelial-protective properties, while limiting S1P1 desensitization and consequent lymphocyte-count reduction associated with higher doses. The aim was to show whether S1P1 activation can promote endothelial effects in patients and, if so, select SAR247799 doses for further clinical investigation. METHODS Type-2 diabetes patients, enriched for endothelial dysfunction (flow-mediated dilation, FMD <7%; n = 54), were randomized, in 2 sequential cohorts, to 28-day once-daily treatment with SAR247799 (1 or 5 mg in ascending cohorts), placebo or 50 mg sildenafil (positive control) in a 5:2:2 ratio per cohort. Endothelial function was assessed by brachial artery FMD. Renal function, biomarkers and lymphocytes were measured following 5-week SAR247799 treatment (3 doses) to Zucker diabetic fatty rats and the data used to select the doses for human testing. RESULTS The maximum FMD change from baseline vs placebo for all treatments was reached on day 35; mean differences vs placebo were 0.60% (95% confidence interval [CI] -0.34 to 1.53%; P = .203) for 1 mg SAR247799, 1.07% (95% CI 0.13 to 2.01%; P = .026) for 5 mg SAR247799 and 0.88% (95% CI -0.15 to 1.91%; P = .093) for 50 mg sildenafil. Both doses of SAR247799 were well tolerated, did not affect blood pressure, and were associated with minimal-to-no lymphocyte reduction and small-to-moderate heart rate decrease. CONCLUSION These data provide the first human evidence suggesting endothelial-protective properties of S1P1 activation, with SAR247799 being as effective as the clinical benchmark, sildenafil. Further clinical testing of SAR247799, at sub-lymphocyte-reducing doses (≤5 mg), is warranted in vascular diseases associated with endothelial dysfunction.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/bcp.14632

Endothelial-protective effects of a G-protein-biased sphingosine-1 phosphate receptor-1 agonist, SAR247799, in type-2 diabetes rats and a randomized placebo-controlled patient trial.

The contribution of metabolomic factors to the association of healthy lifestyle with type 2 diabetes risk is unknown. We assessed the association of a composite measure of lifestyle with plasma metabolite profiles and incident type 2 diabetes, and whether relevant metabolites can explain the prospective association between healthy lifestyle and incident type 2 diabetes.A Healthy Lifestyle Score (HLS) (5-point scale including diet, physical activity, smoking status, alcohol consumption and BMI) was estimated in 1016 Hortega Study participants, who had targeted plasma metabolomic determinations at baseline examination in 2001-2003, and were followed-up to 2015 to ascertain incident type 2 diabetes.The HLS was cross-sectionally associated with 32 (out of 49) plasma metabolites (2.5% false discovery rate). In the subset of 830 participants without prevalent type 2 diabetes, the rate ratio (RR) and rate difference (RD) of incident type 2 diabetes (n cases = 51) per one-point increase in HLS was, respectively, 0.69 (95% CI, 0.51, 0.93), and - 8.23 (95% CI, - 16.34, - 0.13)/10,000 person-years. In single-metabolite models, most of the HLS-related metabolites were prospectively associated with incident type 2 diabetes. In probit Bayesian Kernel Machine Regression, these prospective associations were mostly driven by medium HDL particle concentration and phenylpropionate, followed by small LDL particle concentration, which jointly accounted for ~ 50% of the HLS-related decrease in incident type 2 diabetes.The HLS showed a strong inverse association with incident type 2 diabetes, which was largely explained by plasma metabolites measured years before the clinical diagnosis. 

/pdf/healthy-lifestyle-metabolomics-and-incident-type-2-diabetes-1lnozud0.pdf

Healthy lifestyle, metabolomics and incident type 2 diabetes in a population-based cohort from Spain

Over the last two decades, it has become evident that estrogens preserve the integrity of energy homeostasis at central and peripheral levels. Estrogen deficiency, such as that caused by menopause or ovariectomy, has been linked to obesity and metabolic disorders that can be resolved or reversed by estrogen therapy. 17β-estradiol (E2), as the major estrogen in the body, primarily regulates energy balance via estrogen receptor alpha (ERα). At the central level, E2 plays its catabolic role predominantly by interacting with hypothalamic arcuate neurons and sending signals via ventromedial hypothalamic neurons to control brown adipose tissue-mediated thermogenesis. In peripheral tissues, several organs, particularly the liver, brown and white adipose tissues, and pancreatic β cells, have attracted considerable attention. In this review, we focused on the current state of knowledge of “central and peripheral” estrogen signaling in regulating energy balance via “nuclear and extranuclear pathways” in both “females and males". In this context, according to an exploratory approach, we tried to determine the principal estrogen receptor subtype/isoform in each section, the importance of extranuclear-initiated estrogen signaling on metabolic functions, and how sex differences related to ER signaling affect the prevalence of some of the metabolic disorders. Moreover, we discussed the data from a third viewpoint, understanding the clinical significance of estrogen signaling in abnormal metabolic conditions such as obesity or being on a high-fat diet. Collectively, this review exposes novel and important research gaps in our current understanding of dysmetabolic diseases and can facilitate finding more effective treatment options for these disorders. 

