Therapeutic potential of emerging NAD+-increasing strategies for cardiovascular diseases

Altres ajuts: Fundació La Marató de TV3 (303/C/2016)(201602.30.31)Cardiovascular diseases are the leading cause of death worldwide. Aging and/or metabolic stress directly impact the cardiovascular system. Over the last few years, the contributions of altered nicotinamide adenine dinucleotide (NAD+) metabolism to aging and other pathological conditions closely related to cardiovascular diseases have been intensively investigated. NAD+ bioavailability decreases with age and cardiometabolic conditions in several mammalian tissues. Compelling data suggest that declining tissue NAD+ is commonly related to mitochondrial dysfunction and might be considered as a therapeutic target. Thus, NAD+ replenishment by either genetic or natural dietary NAD+-increasing strategies has been recently demonstrated to be effective for improving the pathophysiology of cardiac and vascular health in different experimental models, as well as human health, to a lesser extent. Here, we review and discuss recent experimental evidence illustrating that increasing NAD+ bioavailability, particularly by the use of natural NAD+ precursors, may offer hope for new therapeutic strategies to prevent and treat cardiovascular diseases

Nicotinamide effects on adiposity, energy metabolism, inflammation and atherosclerosis in mice

Antecedentes e hipótesis La disfunción del tejido adiposo se encuentra frecuentemente asociada con alteraciones en la homeostasis metabólica, cardiovascular e inflamatoria crónica leve de la obesidad. El tejido adiposo es considerado como diana terapéutica para prevenir la obesidad. Precursores de la nicotinamida adenina dinucleotido (NAD)+, tales como el ribósido de nicotinamida y mononucleótido de nicotinamida promueven el metabolismo energético y previenen la ganancia de peso corporal en modelos animales. Sin embargo, en estos trabajos no se abordó directamente su posible efecto sobre las alteraciones fisiológicas y plásticas del tejido adiposo blanco (TAB). Su posible potencial contra la inflamación crónica, cuyo desarrollo se encuentra frecuentemente ligado al de obesidad, tampoco ha sido evaluado. La nicotinamida (NAM) es otro precursor fisiológico de NAD+. No obstante, su posible contribución sobre este fenotipo está aun pendiente. Por otro lado, aunque su acción anti-oxidante y anti-inflamatoria ya ha sido descrita, su posible contribución en la prevención de arteriosclerosis tampoco ha sido demostrada. Objetivos El objetivo principal de este estudio fue doble: investigar el efecto de la administración de una dosis bien tolerada de NAM sobre [1] la prevención de la ganancia de peso corporal y adiposidad, y [2] la mejora de inflamación crónica en modelos murinos de obesidad inducida por una dieta rica en grasas (DIO, del inglés ‘diet-induced obesity’) y arteriosclerosis (i.e., ratones deficientes en ApoE). Resultados La administración de NAM a animales se realizó a través del agua de bebida ad libitum. El agua suplementada con NAM fue bien tolerada y segura a una dosis inferior a 1%. La suplementación con NAM, a la dosis más alta empleada (1%), previno la ganancia de peso corporal, siendo esto último principalmente atribuido a una disminución en la acumulación de grasa y esteatosis hepática. Ello fue principalmente debido a un [i] aumento en el gasto energético global, [ii] desarrollo de ‘browning’ en TAB subcutáneo (TABsc) a juzgar por un aumento en los niveles tisulares de proteína desacopladora Ucp1, e [iii] inducción de la síntesis de novo de NAD+ y aumento de la relación NAD+/NADH en TABsc. El contenido de AMP en TABsc se encontró significativamente elevado en ratones obesos tratados. Además, la relación NAD+/NADH se encontró directamente relacionada con la relación AMP/ATP, posiblemente sugiriendo una situación de demanda energética aumentada en dicho tejido. Consistentemente, se observó un aumento en la abundancia relativa de la forma activa (fosforilada) de la quinasa activada por AMP (AMPK) en dicho tejido. La suplementación con NAM también mejoró el estado inflamatorio global y previno contra el desarrollo de arteriosclerosis en ratones. Ello se acompañó por elevaciones [i] en las concentraciones circulantes de interleuquina (IL-)10 y [ii] niveles relativos de mRNA de Il10 en tejido adiposo epididimal (TABe) y aórtico, sugiriendo un cambio favorable del fenotipo de macrófagos a uno anti-inflamatorio (macrófagos M2). Esto último se observó asociado con una disminución en el desarrollo de arteriosclerosis en ratones deficientes en ApoE. También se investigó su posible efecto anti-oxidante sistémico y en tejidos diana. Las lipoproteínas circulantes