Ecto-F_1-ATPase: A moonlighting protein complex and an unexpected apoA-I receptor

Mitochondrial ATP synthase has been recently detected at the surface of different cell types, where it is a high affinity receptor for apoA-I, the major protein component in high density lipoproteins (HDL). Cell surface ATP synthase (namely ecto-F1-ATPase) expression is related to different biological effects, such as regulation of HDL uptake by hepatocytes, endothelial cell proliferation or antitumor activity of Vγ9/Vδ2 T lymphocytes. This paper reviews the recently discovered functions and regulations of ecto-F1-ATPase. Particularly, the role of the F1-ATPase pathway(s) in HDL-cholesterol uptake and apoA-Imediated endothelial protection suggests its potential importance in reverse cholesterol transport and its regulation might represent a potential therapeutic target for HDL-related therapy for cardiovascular diseases. Therefore, it is timely for us to better understand how this ecto-enzyme and downstream pathways are regulated and to develop pharmacologic interventions.

High doses of catecholamines activate glucose transport in human adipocytes independently from adrenoceptor stimulation or vanadium addition

BACKGROUND When combined with vanadium salts,catecholamines strongly activate glucose uptake in rat and mouse adipocytes.AIM To test whether catecholamines activate glucose transport in human adipocytes.METHODS The uptake of 2-deoxyglucose(2-DG)was measured in adipocytes isolated from pieces of abdominal subcutaneous tissue removed from women undergoing reconstructive surgery.Pharmacological approaches with amine oxidase inhibitors,adrenoreceptor agonists and antioxidants were performed to unravel the mechanisms of action of noradrenaline or adrenaline(also named epinephrine).RESULTS In human adipocytes,45-min incubation with 100μmol/L adrenaline or noradrenaline activated 2-DG uptake up to more than one-third of the maximal response to insulin.This stimulation was not reproduced with millimolar doses of dopamine or serotonin and was not enhanced by addition of vanadate to the incubation medium.Among various natural amines and adrenergic agonists tested,no other molecule was more efficient than adrenaline and noradrenaline in stimulating 2-DG uptake.The effect of the catecholamines was not impaired by pargyline and semicarbazide,contrarily to that of benzylamine or methylamine,which are recognized substrates of semicarbazide-sensitive amine oxidase.Hydrogen peroxide at 1 mmol/L activated hexose uptake but not pyrocatechol or benzoquinone,and only the former was potentiated by vanadate.Catalase and the phosphoinositide 3-kinase inhibitor wortmannin inhibited adrenaline-induced activation of 2-DG uptake.CONCLUSION High doses of catecholamines exert insulin-like actions on glucose transport in human adipocytes.At submillimolar doses,vanadium did not enhance this catecholamine activation of glucose transport.Consequently,this dismantles our previous suggestion to combine the metal ion with catecholamines to improve the benefit/risk ratio of vanadium-based antidiabetic approaches.

Impact of <i>Celosia cristata</i>Extract on Adipogenesis of Native Human CD34⁺/CD31^-Cells

Background: The adipose tissue mainly consists of adipocytes but also contains non-adipose cells. Among them, progenitor cells represent a local pool of immature cells that, in vitro, can undergo various lineage differentiation processes. These cells are thought to contribute to normal homeostasis of the adipose tissue through adipogenesis but also to the growth of the adipose tissue under chronic energy overload. The aim of the present study is to evaluate in vitro the capacity of a Celosia cristata extract to impact the adipogenic potential of native human adipose tissue progenitor cells, i.e. commitment and differentiation towards adipogenic lineage. Methods: Native adipose tissue progenitor cells were isolated by immunoselection/depletion approaches from human subcutaneous adipose tissues. Two distinct cell culture conditions were used to assess the effect of Celosia cristata extract on commitment and differenciation of progenitor cells. Cells were cultured either in differentiation medium for 10 days in the presence/absence of Celosia cristata extracts to study the impact on differentiation or first cultured in a commitment-inducing medium, with or without Celosia cristata extract, for 48 h and then cultured 10 days in differentiation medium to assess the impact on commitment. In both experimental series, the fate of progenitor cells was studied by quantification of lipids and by determining the expression of key genes involved in adipogenesis. Results: Data show that Celosia cristata extract reduces lipid content of progenitor cells undergoing differentiation. This reduction correlates with a reduced expression of C/EBPα. When progenitor cells are placed in commitment-inducing conditions, Celosia cristata extract induces a more potent reduction of lipid content. This reduction correlates with a decrease in the expression levels of master genes involved in adipogenesis: the genes of transcription factors PPARγ2 and C/EBPα as well as marker genes coding for LPL and GPDH. Conclusions: Celosia cristata extract decreases adipogenesis. The effect of the extract is stronger when studying commitment and differentiation than differentiation alone;it suggests that the extract impact the commitment of human adipose tissue progenitor cells.

Interaction of Diet/Lifestyle Intervention and TCF7L2 Genotype on Glycemic Control and Adiposity among Overweight or Obese Adults:Big Data from Seven Randomized Controlled Trials Worldwide

Objective.The strongest locus which associated with type 2 diabetes(T2D)by the common variant rs7903146 is the transcription factor 7-like 2 gene(TCF7L2).We aimed to quantify the interaction of diet/lifestyle interventions and the genetic effect of TCF7L2 rs7903146 on glycemic traits,body weight,or waist circumference in overweight or obese adults in several randomized controlled trials(RCTs).Methods.From October 2016 to May 2018,a large collaborative analysis was performed by pooling individualparticipant data from 7 RCTs.These RCTs reported changes in glycemic control and adiposity of the variant rs7903146 after dietary/lifestyle-related interventions in overweight or obese adults.Gene treatment interaction models which used the genetic effect encoded by the allele dose and common covariates were applicable to individual participant data in all studies.Results.In the joint analysis,a total of 7 eligible RCTs were included(n=4,114).Importantly,we observed a significant effect modification of diet/lifestyle-related interventions on the TCF7L2 variant rs7903146 and changes in fasting glucose.Compared with the control group,diet/lifestyle interventions were related to lower fasting glucose by-3.06(95%CI,-5.77 to-0.36)mg/dL(test for heterogeneity and overall effect:I^(2)=45:1%,p<0:05;z=2:20,p=0:028)per one copy of the TCF7L2 T risk allele.Furthermore,regardless of genetic risk,diet/lifestyle interventions were associated with lower waist circumference.However,there was no significant change for diet/lifestyle interventions in other glycemic control and adiposity traits per one copy of TCF7L2 risk allele.Conclusions.Our findings suggest that carrying the TCF7L2 T risk allele may have a modestly greater benefit for specific diet/lifestyle interventions to improve the control of fasting glucose in overweight or obese adults.