The Role of Fatty Acids in Ceramide Pathways and Their Influence on Hypothalamic Regulation of Energy Balance: A Systematic Review.

Obesity is a global health issue for which no major effective treatments have been well established. High-fat diet consumption is closely related to the development of obesity because it negatively modulates the hypothalamic control of food intake due to metaflammation and lipotoxicity. The use of animal models, such as rodents, in conjunction with in vitro models of hypothalamic cells, can enhance the understanding of hypothalamic functions related to the control of energy balance, thereby providing knowledge about the impact of diet on the hypothalamus, in addition to targets for the development of new drugs that can be used in humans to decrease body weight. Recently, sphingolipids were described as having a lipotoxic effect in peripheral tissues and the central nervous system. Specifically, lipid overload, mainly from long-chain saturated fatty acids, such as palmitate, leads to excessive ceramide levels that can be sensed by the hypothalamus, triggering the dysregulation of energy balance control. However, no systematic review has been undertaken regarding studies of sphingolipids, particularly ceramide and sphingosine-1-phosphate (S1P), the hypothalamus, and obesity. This review confirms that ceramides are associated with hypothalamic dysfunction in response to metaflammation, endoplasmic reticulum (ER) stress, and lipotoxicity, leading to insulin/leptin resistance. However, in contrast to ceramide, S1P appears to be a central satiety factor in the hypothalamus. Thus, our work describes current evidence related to sphingolipids and their role in hypothalamic energy balance control. Hypothetically, the manipulation of sphingolipid levels could be useful in enabling clinicians to treat obesity, particularly by decreasing ceramide levels and the inflammation/endoplasmic reticulum stress induced in response to overfeeding with saturated fatty acids.

Bee products as a source of promising therapeutic and chemoprophylaxis strategies against COVID-19 (SARS-CoV-2).

The emergence of novel coronavirus (SARS-CoV-2) in 2019 in China marked the third outbreak of a highly pathogenic coronavirus infecting humans. The novel coronavirus disease (COVID-19) spread worldwide, becoming an emergency of major international concern. However, even after a decade of coronavirus research, there are still no licensed vaccines or therapeutic agents to treat the coronavirus infection. In this context, apitherapy presents as a promising source of pharmacological and nutraceutical agents for the treatment and/or prophylaxis of COVID-19. For instance, several honeybee products, such as honey, pollen, propolis, royal jelly, beeswax, and bee venom, have shown potent antiviral activity against pathogens that cause severe respiratory syndromes, including those caused by human coronaviruses. In addition, the benefits of these natural products to the immune system are remarkable, and many of them are involved in the induction of antibody production, maturation of immune cells, and stimulation of the innate and adaptive immune responses. Thus, in the absence of specific antivirals against SARS-CoV-2, apitherapy could offer one hope toward mitigating some of the risks associated with COVID-19.

Ruminal fatty acid outflow in dry cows fed different sources of linoleic acid: reticulum and omasum as alternative sampling sites to abomasum.

This study was designed to determine the rumen outflow of fatty acids (FA) and biohydrogenation (BH) extent using alternative sampling sites (reticulum and omasum) to abomasum in dry cows fed different sources of FA. Four Holstein non-pregnant dry cows (≥3 parturitions, and 712 ± 125 kg BW), cannulated in the rumen and abomasum, were randomly assigned to a 4 × 4 Latin square design experiment, containing the following treatments: 1) control (CON); 2) soya bean oil (SO), dietary inclusion at 30 g/kg; 3) whole raw soya beans (WS), dietary inclusion at 160 g/kg; and 4) calcium salts of FA (CSFA), dietary inclusion at 32 g/kg. Rumen outflow of nutrients was estimated using the three markers reconstitution system (cobalt-EDTA, ytterbium chloride, and indigestible neutral detergent fibre [NDF]). Diets with FA sources decreased feed intake and increased FA intake. No differences in nutrient intake and digestibility were detected among cows fed diets supplemented with different FA sources. Diets with FA sources reduced the rumen outflow of DM and NDF, hence decreasing their passage rates. In addition, SO diet reduced the ruminal outflow of DM and NDF in comparison with WS and CSFA. Omasal sampling yielded the highest values of rumen outflow of NDF and potentially degradable NDF (pdNDF), whereas the reticular and abomasal samplings yielded intermediate and least values, respectively. The interaction effect between diet and sampling site was observed for rumen outflow of majority FA (except for C16:0, C18:0, and C18:2 trans-10, cis-12) and BH extension of C18:1 cis, C18:2, and C18:3. Calculations derived from abomasal sampling revealed that WS and CSFA diets had lower BH extent of C18:1 cis and C18:2 in comparison with SO, whereas cows fed CSFA had greater BH extent of C18:3 and lower BH extent of C18:1 cis compared to those fed WS. However, the latter results were not similar when calculations were performed based on the reticular and omasal samplings. Thus, there is evidence that neither reticular nor omasal samplings are suitable for estimating rumen outflow of FA in dry cows. In addition, WS and CSFA diets can increase the abomasal flow of polyunsaturated FA in dry cows.