no-HDL de ratones deficientes de ApoE tratados con NAM presentaron menor susceptibilidad a la oxidación que las de los no tratados, siendo este efecto debido al menos en parte a la acción antioxidante intrínseca por parte de NAM. Conclusiones La suplementación dietética de NAM previno la ganancia de peso corporal y adiposidad a través de la estimulación del gasto energético en ratones. Ello se acompañó de una inducción de ‘browning’ y aumento de demanda energética en TAB. NAM también promovió acciones anti-inflamatoria y anti-oxidante. Su administración aumentó la expression génica de Il10 en tejidos diana, incluyendo la aorta, y protegió contra el desarrollo de arteriosclerosis.Background and hypothesis Adipose tissue dysfunction is a hallmark of obesity and is frequently associated with distorted metabolic homeostasis, cardiovascular and chronic, low-grade inflammatory diseases. Several recent studies point to pharmacological and/or nutritional health initiatives targeting adipose tissue being a promising approach to obesity prevention. In this regard, nicotinamide adenine dinucleotide (NAD)+ precursors, such as nicotinamide riboside and mononucleotide nicotinamide has been proven beneficial in increasing energy metabolism and preventing body weight gain in vivo. However, neither their favorable anti-obesity impact on disturbed white adipose tissue (WAT) physiology and plasticity nor in alleviating chronic inflammation, which frequently accompanies obesity, was not eventually pursued in any of these studies. In addition to the above-mentioned NAD precursors, nicotinamide (NAM) is also a physiological precursor of NAD+. However, its contribution in boosting energy metabolism and body weight gain still remains elusive. Although a growing body of evidences also supports a role for NAM as an anti-oxidant and anti-inflammatory agent both in vitro and in vivo, its potential contribution in preventing atherosclerosis, which is one of the main mechanisms involved in cardiovascular disease in vivo, has not previously been proven yet. Aims The aim of this study was twofold: to investigate the effect of NAM supplementation in (1) preventing weight gain and adiposity; (2) improving features of chronic inflammation in appropriate mouse models of obesity (diet-induced obesity -DIO- mice) and atherosclerosis (i.e., ApoE-deficient mice). Results NAM administration to mice was provided orally via tap water at libitum. Its administration was shown palatable, safe and well tolerated at doses below 1%. NAM supplementation, at the highest dose used (1%) (NAM HD-treated mice), prevented body weight gain, with the latter being mainly and repeatedly accompanied by reduction in fat accumulation in different regional depots, and hepatic steatosis. Mechanistically, such anti-adiposity effect by NAM was mainly accompanied by an [i] increased global energy expenditure, [ii] enhanced promotion of browning in subcutaneous (sc)WAT, as revealed by elevations in the relative mRNA and protein abundance of the uncoupling protein (Ucp)-1, and [iii] elevation of the de novo synthesis of NAD+ and NAD/NADH ratio in scWAT of NAM HD-treated, DIO mice. Notably, the AMP content was significantly elevated in scWAT of NAM HD-treated, DIO mice. Also, the NAD+/NADH ratio was directly related to the AMP/ATP ratio. Overall these data suggested a situation of energy demand in scWAT from NAM HD-treated mice. Concomitantly, the protein abundance of the active (phosphorylated) form of AMP-activated kinase was also elevated in this tissue of NAM HD-treated mice. NAM supplementation also improved the global inflammatory condition and prevented atherosclerosis development in mice. This was revealed by [i] elevations in the circulating concentrations of interleukin (IL-)10 and [ii] up-regulation of relative mRNA of Il10 in both adipose and aortic tissues, which potentially suggested a switch to anti-inflammatory M2 macrophages. This phenotype was accompanied by a commensurate reduction in atherosclerosis development in NAM-treated, ApoE-deficient mice. In addition to improved inflammation, non-HDL of NAM-treated, ApoE-deficient mice were less prone to oxidation than those from untreated mice, being this effect at least partly provided by the intrinsic anti-oxidant action of NAM. Conclusions Dietary supplementation with NAM to mice prevented body weight gain and adiposity by boosting energy expenditure, with this being mainly attributed to induction of browning and energy demand in scWAT. NAM also promoted anti-inflammatory and anti-oxidant actions. Its administration increased gene expression Il10 in target tissues, including aorta, and protected against development of atherosclerosis

