Associations between physical activity levels and ATPase inhibitory factor 1 concentrations in older adults

Background:Adenosine triphosphatase inhibitory factor 1(IF1)is a key protein involved in energy metabolism.IF1 has been linked to various agerelated diseases,although its relationship with physical activity(PA)remains unclear.Additionally,the apolipoprotein A-I(apoA-I),a PA-modulated lipoprotein,could play a role in this relationship because it shares a binding site with IF1 on the cell-surface ATP synthase.We examined here the associations between chronic PA and plasma IF1 concentrations among older adults,and we investigated whether apoA-I mediated these associations.Methods:In the present work,1096 healthy adults(63.8%females)aged 70 years and over who were involved in the Multidomain Alzheimer Prevention Trial study were included.IF1 plasma concentrations(square root of ng/mL)were measured at the 1-year visit of the Multidomain Alzheimer Prevention Trial,while PA levels(square root of metabolic equivalent task min/week)were assessed using questionnaires administered each year from baseline to the 3-year visit.Multiple linear regressions were performed to investigate the associations between the first-year mean PA levels and IF1 concentrations.Mediation analyses were conducted to examine whether apoA-I mediated these associations.Mixedeffect linear regressions were carried out to investigate whether the 1-year visit IF1 concentrations predicted subsequent changes in PA.Results:Multiple linear regressions indicated that first-year mean PA levels were positively associated with IF1 concentrations(B=0.021;SE=0.010;p=0.043).Mediation analyses revealed that about 37.7%of this relationship was mediated by apoA-I(B_(ab)=0.008;SE=0.004;p=0.023).Longitudinal investigations demonstrated that higher concentrations of IF1 at the 1-year visit predicted a faster decline in PA levels over the subsequent 2 years(time×IF1:B=0.148;SE=0.066;p=0.025).Conclusion:This study demonstrates that regular PA is associated with plasma IF1 concentrations,and it suggests that apoA-I partly mediates this association.Additionally,this study finds that baseline concentrations of IF1 can predict future changes in PA.However,further research is needed to fully understand the mechanisms underlying these observations.

Insulin-mimetic compound hexaquis(benzylammonium) decavanadate is antilipolytic in human fat cells

AIM To assess in rodent and human adipocytes the antilipolytic capacity of hexaquis(benzylammonium) decavanadate(B6V10), previously shown to exert antidiabetic effects in rodent models, such as lowering free fatty acids(FFA) and glucose circulating levels.METHODS Adipose tissue(AT) samples were obtained after informed consent from overweight women undergoing plastic surgery. Comparison of the effects of B6V10 and reference antilipolytic agents(insulin,benzylamine,vanadate) on the lipolytic activity was performed on adipocytes freshly isolated from rat, mouse and human AT. Glycerol release was measured using colorimetric assay as an index of lipolytic activity. The influence of B6V10 and reference agents on glucose transport into human fat cells was determined using the radiolabelled 2-deoxyglucose uptake assay.RESULTS In all the species studied, B6V10 exhibited a dosedependent inhibition of adipocyte lipolysis when triglyceride breakdown was moderately enhanced by β-adrenergic receptor stimulation. B6V10 exerted on human adipocyte a maximal lipolysis inhibition of glycerol release that was stronger than that elicited by insulin. However, B6V10 did not inhibit basal and maximally stimulated lipolysis. When incubated at dose ≥ 10 μmol/L, B6V10 stimulated by twofold the glucose uptake in human fat cells, but-similarly to benzylamine-without reaching the maximal effect of insulin, while it reproduced one-half of the insulin-stimulation of lipogenesis in mouse fat cells. CONCLUSION B6V10 exerts insulin-like actions in adipocytes, including lipolysis inhibition and glucose transport activation. B6V10 may be useful in limiting lipotoxicity related to obesity and insulin resistance.