Substrate and inhibitor selectivity, and biological activity of an epoxide hydrolase from Trichoderma reesei.

Epoxide hydrolases (EHs) are present in all living organisms and catalyze the hydrolysis of epoxides to the corresponding vicinal diols. EH are involved in the metabolism of endogenous and exogenous epoxides, and thus have application in pharmacology and biotechnology. In this work, we describe the substrates and inhibitors selectivity of an epoxide hydrolase recently cloned from the filamentous fungus Trichoderma reesei QM9414 (TrEH). We also studied the TrEH urea-based inhibitors effects in the fungal growth. TrEH showed high activity on radioative and fluorescent surrogate and natural substrates, especially epoxides from docosahexaenoic acid. Using a fluorescent surrogate substrate, potent inhibitors of TrEH were identified. Interestingly, one of the best compounds inhibit up to 60% of T. reesei growth, indicating an endogenous role for TrEH. These data make TrEH very attractive for future studies about fungal metabolism of fatty acids and possible development of novel drugs for human diseases.

Hormone deprivation alters mitochondrial function and lipid profile in the hippocampus.

Mitochondrial dysfunction is a common hallmark in aging. In the female, reproductive senescence is characterized by loss of ovarian hormones, many of whose neuroprotective effects converge upon mitochondria. The functional integrity of mitochondria is dependent on membrane fatty acid and phospholipid composition, which are also affected during aging. The effect of long-term ovarian hormone deprivation upon mitochondrial function and its putative association with changes in mitochondrial membrane lipid profile in the hippocampus, an area primarily affected during aging and highly responsive to ovarian hormones, is unknown. To this aim, Wistar adult female rats were ovariectomized or sham-operated. Twelve weeks later, different parameters of mitochondrial function (O2 uptake, ATP production, membrane potential and respiratory complex activities) as well as membrane phospholipid content and composition were evaluated in hippocampal mitochondria. Chronic ovariectomy reduced mitochondrial O2 uptake and ATP production rates and induced membrane depolarization during active respiration without altering the activity of respiratory complexes. Mitochondrial membrane lipid profile showed no changes in cholesterol levels but higher levels of unsaturated fatty acids and a higher peroxidizability index in mitochondria from ovariectomized rats. Interestingly, ovariectomy also reduced cardiolipin content and altered cardiolipin fatty acid profile leading to a lower peroxidizability index. In conclusion, chronic ovarian hormone deprivation induces mitochondrial dysfunction and changes in the mitochondrial membrane lipid profile comparable to an aging phenotype. Our study provides insights into ovarian hormone loss-induced early lipidomic changes with bioenergetic deficits in the hippocampus that may contribute to the increased risk of Alzheimer's disease and other age-associated disorders observed in postmenopause.

Role of bioactive fatty acids in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is characterized by fat deposition in hepatocytes, and a strong association with nutritional factors. Dietary fatty acids are classified according to their biochemical properties, which confer their bioactive roles. Monounsaturated fatty acids have a dual role in various human and murine models. In contrast, polyunsaturated fatty acids exhibit antiobesity, anti steatosic and anti-inflammatory effects. The combination of these forms of fatty acids-according to dietary type, daily intake and the proportion of n-6 to n-3 fats-can compromise hepatic lipid metabolism. A chemosensory rather than a nutritional role makes bioactive fatty acids possible biomarkers for NAFLD. Bioactive fatty acids provide health benefits through modification of fatty acid composition and modulating the activity of liver cells during liver fibrosis. More and better evidence is necessary to elucidate the role of bioactive fatty acids in nutritional and clinical treatment strategies for patients with NAFLD.

Nitro-fatty acids as novel electrophilic ligands for peroxisome proliferator-activated receptors.