Nicotinamide effects on adiposity, energy metabolism, inflammation and atherosclerosis in mice /

Departament responsable de la tesi: Departament de Bioquímica i Biologia Molecular.Antecedentes e hipótesisLa disfunción del tejido adiposo se encuentra frecuentemente asociada con alteraciones en la homeostasis metabólica, cardiovascular e inflamatoria crónica leve de la obesidad. El tejido adiposo es considerado como diana terapéutica para prevenir la obesidad. Precursores de la nicotinamida adenina dinucleotido (NAD)+, tales como el ribósido de nicotinamida y mononucleótido de nicotinamida promueven el metabolismo energético y previenen la ganancia de peso corporal en modelos animales. Sin embargo, en estos trabajos no se abordó directamente su posible efecto sobre las alteraciones fisiológicas y plásticas del tejido adiposo blanco (TAB). Su posible potencial contra la inflamación crónica, cuyo desarrollo se encuentra frecuentemente ligado al de obesidad, tampoco ha sido evaluado. La nicotinamida (NAM) es otro precursor fisiológico de NAD+. No obstante, su posible contribución sobre este fenotipo está aun pendiente. Por otro lado, aunque su acción anti-oxidante y anti-inflamatoria ya ha sido descrita, su posible contribución en la prevención de arteriosclerosis tampoco ha sido demostrada.ObjetivosEl objetivo principal de este estudio fue doble: investigar el efecto de la administración de una dosis bien tolerada de NAM sobre [1] la prevención de la ganancia de peso corporal y adiposidad, y [2] la mejora de inflamación crónica en modelos murinos de obesidad inducida por una dieta rica en grasas (DIO, del inglés 'diet-induced obesity') y arteriosclerosis (i.e., ratones deficientes en ApoE).ResultadosLa administración de NAM a animales se realizó a través del agua de bebida ad libitum. El agua suplementada con NAM fue bien tolerada y segura a una dosis inferior a 1%.La suplementación con NAM, a la dosis más alta empleada (1%), previno la ganancia de peso corporal, siendo esto último principalmente atribuido a una disminución en la acumulación de grasa y esteatosis hepática. Ello fue principalmente debido a un [i] aumento en el gasto energético global, [ii] desarrollo de 'browning' en TAB subcutáneo (TABsc) a juzgar por un aumento en los niveles tisulares de proteína desacopladora Ucp1, e [iii] inducción de la síntesis de novo de NAD+ y aumento de la relación NAD+/NADH en TABsc. El contenido de AMP en TABsc se encontró significativamente elevado en ratones obesos tratados. Además, la relación NAD+/NADH se encontró directamente relacionada con la relación AMP/ATP, posiblemente sugiriendo una situación de demanda energética aumentada en dicho tejido. Consistentemente, se observó un aumento en la abundancia relativa de la forma activa (fosforilada) de la quinasa activada por AMP (AMPK) en dicho tejido.La suplementación con NAM también mejoró el estado inflamatorio global y previno contra el desarrollo de arteriosclerosis en ratones. Ello se acompañó por elevaciones [i] en las concentraciones circulantes de interleuquina (IL-)10 y [ii] niveles relativos de mRNA de Il10 en tejido adiposo epididimal (TABe) y aórtico, sugiriendo un cambio favorable del fenotipo de macrófagos a uno anti-inflamatorio (macrófagos M2). Esto último se observó asociado con una disminución en el desarrollo de arteriosclerosis en ratones deficientes en ApoE. También se investigó su posible efecto anti-oxidante sistémico y en tejidos diana. Las lipoproteínas circulantes no-HDL de ratones deficientes de ApoE tratados con NAM presentaron menor susceptibilidad a la oxidación que las de los no tratados, siendo este efecto debido al menos en parte a la acción antioxidante intrínseca por parte de NAM. ConclusionesLa suplementación dietética de NAM previno la ganancia de peso corporal y adiposidad a través de la estimulación del gasto energético en ratones. Ello se acompañó de una inducción de 'browning' y aumento de demanda energética en TAB. NAM también promovió acciones anti-inflamatoria y anti-oxidante. Su administración aumentó la expression