Serum Fatty Acid Binding Protein 4 (FABP4) Predicts Pre-eclampsia in Women with Type 1 Diabetes

Objective: To examine the association between fatty acid binding protein 4 (FABP4) and pre-eclampsia risk in women with type 1 diabetes.
Reesearch Design and Methods: Serum FABP4 was measured in 710 women from the Diabetes and Pre-eclampsia Intervention Trial (DAPIT) in early pregnancy and in the second trimester (median 14 and 26 weeks gestation, respectively).
Results: FABP4 was significantly elevated in early pregnancy (geometric mean 15.8 ng/mL [interquartile range 11.6–21.4] vs. 12.7 ng/mL [interquartile range 9.6–17]; P < 0.001) and the second trimester (18.8 ng/mL [interquartile range 13.6–25.8] vs. 14.6 ng/mL [interquartile range 10.8–19.7]; P < 0.001) in women in whom pre-eclampsia later developed. Elevated second-trimester FABP4 level was independently associated with pre-eclampsia (odds ratio 2.87 [95% CI 1.24, 6.68], P = 0.03). The addition of FABP4 to established risk factors significantly improved net reclassification improvement at both time points and integrated discrimination improvement in the second trimester.
Conclusions: Increased second-trimester FABP4 independently predicted pre-eclampsia and significantly improved reclassification and discrimination. FABP4 shows potential as a novel biomarker for pre-eclampsia prediction in women with type 1 diabetes.

Free fatty acid receptor 1 (GPR40) agonists containing spirocyclic periphery inspired by LY2881835

The free fatty acid receptor 1 (FFA1), a G protein-coupled receptor (GPCR) naturally activated by long-chain fatty acids is a novel target for the treatment of metabolic diseases. The basic amine spirocyclic periphery of Eli Lilly's drug candidate LY2881835 for treatment of type 2 diabetes mellitus (which reached phase I clinical trials) inspired a series of novel FFA1 agonists. These were designed to incorporate the 3-[4-(benzyloxy)phenyl]propanoic acid pharmacophore core decorated with a range of spirocyclic motifs. The latter were prepared via the Prins cyclization and subsequent modification of the 4-hydroxytetrahydropyran moiety in the Prins product. Here, we synthesize 19 compounds and test for FFA1 activity. Within this pilot set, a nanomolar potency (EC50=55nM) was reached. Four lead compounds (EC50 range 55-410nM) were characterized for aqueous solubility, metabolic stability, plasma protein binding and Caco-2 permeability. While some instability in the presence of mouse liver microsomes was noted, mouse pharmacokinetic profile of the compound having the best overall ADME properties was evaluated to reveal acceptable bioavailability (F=10.3%) and plasma levels achieved on oral administration.

Application of GPCR Structures for Modelling of Free Fatty Acid Receptors

Five G protein-coupled receptors (GPCRs) have been identified to be activated by free fatty acids (FFA). Among them, FFA1 (GPR40) and FFA4 (GPR120) bind long-chain fatty acids, FFA2 (GPR43) and FFA3 (GPR41) bind short-chain fatty acids and GPR84 binds medium-chain fatty acids. Free fatty acid receptors have now emerged as potential targets for the treatment of diabetes, obesity and immune diseases. The recent progress in crystallography of GPCRs has now enabled the elucidation of the structure of FFA1 and provided reliable templates for homology modelling of other FFA receptors. Analysis of the crystal structure and improved homology models, along with mutagenesis data and structure activity, highlighted an unusual arginine charge pairing interaction in FFA1-3 for receptor modulation, distinct structural features for ligand binding to FFA1 and FFA4 and an arginine of the second extracellular loop as a possible anchoring point for FFA at GPR84. Structural data will be helpful for searching novel small molecule modulators at the FFA receptors.

Comparison of prophylactic and therapeutic use of short-chain fatty acid enemas in diversion colitis: a study in Wistar rats

OBJECTIVES: To study the effect of short-chain fatty-acids on atrophy and inflammation of excluded colonic segments before and after the development of diversion colitis. INTRODUCTION: Diversion colitis is a chronic inflammatory process affecting the dysfunctional colon, possibly evolving with mucous and blood discharge. The most favored hypotheses to explain its development is short-chain fatty-acid deficiency in the colon lumen. METHODS: Wistar rats were submitted to colostomy with distal colon exclusion. Two control groups (A1 and B1) received rectally administered physiological saline, whereas two experimental groups (A2 and B2) received rectally administered short-chain fatty-acids. The A groups were prophylactically treated (5th to 40th days postoperatively), whereas the B groups were therapeutically treated (after post-operative day 40). The mucosal thickness of the excluded colon was measured histologically. The inflammatory reaction of the mucosal lamina propria and the lymphoid tissue response were quantified through established scores. RESULTS: There was a significant thickness recovery of the colonic mucosa in group B2 animals (p = 0.0001), which also exhibited a significant reduction in the number of eosinophilic polymorphonuclear cells in the lamina propria (p = 0.0126) and in the intestinal lumen (p = 0.0256). Group A2 showed no mucosal thickness recovery and significant increases in the numbers of lymphocytes (p = 0.0006) and eosinophilic polymorphonuclear cells in the lamina propria of the mucosa (p = 0.0022). CONCLUSION: Therapeutic use of short-chain fatty-acids significantly reduced eosinophilic polymorphonuclear cell numbers in the intestinal wall and in the colonic lumen; it also reversed the atrophy of the colonic mucosa. Prophylactic use did not impede the development of mucosal atrophy