Lipid nitration has been observed during oxidative/nitrative stress conditions generating a variety of biomolecules capable of modulating cellular responses. This concept has grown as a result of studies with nitro-derivatives of long-chain unsaturated fatty acids containing a nitroalkene group (nitro-fatty acids). This review focuses on the interactions of nitro-fatty acids with members of the peroxisome proliferator-activated receptors (PPARs) family. These nuclear receptors belong to a superfamily of ligand-activated transcription factors, which serve as sensors of lipophilic molecules and regulate the expression of a set of genes involved in glucose and lipid metabolism. Here we discuss how nitro-fatty acids bind and activate PPARs, including the current knowledge of the molecular interactions and cell signaling events involved as well as their therapeutic potential associated with chronic inflammation and metabolic disorders.

[The role of innate immunity in obesity]. / El papel de la inmunidad innata en la obesidad.

Obesity in Mexico is alarmingly increasing in prevalence in adults and children, and it is a risk factor for the development of insulin resistance, as well as, of other metabolic alterations. The discovery of the expression of the Toll-like receptors (TLRs) in adipocytes, suggests an important role in innate immunity. In different models of obesity, there has been observed an increase of TLRs expression in the fat tissue, therefore TLRs could be involved in systemic inflammation in this disease, and in the development of insulin resistance. TLR activation is mediated by fatty acids and their expression is regulated by leptin, adiponectin and PPARs. Knowledge of the role of TLRs in inflammation and adipocyte differentiation and their regulation, then it is important to try to develop new therapeutic anti-inflammatory targets that contribute in the treatment of obesity.

El papel de la inmunidad innata en la obesidad / The role of innate immunity in obesity

La obesidad en México es un problema de salud preocupante por el incremento en la prevalencia en adultos y niños, y se considera un factor de riesgo para el desarrollo de resistencia a la insulina, así como de otras alteraciones metabólicas. En esta patología se ha observado un incremento en la expresión de los receptores tipo Toll (TLRs) en el adipocito, receptores con participación crucial en la respuesta inmune innata. Se propone que los TLRs están implicados en la inflamación sistémica y en el desarrollo de la resistencia a la insulina. La activación de los TLRs es mediada por ácidos grasos y su expresión está regulada por leptina, adiponectina y PPAR. El conocimiento de la función de los TLRs, tanto en la inflamación como en la diferenciación del adipocito es importante en la búsqueda de nuevos blancos terapéuticos antiinflamatorios que coadyuven en el tratamiento de la obesidad.

Obesity in Mexico is alarmingly increasing in prevalence in adults and children, and it is a risk factor for the development of insulin resistance, as well as, of other metabolic alterations. The discovery of the expression of the Toll-like receptors (TLRs) in adipocytes, suggests an important role in innate immunity. In different models of obesity, there has been observed an increase of TLRs expression in the fat tissue, therefore TLRs could be involved in systemic inflammation in this disease, and in the development of insulin resistance. TLR activation is mediated by fatty acids and their expression is regulated by leptin, adiponectin and PPARs. Knowledge of the role of TLRs in inflammation and adipocyte differentiation and their regulation, then it is important to try to develop new therapeutic anti-inflammatory targets that contribute in the treatment of obesity.

A proteomic analysis of the functional effects of fatty acids in NIH 3T3 fibroblasts.

Previous studies have demonstrated that long chain fatty acids influence fibroblast function at sub-lethal concentrations. This study is the first to assess the effects of oleic, linoleic or palmitic acids on protein expression of fibroblasts, as determined by standard proteomic techniques. The fatty acids were not cytotoxic at the concentration used in this work as assessed by membrane integrity, DNA fragmentation and the MTT assay but significantly increased cell proliferation. Subsequently, a proteomic analysis was performed using two dimensional difference gel electrophoresis (2D-DIGE) and MS based identification. Cells treated with 50 µM oleic, linoleic or palmitic acid for 24 h were associated with 24, 22, 16 spots differentially expressed, respectively. Among the identified proteins, α-enolase and far upstream element binding protein 1 (FBP-1) are of importance due to their function in fibroblast-associated diseases. However, modulation of α-enolase and FBP-1 expression by fatty acids was not validated by the Western blot technique.