génica de Il10 en tejidos diana, incluyendo la aorta, y protegió contra el desarrollo de arteriosclerosis.Antecedentes e hipótesis La disfunción del tejido adiposo se encuentra frecuentemente asociada con alteraciones en la homeostasis metabólica, cardiovascular e inflamatoria crónica leve de la obesidad. El tejido adiposo es considerado como diana terapéutica para prevenir la obesidad. Precursores de la nicotinamida adenina dinucleotido (NAD)+, tales como el ribósido de nicotinamida y mononucleótido de nicotinamida promueven el metabolismo energético y previenen la ganancia de peso corporal en modelos animales. Sin embargo, en estos trabajos no se abordó directamente su posible efecto sobre las alteraciones fisiológicas y plásticas del tejido adiposo blanco (TAB). Su posible potencial contra la inflamación crónica, cuyo desarrollo se encuentra frecuentemente ligado al de obesidad, tampoco ha sido evaluado. La nicotinamida (NAM) es otro precursor fisiológico de NAD+. No obstante, su posible contribución sobre este fenotipo está aun pendiente. Por otro lado, aunque su acción anti-oxidante y anti-inflamatoria ya ha sido descrita, su posible contribución en la prevención de arteriosclerosis tampoco ha sido demostrada. Objetivos El objetivo principal de este estudio fue doble: investigar el efecto de la administración de una dosis bien tolerada de NAM sobre [1] la prevención de la ganancia de peso corporal y adiposidad, y [2] la mejora de inflamación crónica en modelos murinos de obesidad inducida por una dieta rica en grasas (DIO, del inglés 'diet-induced obesity') y arteriosclerosis (i.e., ratones deficientes en ApoE). Resultados La administración de NAM a animales se realizó a través del agua de bebida ad libitum. El agua suplementada con NAM fue bien tolerada y segura a una dosis inferior a 1%. La suplementación con NAM, a la dosis más alta empleada (1%), previno la ganancia de peso corporal, siendo esto último principalmente atribuido a una disminución en la acumulación de grasa y esteatosis hepática. Ello fue principalmente debido a un [i] aumento en el gasto energético global, [ii] desarrollo de 'browning' en TAB subcutáneo (TABsc) a juzgar por un aumento en los niveles tisulares de proteína desacopladora Ucp1, e [iii] inducción de la síntesis de novo de NAD+ y aumento de la relación NAD+/NADH en TABsc. El contenido de AMP en TABsc se encontró significativamente elevado en ratones obesos tratados. Además, la relación NAD+/NADH se encontró directamente relacionada con la relación AMP/ATP, posiblemente sugiriendo una situación de demanda energética aumentada en dicho tejido. Consistentemente, se observó un aumento en la abundancia relativa de la forma activa (fosforilada) de la quinasa activada por AMP (AMPK) en dicho tejido. La suplementación con NAM también mejoró el estado inflamatorio global y previno contra el desarrollo de arteriosclerosis en ratones. Ello se acompañó por elevaciones [i] en las concentraciones circulantes de interleuquina (IL-)10 y [ii] niveles relativos de mRNA de Il10 en tejido adiposo epididimal (TABe) y aórtico, sugiriendo un cambio favorable del fenotipo de macrófagos a uno anti-inflamatorio (macrófagos M2). Esto último se observó asociado con una disminución en el desarrollo de arteriosclerosis en ratones deficientes en ApoE. También se investigó su posible efecto anti-oxidante sistémico y en tejidos diana. Las lipoproteínas circulantes no-HDL de ratones deficientes de ApoE tratados con NAM presentaron menor susceptibilidad a la oxidación que las de los no tratados, siendo este efecto debido al menos en parte a la acción antioxidante intrínseca por parte de NAM. Conclusiones La suplementación dietética de NAM previno la ganancia de peso corporal y adiposidad a través de la estimulación del gasto energético en ratones. Ello se acompañó de una inducción de 'browning' y aumento de demanda energética en TAB. NAM también promovió acciones anti-inflamatoria y anti-oxidante. Su administración aumentó la expression génica de Il10 en tejidos diana, incluyendo la aorta, y protegió