Estrogen as a key regulator of energy homeostasis and metabolic health.

Obesity is a pathophysiological condition where excess free fatty acids (FFA) target and promote the dysfunctioning of insulin sensitive tissues and of pancreatic β cells. This leads to the dysregulation of glucose homeostasis, which culminates in the onset of type 2 diabetes (T2D). FFA, which accumulate in these tissues, are metabolized as lipid derivatives such as ceramide, and the ectopic accumulation of the latter has been shown to lead to lipotoxicity. Ceramide is an active lipid that inhibits the insulin signaling pathway as well as inducing pancreatic β cell death. In mammals, ceramide is a key lipid intermediate for sphingolipid metabolism as is sphingosine-1-phosphate (S1P). S1P levels have also been associated with the development of obesity and T2D. In this review, the current knowledge on S1P metabolism in regulating insulin signaling in pancreatic β cell fate and in the regulation of feeding by the hypothalamus in the context of obesity and T2D is summarized. It demonstrates that S1P can display opposite effects on insulin sensitive tissues and pancreatic β cells, which depends on its origin or its degradation pathway.

/pdf/sphingosine-1-phosphate-metabolism-in-the-regulation-of-16234am1i1.pdf

Sphingosine-1-Phosphate Metabolism in the Regulation of Obesity/Type 2 Diabetes.

Oestrogens regulate body weight through their action on hypothalamus to modulate food intake and energy expenditure. Hypothalamic de novo ceramide synthesis plays a central role on obesity induced by oestrogen deficiency. Depletion in oestrogens is also known to be associated with glucose intolerance, which favours type 2 diabetes (T2D). However, the implication of hypothalamic ceramide in the regulation of glucose homeostasis by oestrogen is unknown. Here, we studied glucose homeostasis and insulin secretion in ovariectomized (OVX) female rats. OVX induces body weight gain associated with a hypothalamic inflammation and impaired glucose homeostasis. Genetic blockade of ceramide synthesis in the ventromedial nucleus of the hypothalamus (VMH) reverses hypothalamic inflammation and partly restored glucose tolerance induced by OVX. Furthermore, glucose-stimulated insulin secretion (GSIS) is increased in OVX rats due to a raise of insulin secretion second phase, a characteristic of early stage of T2D. In contrast, GSIS from isolated islets of OVX rats is totally blunted. Inhibition of ceramide synthesis in the VMH restores GSIS from isolated OVX islets and represses the second phase of insulin secretion. Stimulation of oestrogen receptor α (ERα) by oestradiol (E2) down-regulates ceramide synthesis in hypothalamic neuronal GT1-7 cells but no in microglial SIM-A9 cells. In contrast, genetic inactivation of ERα in VMH upregulates ceramide synthesis. These results indicate that hypothalamic neuronal de novo ceramide synthesis triggers the OVX-dependent impairment of glucose homeostasis which is partly mediated by a dysregulation of GSIS.

Ovarian insufficiency impairs glucose-stimulated insulin secretion through activation of hypothalamic de novo ceramide synthesis.

Pour la troisieme annee, dans le cadre du module d’enseignement « Physiopathologie de la signalisation » propose par l’universite Paris-sud, les etudiants du Master « Biologie Sante » de l’universite Paris-Saclay se sont confrontes a l’ecriture scientifique. Ils ont selectionne 8 articles scientifiques recents dans le domaine de la signalisation cellulaire presentant des resultats originaux, via des approches experimentales variees, sur des themes allant des relations hote-pathogene aux innovations therapeutiques, en passant par la signalisation hepatique et le metabolisme. Apres un travail preparatoire realise avec l’equipe pedagogique, les etudiants, organises en binomes, ont ensuite redige, guides par des chercheurs, une Nouvelle soulignant les resultats majeurs et l’originalite de l’article etudie. Ils ont beaucoup apprecie cette initiation a l’ecriture d’articles scientifiques et, comme vous pourrez le lire, se sont investis dans ce travail avec enthousiasme ! Deux de ces Nouvelles sont publiees dans ce numero, les autres le seront dans les prochains numeros de m/s .

/pdf/les-proteines-fe-s-wbl-de-nouvelles-cibles-therapeutiques-4oubjqmh7e.pdf

Jeanne Guitton

Papers

Sphingosine-1-Phosphate Metabolism in the Regulation of Obesity/Type 2 Diabetes.

Ovarian insufficiency impairs glucose-stimulated insulin secretion through activation of hypothalamic de novo ceramide synthesis.

Les protéines Fe-S Wbl, de nouvelles cibles thérapeutiques pour lutter contre la tuberculose