Motilidad intestinal y microflora / Intestinal motility and microflora

La microflora es el conjunto de colonias microbacterianas que cubren la superficie del tubo digestivo. Cada sujeto humano alberga unos 100 billones de colonias de unas 400 especies distintas, biodiversidad que facilita la vida y el desarrollo del conjunto. La concentración de bacterias va aumentando a lo largo del tubo digestivo, alcanzando concentraciones de 1012 UFC/ml. en el colon. La motilidad del intestino delgado es propulsiva con una fase de barrido que no permite el crecimiento de bacterias. Por el contrario, la motilidad del colon es muy lenta y no propulsiva durante el ayuno y el sueño. Sólo en vigilia y en período postprandial existen ondas de contracción de alta amplitud y rápidamente progresivas en dirección oral-anal. La interacción entre las bacterias presentes en el lumen y las ondas de contracción motora es muy difícil de evaluar. Este efecto se ha estudiado en base a los fármacos que alteran la motilidad y que al aumentar ésta, barren con la flora bacteriana presente. En ese sentido se sabe que el uso de cisaprida acelera el tránsito, reduciendo la densidad de bacterias metanogénicas con un aumento de la excreción de hidrógeno. En cambio, loperamida disminuye el tránsito, aumentando la flora metanogénica (hecho que representa lo que sucede a pacientes constipadas, que tienen flora mayoritariamente productora de metano). Conclusión: La interacción entre motilidad y flora bacteriana es compleja y está poco estudiada fundamentalmente debido a dificultades técnicas.

Microflora is the set of microbacterium colonies covering the digestive tract surface. Each human subject hosts ca. 100 billions of colonies of 400 different species, b23wiodiversity that facilitates life and development of the whole. Bacteria concentration increases throughout the digestive tract, reaching concentrations of 1012 CFU/ml in the colon. Motility of the small intestine is propulsive with a sweeping phase, allowing for the growth of bacteria. On the contrary, motility of the colon is very slow and non-propulsive during fasting and sleeping. Only during wakefulness and postprandial period there are wide-ranging and quickly progressive contraction waves in oral-anal direction. Interaction between bacteria present in lumen and the contraction waves is very hard to assess. This effect has been studied based on drugs that alter motility, and when it increases, they sweep the existing gut flora. In this sense, it is known that the use of cisapride accelerates the transit, reducing the density of methanogenic bacteria with an increase in the hydrogen excretion. On the other hand, loperamide slows down transit, causing an increase of the methanogenic flora (which represents what happens to constipated patients with flora that produces mainly methane). Conclusion: Interaction between motility and gut flora is complex and has not been enough studied mainly due to technical difficulties.

Boundary lipids in the nicotinic acetylcholine receptor microenvironment.

The structural and functional properties of the nicotinic acetylcholine receptor (AChR), the archetype molecule in the superfamily of Cys-looped ligand-gated ion channels, are strongly dependent on the lipids in the vicinal microenvironment. The influence on receptor properties is mainly exerted by the AChR-vicinal ("shell" or "annular") lipids, which occur in the liquid-ordered phase as opposed to the more disordered and "fluid" bulk membrane lipids. Fluorescence studies from our laboratory have identified discrete sites for fatty acids, phospholipids, and cholesterol on the AChR protein, and electron-spin resonance spectroscopy has enabled the establishment of the stoichiometry and selectivity of the shell lipid for the AChR and the disclosure of lipid sites in the AChR transmembrane region. Experimental evidence supports the notion that the interface between the protein moiety and the adjacent lipid shell is the locus of a variety of pharmacologically relevant processes, including the action of steroids and other lipids. I surmise that the outermost ring of M4 helices constitutes the boundary interface, most suitable to convey the signals from the lipid microenvironment to the rest of the transmembrane region, and to the channel inner ring in particular.

Modulação da ativação dos receptores ativados por proliferadores de peroxissoma (PPAR) e dos receptores X hepáticos (LXR) por LN´O IND. 2´ / Modulation of activity of peroxissome prolifetor-activated (PPAR) and liver X receptors(LXR) by LN´O IND. 2´