contra el desarrollo de arteriosclerosis.Background and hypothesis Adipose tissue dysfunction is a hallmark of obesity and is frequently associated with distorted metabolic homeostasis, cardiovascular and chronic, low-grade inflammatory diseases. Several recent studies point to pharmacological and/or nutritional health initiatives targeting adipose tissue being a promising approach to obesity prevention. In this regard, nicotinamide adenine dinucleotide (NAD)+ precursors, such as nicotinamide riboside and mononucleotide nicotinamide has been proven beneficial in increasing energy metabolism and preventing body weight gain in vivo. However, neither their favorable anti-obesity impact on disturbed white adipose tissue (WAT) physiology and plasticity nor in alleviating chronic inflammation, which frequently accompanies obesity, was not eventually pursued in any of these studies. In addition to the above-mentioned NAD precursors, nicotinamide (NAM) is also a physiological precursor of NAD+. However, its contribution in boosting energy metabolism and body weight gain still remains elusive. Although a growing body of evidences also supports a role for NAM as an anti-oxidant and anti-inflammatory agent both in vitro and in vivo, its potential contribution in preventing atherosclerosis, which is one of the main mechanisms involved in cardiovascular disease in vivo, has not previously been proven yet. Aims The aim of this study was twofold: to investigate the effect of NAM supplementation in (1) preventing weight gain and adiposity; (2) improving features of chronic inflammation in appropriate mouse models of obesity (diet-induced obesity -DIO- mice) and atherosclerosis (i.e., ApoE-deficient mice). Results NAM administration to mice was provided orally via tap water at libitum. Its administration was shown palatable, safe and well tolerated at doses below 1%. NAM supplementation, at the highest dose used (1%) (NAM HD-treated mice), prevented body weight gain, with the latter being mainly and repeatedly accompanied by reduction in fat accumulation in different regional depots, and hepatic steatosis. Mechanistically, such anti-adiposity effect by NAM was mainly accompanied by an [i] increased global energy expenditure, [ii] enhanced promotion of browning in subcutaneous (sc)WAT, as revealed by elevations in the relative mRNA and protein abundance of the uncoupling protein (Ucp)-1, and [iii] elevation of the de novo synthesis of NAD+ and NAD/NADH ratio in scWAT of NAM HD-treated, DIO mice. Notably, the AMP content was significantly elevated in scWAT of NAM HD-treated, DIO mice. Also, the NAD+/NADH ratio was directly related to the AMP/ATP ratio. Overall these data suggested a situation of energy demand in scWAT from NAM HD-treated mice. Concomitantly, the protein abundance of the active (phosphorylated) form of AMP-activated kinase was also elevated in this tissue of NAM HD-treated mice. NAM supplementation also improved the global inflammatory condition and prevented atherosclerosis development in mice. This was revealed by [i] elevations in the circulating concentrations of interleukin (IL-)10 and [ii] up-regulation of relative mRNA of Il10 in both adipose and aortic tissues, which potentially suggested a switch to anti-inflammatory M2 macrophages. This phenotype was accompanied by a commensurate reduction in atherosclerosis development in NAM-treated, ApoE-deficient mice. In addition to improved inflammation, non-HDL of NAM-treated, ApoE-deficient mice were less prone to oxidation than those from untreated mice, being this effect at least partly provided by the intrinsic anti-oxidant action of NAM. Conclusions Dietary supplementation with NAM to mice prevented body weight gain and adiposity by boosting energy expenditure, with this being mainly attributed to induction of browning and energy demand in scWAT. NAM also promoted anti-inflammatory and anti-oxidant actions. Its administration increased gene expression Il10 in target tissues, including aorta, and protected against development of atherosclerosis