Hyperglycemia and reduced adiposity of streptozotocin-induced diabetic mice are not alleviated by oral benzylamine supplementation

BACKGROUND Benzylamine(Bza)oral administration delays the onset of hyperglycemia in insulin-resistant db-/-mice;a genetic model of obesity and type 2 diabetes.AIM To extend the antihyperglycemic properties of oral benzylamine to a model of insulin-deficient type 1 diabetes.METHODS Male Swiss mice were rendered diabetic by streptozotocin treatment(STZ)and divided in two groups:one received 0.5%Bza as drinking solution for 24 d(STZ Bza-drinking)while the other was drinking water ad libitum.Similar groups were constituted in age-matched,nondiabetic mice.Food intake,liquid intake,body weight gain and nonfasting blood glucose levels were followed during treatment.At the end of treatment,fasted glycemia,liver and white adipose tissue(WAT)mass were measured,while glucose uptake assays were performed in adipocytes.RESULTS STZ diabetic mice presented typical features of insulin-deficient diabetes:reduced body mass and increased blood glucose levels.These altered parameters were not normalized in the Bza-drinking group in spite of restored food and water intake.Bza consumption could not reverse the severe fat depot atrophy of STZ diabetic mice.In the nondiabetic mice,no difference was found between control and Bza-drinking mice for any parameter.In isolated adipocytes,hexose uptake was partially activated by 0.1 mmol/L Bza in a manner that was obliterated in vitro by the amine oxidase inhibitor phenelzine and that remained unchanged after Bza supplementation.Oxidation of 0.1 mmol/L Bza in WAT was lower in STZ diabetic than in normoglycemic mice.CONCLUSION Bza supplementation could not normalize the altered glucose handling of STZ diabetic mice with severe WAT atrophy.Consequently,its antidiabetic potential in obese and diabetic rodents does not apply to lipoatrophic type 1 diabetic mice.

Vanadium-dependent activation of glucose transport in adipocytes by catecholamines is not mediated via adrenoceptor stimulation or monoamine oxidase activity

BACKGROUND Benzylamine and methylamine activate glucose uptake in adipocytes.For tyramine,this effect has even been extended to cardiomyocytes.AIM To investigate the effects of catecholamines and other amines on glucose uptake.METHODS A screening compared 25 biogenic amines on 2-deoxyglucose(2-DG)uptake activation in rat adipocytes.Pharmacological approaches and transgenic mouse models were then used to decipher the mode of action of several hits.RESULTS In rat adipocytes,insulin stimulation of 2-DG uptake was reproduced with catecholamines.100μmol/L or 1 mmol/L adrenaline,noradrenaline,dopamine and deoxyepinephrine,maximally activated hexose transport only when sodium orthovanadate was added at 100μmol/L.Such activation was similar to that already reported for benzylamine,methylamine and tyramine,well-recognized substrates of semicarbazide-sensitive amine oxidase(SSAO)and monoamine oxidase(MAO).Several,but not all,tested agonists ofβ-adrenoreceptors(β-ARs)also activated glucose transport whileα-AR agonists were inactive.Lack of blockade byα-andβ-AR antagonists indicated that catecholamine-induced 2-DG uptake was not mediated by AR stimulation.Adipocytes from mice lackingβ1-,β2-andβ3-ARs(triple KO)also responded to millimolar doses of adrenaline or noradrenaline by activating hexose transport in the presence of 100μmol/L vanadate.The MAO blocker pargyline,and SSAO inhibitors did not block the effects of adrenaline or noradrenaline plus vanadate,which were blunted by antioxidants.CONCLUSION Catecholamines exert unexpected insulin-like actions in adipocytes when combined with vanadium.For limiting insulin resistance by activating glucose consumption at least in fat stores,we propose that catecholamine derivatives combined with vanadium can generate novel complexes that may have low toxicity and promising anti-diabetic properties.

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.