A atividade dos receptores ativados por proliferadores de peroxissoma (PPAR) e receptor X hepático (LXR) são regulados por ácidos graxos. Entretanto, o papel do LNO2, um produto endógeno da nitração do ácido linoléico por espécies reativas derivadas de óxido nítrico (•NO), na via de sinalização que regula a ativação destes receptores ainda não está elucidada. Assim, considerando a propriedade do LNO2 como doador de NO, nós investigamos a participação da via de sinalização p21Ras/Raf/ERK na ativação de PPAR e LXR por LNO2. Os resultados obtidos demonstraram que LNO2, na concentração de 0.01µM, foi um potente ativador de PPAR quando comparado ao ligante natural ácido linoléico, o qual apresentou ativação equivalente do PPAR na concentração de 0.01µM. O LN02, contudo não teve efeito na ativação de LXR. LNO2 foi um potente ativador de p21Ras quando comparado ao ácido linoléico. A ativação de Ras ocorreu após 5 minutos de incubação com LNO2 em células parentais. Entretanto, em células transfectadas com p21RasC118S, o LNO2 não foi capaz de ativar Ras. A ativação de Ras e PP AR foi dependente da liberação de NO a partir de LN02, o que foi evidenciado na presença de C-PTIO, um seqüestrador de NO. LNO2 ativou ERK, mas não demonstrou efeito relevante na ativação de p38 MAP kinase...

Mechanisms by which fatty acids regulate leucocyte function.

Fatty acids (FAs) have been shown to alter leucocyte function and thus to modulate inflammatory and immune responses. In this review, the effects of FAs on several aspects of lymphocyte, neutrophil and macrophage function are discussed. The mechanisms by which FAs modulate the production of lipid mediators, activity of intracellular signalling pathways, activity of lipid-raft-associated proteins, binding to TLRs (Toll-like receptors), control of gene expression, activation of transcription factors, induction of cell death and production of reactive oxygen and nitrogen species are described in this review. The rationale for the use of specific FAs to treat patients with impaired immune function is explained. Substantial improvement in the therapeutic usage of FAs or FA derivatives may be possible based on an improvement in the understanding of the precise molecular mechanisms of action with respect to the different leucocyte types and outcome with respect to the inflammatory responses.

cAMP increases mitochondrial cholesterol transport through the induction of arachidonic acid release inside this organelle in Leydig cells.

We have investigated the direct effect of arachidonic acid on cholesterol transport in intact cells or isolated mitochondria from steroidogenic cells and the effect of cyclic-AMP on the specific release of this fatty acid inside the mitochondria. We show for the first time that cyclic-AMP can regulate the release of arachidonic acid in a specialized compartment of MA-10 Leydig cells, e.g. the mitochondria, and that the fatty acid induces cholesterol transport through a mechanism different from the classical pathway. Arachidonic acid and arachidonoyl-CoA can stimulate cholesterol transport in isolated mitochondria from nonstimulated cells. The effect of arachidonoyl-CoA is inhibited by the reduction in the expression or in the activity of a mitochondrial thioesterase that uses arachidonoyl-CoA as a substrate to release arachidonic acid. cAMP-induced arachidonic acid accumulation into the mitochondria is also reduced when the mitochondrial thioesterase activity or expression is blocked. This new feature in the regulation of cholesterol transport by arachidonic acid and the release of arachidonic acid in specialized compartment of the cells could offer novel means for understanding the regulation of steroid synthesis but also would be important in other situations such as neuropathological disorders or oncology disorders, where cholesterol transport plays an important role.

Dietary fatty acids early in life affect lipid metabolism and adiposity in young rats.

The purpose of this study was to evaluate the effects of four isoenergetic diets of differing fat composition on blood lipid profile and adiposity in young rats. Diets containing different lipid sources--partially hydrogenated vegetable oil (PHVO), palm oil (PO), canola oil (CO), and soy oil (SO)--were fed to lactating rats during the 21 days of lactation, and then fed to young males following weaning until the 45th day of life. In vivo lipogenesis rate (LR), lipid content (LC), relative level of FA, and the activity of lipoprotein lipase (LPL) enzyme were measured in epididymal adipose tissue (EPI). Fasting blood lipoproteins and LC in the carcass were also appraised. Body weight of PO and PHVO groups was significantly higher than CO and SO groups from day 14 of lactation to day 45, despite the lower food intake in the PHVO group. PO and PHVO groups presented higher LR and LC in EPI than SO and CO groups. Carcass fat content was significantly higher in PHVO and PO groups than in CO and SO groups. The LPL activity in EPI was unaffected by dietary lipids. PHVO group had increased total cholesterol and TAG concentrations in comparison with the PO group, and significantly lower HDL level compared with the other groups. These results show that the kind of FA in the dietary lipid offered early in life can affect lipid metabolism and adiposity.

Role of fatty acids in the transition from anaerobic to aerobic metabolism in skeletal muscle during exercise.