Novel Insights into the Role of HDL-Associated Sphingosine-1-Phosphate in Cardiometabolic Diseases

Altres ajuts: Fundació La Marató de TV3 2015 (20152431) (to F. B.-V.) and 2016 (201602.30.31) (to N.A. and J.J.).Sphingolipids are key signaling molecules involved in the regulation of cell physiology. These species are found in tissues and in circulation. Although they only constitute a small fraction in lipid composition of circulating lipoproteins, their concentration in plasma and distribution among plasma lipoproteins appears distorted under adverse cardiometabolic conditions such as diabetes mellitus. Sphingosine-1-phosphate (S1P), one of their main representatives, is involved in regulating cardiomyocyte homeostasis in different models of experimental cardiomyopathy. Cardiomyopathy is a common complication of diabetes mellitus and represents a main risk factor for heart failure. Notably, plasma concentration of S1P, particularly high-density lipoprotein (HDL)-bound S1P, may be decreased in patients with diabetes mellitus, and hence, inversely related to cardiac alterations. Despite this, little attention has been given to the circulating levels of either total S1P or HDL-bound S1P as potential biomarkers of diabetic cardiomyopathy. Thus, this review will focus on the potential role of HDL-bound S1P as a circulating biomarker in the diagnosis of main cardiometabolic complications frequently associated with systemic metabolic syndromes with impaired insulin signaling. Given the bioactive nature of these molecules, we also evaluated its potential of HDL-bound S1P-raising strategies for the treatment of cardiometabolic disease

Nicotinamide Prevents Apolipoprotein B-Containing Lipoprotein Oxidation, Inflammation and Atherosclerosis in Apolipoprotein E-Deficient Mice

Altres ajuts: Fundació La Marató de TV3 2016 (303/C/2016) (201602.31) (to J.J.) and (97/C/2016) (201605-31) (to A.F.V.).The potential of nicotinamide (NAM) to prevent atherosclerosis has not yet been examined. This study investigated the effect of NAM supplementation on the development of atherosclerosis in a mouse model of the disease. The development of aortic atherosclerosis was significantly reduced (NAM low dose: 45%; NAM high dose: 55%) in NAM-treated, apolipoprotein (Apo)E-deficient mice challenged with a Western diet for 4 weeks. NAM administration significantly increased (1.8-fold) the plasma concentration of proatherogenic ApoB-containing lipoproteins in NAM high-dose (HD)-treated mice compared with untreated mice. However, isolated ApoB-containing lipoproteins from NAM HD mice were less prone to oxidation than those of untreated mice. This result was consistent with the decreased (1.5-fold) concentration of oxidized low-density lipoproteins in this group. Immunohistochemical staining of aortas from NAM-treated mice showed significantly increased levels of IL-10 (NAM low-dose (LD): 1.3-fold; NAM HD: 1.2-fold), concomitant with a significant decrease in the relative expression of TNFα (NAM LD: −44%; NAM HD: −57%). An improved anti-inflammatory pattern was reproduced in macrophages cultured in the presence of NAM. Thus, dietary NAM supplementation in ApoE-deficient mice prevented the development of atherosclerosis and improved protection against ApoB-containing lipoprotein oxidation and aortic inflammation

Administration of CORM-2 inhibits diabetic neuropathy but does not reduce dyslipidemia in diabetic mice.