Short-term effects of obestatin on hexose uptake and triacylglycerol breakdown in human subcutaneous adipocytes

AIM To study complete dose-dependent effects of obestatin on lipolytic and glucose transport activities in human adipocyte preparations highly responsive to insulin.METHODS Adipocytes were prepared by liberase digestion from subcutaneous abdominal adipose tissue obtained from overweight subjects undergoing plastic surgery. The index of lipolytic activity was the glycerol released in the incubation medium, while glucose transport was assessed by [~3H]-2-deoxyglucose uptake assay.RESULTS When tested from 0.1 nmol/L to 1 μmol/L, obestatin did not stimulate glycerol release; it did not inhibit the lipolytic effect of isoprenaline and did not alter the insulin antilipolytic effect. Obestatin hardly activated glucose transport at 1 μmol/L only. Moreover, the obestatin stimulation effect was clearly lower than the threefold increase induced by insulin 100 nmol/L.CONCLUSION Low doses of obestatin cannot directly influence lipolysis and glucose uptake in human fat cells.

Increased monoamine oxidase activity and imidazoline binding sites in insulin-resistant adipocytes from obese Zucker rats

BACKGROUND Despite overt insulin resistance,adipocytes of genetically obese Zucker rats accumulate the excess of calorie intake in the form of lipids.AIM To investigate whether factors can replace or reinforce insulin lipogenic action by exploring glucose uptake activation by hydrogen peroxide,since it is produced by monoamine oxidase(MAO)and semicarbazide-sensitive amine oxidase(SSAO)in adipocytes.METHODS 3H-2-deoxyglucose uptake(2-DG)was determined in adipocytes from obese and lean rats in response to insulin or MAO and SSAO substrates such as tyramine and benzylamine.14C-tyramine oxidation and binding of imidazolinic radioligands[3H-Idazoxan,3H-(2-benzofuranyl)-2-imidazoline]were studied in adipocytes,the liver,and muscle.The influence of in vivo administration of tyramine+vanadium on glucose handling was assessed in lean and obese rats.RESULTS 2-DG uptake and lipogenesis stimulation by insulin were dampened in adipocytes from obese rats,when compared to their lean littermates.Tyramine and benzylamine activation of hexose uptake was vanadate-dependent and was also limited,while MAO was increased and SSAO decreased.These changes were adipocyte-specific and accompanied by a greater number of imidazoline I2 binding sites in the obese rat,when compared to the lean.In vitro,tyramine precluded the binding to I2 sites,while in vivo,its administration together with vanadium lowered fasting plasma levels of glucose and triacylglycerols in obese CONCLUSION The adipocytes from obese Zucker rats exhibit increased MAO activity and imidazoline binding site number.However,probably as a consequence of SSAO down-regulation,the glucose transport stimulation by tyramine is decreased as much as that of insulin in these insulin-resistant adipocytes.The adipocyte amine oxidases deserve more studies with respect to their putative contribution to the management of glucose and lipid handling.

Scalable batch fabrication of ultrathin flexible neural probes using a bioresorbable silk layer

Flexible intracerebral probes for neural recording and electrical stimulation have been the focus of many research works to achieve better compliance with the surrounding tissue while minimizing rejection.Strategies have been explored to find the best way to insert flexible probes into the brain while maintaining their flexibility once positioned.Here,we present a novel and versatile scalable batch fabrication approach to deliver ultrathin and flexible probes consisting of a silk-parylene bilayer.The biodegradable silk layer,whose degradation time is programmable,provides a temporary and programmable stiffener to allow the insertion of ultrathin parylene-based flexible devices.Our innovative and robust batch fabrication technology allows complete freedom over probe design in terms of materials,size,shape,and thickness.We demonstrate successful ex vivo insertion of the probe with acute high-fidelity recordings of epileptic seizures in field potentials as well as single-unit action potentials in mouse brain slices.Our novel technological solution for implanting ultraflexible devices in the brain while minimizing rejection risks shows high potential for use in both brain research and clinical therapies.