In moderate physical exercise, the transition from predominantly anaerobic towards predominantly aerobic metabolism is a key step to improve performance. Increase in the supply of oxygen and nutrients, such as free fatty acids (FFA) and glucose, which accompanies high blood flow, is required for this transition. The mechanisms involved in the vasodilation in skeletal muscle during physical activity are not completely known yet. In this article, we postulate a role of FFA and heat production in this process. The presence of uncoupling protein-2 and -3 (UCP-2 and -3) in skeletal muscle, whose activity is dependent on FFA, suggests that these metabolites can act as mitochondrial uncouplers in this tissue. Evidence indicates however that UCPs act as uncouplers only when coenzyme Q is predominantly in the reduced state (i.e. under nonphosphorylation conditions or state 4 respiration) as is observed in resting muscles and in the beginning of physical activity (predominantly anaerobic metabolism). The increase in the lipolytic activity in adipose tissue in the beginning of physical activity results in elevated plasma FFA levels. The FFA can then act on the UCPs, increasing the local heat production. We propose that this calorigenic effect of FFA is important to activate nitric oxide synthase, resulting in nitric oxide production and consequent vasodilation. Therefore, FFA would be important mediators for the changes that occur in muscle metabolism during prolonged physical activity, ensuring the appropriate supply of oxygen and nutrients by increasing blood flow at the beginning of exercise in the contracting skeletal muscles.

Cambios en los acidos grasos de membranas de Microbacterium esteraromaticum GNP-5 con diferentes temperaturas y osmolaridades / Changes in Membrane Fatty Acids of Microbacterium esteraromaticum GNP5 with Changes of Temperature and Osmolarity

Microbacterium esteraromaticum es un microorganismo que se aísla con frecuencia de landfarming o procesos de biorremediación de hidrocarburos en la meseta de la Patagonia central (Argentina) y se halla sometido a variaciones de temperatura y a cambios de salinidad que se producen naturalmente. Su adaptabilidad a esos cambios climáticos indujo al estudio de las modificaciones que se producen en su membrana celular para resistirlos. En este trabajo se estudió el efecto conjunto de la temperatura y la concentración de cloruro de sodio sobre la composición de los ácidos grasos de membrana en la cepa de Microbacterium esteraromaticum GNP5b. M. esteraromaticum utiliza, frente al incremento de la temperatura, la estrategia es aumentar la longitud de sus ácidos grasos de cadenas ramificada impar (17 átomos de carbono) con disminución de 15:0 anteiso, así como el porcentaje de ácidos grasos 15:0 iso (de mayor punto de fusión) a partir del respectivo anteiso. El aumento de la salinidad modifica la composición de ácidos grasos siguiendo patrones diferentes según sea la temperatura de incubación. A 14 y 28 °C incrementa los 15:0 iso y 17:0 iso en detrimento de sus homólogos anteiso. A 37 °C este grupo de ácidos grasos no sigue los mismos patrones anteriores. La longitud de cadena, expresada como el índice C15/C17, es errática con el aumento de la salinidad.

[Cytokines, endothelial dysfunction, and insulin resistance]. / Citocinas, disfunção endotelial e resistência à insulina.

Endothelial dysfunction is associated with several vascular conditions as atherosclerosis, hypertension, hyperlipidemia and diabetes mellitus. In all these conditions insulin resistance (IR) is present. Cytokines are low molecular weight proteins with several endocrine and metabolic functions that participate of inflammation and immune response. Several of these cytokines are independent risk factors for cerebrovascular and coronary artery disease. The major sources of cytokines (adipokines) are the visceral and subcutaneous adipose tissues. Thus, increased adipose tissue mass is associated with alteration in adipokine production as over expression of tumor necrosis factor alpha, interleukin 6, plasminogen activator inhibitor 1, and under expression of adiponectin in adipocite tissue. The pro-inflammatory status associated with these changes provides a potential link between IR and endothelial dysfunction, the early stage in the atherosclerotic process, in obese individuals, and type 2 diabetic patients. Reduction of adipose tissue mass through weight reduction in association with exercise reduces TNF-alpha, IL-6, and PAI-1, increases adiponectin, and is associated with improved insulin sensitivity and endothelial function. This review will focus on the evidence for regulation of endothelial function by insulin and the adypokines such as adyponectin, leptin, resistin, IL-6 and TNF-alpha. Interaction between insulin signaling and adypokines will be discussed, as well as the concept that aberrant adypokine secretion in IR and/or obesity impairs endothelial function and contributes further to reduce insulin sensitivity.