The antinociceptive effects of the carbon monoxide-releasing molecule tricarbonyldichlororuthenium (II) dimer (CORM-2) during chronic pain are well documented, but most of its possible side-effects remain poorly understood. In this work, we examine the impact of CORM-2 treatment on the lipoprotein profile and two main atheroprotective functions attributed to high-density lipoprotein (HDL) in a mouse model of type 1 diabetes while analyzing the effect of this drug on diabetic neuropathy. Streptozotocin (Stz)-induced diabetic mice treated with CORM-2 (Stz-CORM-2) or vehicle (Stz-vehicle) were used to evaluate the effect of this drug on the modulation of painful diabetic neuropathy using nociceptive behavioral tests. Plasma and tissue samples were used for chemical and functional analyses, as appropriate. Two main antiatherogenic properties of HDL, i.e., the ability of HDL to protect low-density lipoprotein (LDL) from oxidation and to promote reverse cholesterol transport from macrophages to the liver and feces in vivo (m-RCT), were also assessed. Stz-induced diabetic mice displayed hyperglycemia, dyslipidemia and pain hypersensitivity. The administration of 10 mg/kg CORM-2 during five consecutive days inhibited allodynia and hyperalgesia and significantly ameliorated spinal cord markers (Cybb and Bdkrb1expression) of neuropathic pain in Stz mice, but it did not reduce the combined dyslipidemia shown in Stz-treated mice. Its administration to Stz-treated mice led to a significant increase in the plasma levels of cholesterol (∼ 1.4-fold vs. Ctrl, ∼ 1.3- fold vs. Stz-vehicle; p < 0.05) and was attributed to significant elevations in both non-HDL (∼ 1.8-fold vs. Ctrl; ∼ 1.6-fold vs. Stz-vehicle; p < 0.05) and HDL cholesterol (∼ 1.3-fold vs. Ctrl, ∼ 1.2-fold vs. Stz-vehicle; p < 0.05). The increased HDL in plasma was not accompanied by a commensurate elevation in m-RCT in Stz-CORM-2 compared to Stz-vehicle mice; instead, it was worsened as revealed by decreased [3H]-tracer trafficking into the feces in vivo. Furthermore, the HDL-mediated protection against LDL oxidation ex vivo shown by the HDL isolated from Stz-CORM-2 mice did not differ from that obtained in Stz-vehicle mice. In conclusion, the antinociceptive effects produced by a high dose of CORM-2 were accompanied by antioxidative effects but were without favorable effects on the dyslipidemia manifested in diabetic mice

Phenol-enriched virgin olive oil promotes macrophage-specific reverse cholesterol transport in vivo

The intake of olive oil (OO) enriched with phenolic compounds (PCs) promotes ex vivo HDL-mediated macrophage cholesterol efflux in humans. We aimed to determine the effects of PC-enriched virgin OO on reverse cholesterol transport (RevCT) from macrophages to feces in vivo. Female C57BL/6 mice were given intragastric doses of refined OO (ROO) and a functional unrefined virgin OO enriched with its own PC (FVOO) for 14 days. Our experiments included two independent groups of mice that received intragastric doses of the phenolic extract (PE) used to prepare the FVOO and the vehicle solution (saline), as control, for 14 days. FVOO intake led to a significant increase in serum HDL cholesterol and its ability to induce macrophage cholesterol efflux in vitro when compared with ROO group. This was concomitant with the enhanced macrophage-derived [3H]cholesterol transport to feces in vivo. PE intake per se also increased HDL cholesterol levels and significantly promoted in vivo macrophage-to-feces RevCT rate when compared with saline group. PE upregulated the expression of the main macrophage transporter involved in macrophage cholesterol efflux, the ATP binding cassettea1. Our data provide direct evidence of the crucial role of OO PCs in the induction of macrophage-specific RevCT in vivo.This work was partly funded by the Instituto de Salud Carlos III and FEDER “Una manera de hacer Europa” grants PI14-01648 and PI18-00164 (to F.B.-V.), PI16-00139 and PI19-00136 (to J.C.E-G), and CB06/03/0028 (to M.F. (Montserrat Fitó)); by the Ministerio de Economía, Indústria y Competitividad and FEDER AppleCOR Project (subproject AGL2016-76943-C2-2-R and subproject AGL2016- 76943-C2-1-R) (to R.S.), AGL2009-13517-C03-01 and AGL2012-40144-C03-01 (to M.F. (Montserrat Fitó)); by the Agència de Gestió d’Ajuts Universitaris i de Recerca 2014-SGR-240, 2017-SGR-522, 2017-SGR-222, and 2017-BP-00021; by the Jane and Aatos Erkko Foundation (to M.J. and J.M.); and the Finnish Foundation for Cardiovascular Research (to M.J.). M.F. (Marta Farràs) has a Sara Borrell contract (CD17/00233). CIBERDEM and CIBEROBN are initiatives of the Instituto de Salud Carlos III

Human ApoA-I Overexpression Enhances Macrophage-Specific Reverse Cholesterol Transport but Fails to Prevent Inherited Diabesity in Mice

Human apolipoprotein A-I (hApoA-I) overexpression improves high-density lipoprotein (HDL) function and the metabolic complications of obesity. We used a mouse model of diabesity, the db/db mouse, to examine the effects of hApoA-I on the two main functional properties of HDL, i.e., macrophage-specific reverse cholesterol transport (m-RCT) in vivo and the antioxidant potential, as well as the phenotypic features of obesity. HApoA-I transgenic (hA-I) mice were bred with nonobese control (db/+) mice to generate hApoA-I-overexpressing db/+ offspring, which were subsequently bred to obtain hA-I-db/db mice. Overexpression of hApoA-I significantly increased weight gain and the incidence of fatty liver in db/db mice. Weight gain was mainly explained by the increased caloric intake of hA-I-db/db mice (&gt;1.2-fold). Overexpression of hApoA-I also produced a mixed type of dyslipidemia in db/db mice. Despite these deleterious effects, the overexpression of hApoA-I partially restored m-RCT in db/db mice to levels similar to nonobese control mice. Moreover, HDL from hA-I-db/db mice also enhanced the protection against low-density lipoprotein (LDL) oxidation compared with HDL from db/db mice. In conclusion, overexpression of hApoA-I in db/db mice enhanced two main anti-atherogenic HDL properties while exacerbating weight gain and the fatty liver phenotype. These adverse metabolic side-effects were also observed in obese mice subjected to long-term HDL-based therapies in independent studies and might raise concerns regarding the use of hApoA-I-mediated therapy in obese humans

Nicotinamide protects against diet-induced body weight gain, increases energy expenditure, and induces white adipose tissue beiging

Altres ajuts: Fundacio La Marató de TV3, 201602.30.31; Ministerio de Educación (República de Paraguay), BCAL04-451 - 3824321Scope: Interventions that boost NAD+ availability are of potential therapeutic interest for obesity treatment. The potential of nicotinamide (NAM), the amide form of vitamin B3 and a physiological precursor of nicotinamide adenine dinucleotide (NAD)+, in preventing weight gain has not previously been studied in vivo. Other NAD+ precursors have been shown to decrease weight gain; however, their impact on adipose tissue is not addressed. Methods and results: Two doses of NAM (high dose: 1% and low dose: 0.25%) are given by drinking water to C57BL/6J male mice, starting at the same time as the high-fat diet feeding. NAM supplementation protects against diet-induced obesity by augmenting global body energy expenditure in C57BL/6J male mice. The manipulation markedly alters adipose morphology and metabolism, particularly in inguinal (i) white adipose tissue (iWAT). An increased number of brown and beige adipocyte clusters, protein abundance of uncoupling protein 1 (UCP1), mitochondrial activity, adipose NAD+, and phosphorylated AMP-activated protein kinase (P-AMPK) levels are observed in the iWAT of treated mice. Notably, a significant improvement in hepatic steatosis, inflammation, and glucose tolerance is also observed in NAM high-dose treated mice. Conclusion: NAM influences whole-body energy expenditure by driving changes in the adipose phenotype. Thus, NAM is an attractive potential treatment for preventing obesity and associated complications