Perturbations in Blood Phosphatidylcholine and Sphingomyelin Fatty Acid Composition in a Sample Population of Cigarette Smokers

Docosahexaenoic (DHA) and arachidonic acids (AA) are polyunsaturated fatty acids (PUFAs), major components of brain tissue and neural systems, and the precursors of a number of biologically active metabolites with functions in inflammation resolution, neuroprotection and other actions. As PUFAs are highly susceptible to peroxidation, we hypothesised whether cigarette smokers would present altered PUFAs levels in plasma and erythrocyte phospholipids. Adult males from Indian, Sri-Lankan or Bangladeshi genetic backgrounds who reported smoking between 20 and 60 cigarettes per week were recruited. The control group consisted of matched non-smokers. A blood sample was taken, plasma and erythrocyte total lipids were extracted, phospholipids were separated by thin layer chromatography, and the fatty acid content analysed by gas chromatography. In smokers, dihomo-gamma-linolenic acid, the AA precursor, was significantly reduced in plasma and erythrocyte phosphatidylcholine. AA and DHA were significantly reduced in erythrocyte sphingomyelin. Relatively short term smoking has affected the fatty acid composition of plasma and erythrocyte phospholipids with functions in neural tissue composition, cell signalling, cell growth, intracellular trafficking, neuroprotection and inflammation, in a relatively young population. As lipid peroxidation is pivotal in the pathogenesis of atherosclerosis and neurodegenerative diseases such as Alzheimer disease, early effects of smoking may be relevant for the development of such conditions.

Effect of insulin resistance on monounsaturated fatty acid levels : a multi-cohort non-targeted metabolomics and mendelian randomization study

Insulin resistance (IR) and impaired insulin secretion contribute to type 2 diabetes and cardiovascular disease. Both are associated with changes in the circulating metabolome, but causal directions have been difficult to disentangle. We combined untargeted plasma metabolomics by liquid chromatography/mass spectrometry in three non-diabetic cohorts with Mendelian Randomization (MR) analysis to obtain new insights into early metabolic alterations in IR and impaired insulin secretion. In up to 910 elderly men we found associations of 52 metabolites with hyperinsulinemic-euglycemic clamp-measured IR and/or β-cell responsiveness (disposition index) during an oral glucose tolerance test. These implicated bile acid, glycerophospholipid and caffeine metabolism for IR and fatty acid biosynthesis for impaired insulin secretion. In MR analysis in two separate cohorts (n = 2,613) followed by replication in three independent studies profiled on different metabolomics platforms (n = 7,824 / 8,961 / 8,330), we discovered and replicated causal effects of IR on lower levels of palmitoleic acid and oleic acid. A trend for a causal effect of IR on higher levels of tyrosine reached significance only in meta-analysis. In one of the largest studies combining "gold standard" measures for insulin responsiveness with non-targeted metabolomics, we found distinct metabolic profiles related to IR or impaired insulin secretion. We speculate that the causal effects on monounsaturated fatty acid levels could explain parts of the raised cardiovascular disease risk in IR that is independent of diabetes development.

Outcome of the Public Consultation on the Draft Opinion of the Scientific Panel on Dietetic Products, Nutrition, and Allergies (NDA) on Dietary Reference Values for Fats, Including Saturated Fatty Acids, Polyunsaturated Fatty Acids, Monounsaturated Fatty Acids, Trans Fatty Acids, and Cholesterol

On 2 July 2009, the EFSA Panel on Dietetic products, Nutrition and Allergies (NDA) endorsed a draft Opinion on Dietary Reference Values for fats to be released for public consultation. This Scientific Report summarises the comments received through the public consultation and outlines how these were taken into account in the final opinion. EFSA had received contributions from 40 interested parties (individuals, non-governmental organisations, industry organisations, academia and national assessment bodies). The main comments which were received during the public consultation related to: the availability of more recent data, the nomenclature used, the use of a non-European food composition data base, the impact of genetic factors in modulating the absorption, metabolism and health effects of different fatty acids, the definition of “nutritionally adequate diet”, the use of Dietary Reference Values in the labelling of foods, the translation of advice into food-based dietary guidelines, nutrient goals and recommendations, certain risk management issues, and to Dietary Reference Values of fats, individual fatty acids, and cholesterol. All the public comments received that related to the remit of EFSA were assessed and the Opinion on Dietary Reference Values for fats has been revised taking relevant comments into consideration.

Fatty acid synthesis from U-14C glucose, U-14C fructose, L-U-14C alanine and 3H2O in liver slices and adipose tissue from Bar-Harbor obese-hyperglycemic mice.

info:eu-repo/semantics/published

Role of mitochondrial antioxidant defense systems in fatty acid β-oxidation defects

Mitochondrial fatty acid oxidation (FAO) plays a pivotal role in energy homeostasis, namely during periods of fasting or metabolic stress. FAO defects are a group of inherited metabolic disorders that encompass at least twelve distinct enzyme or transporter deficiencies, and can present with a wide range of clinical symptoms with various degrees of severity. Besides recent advances, many doubts still remain on the degree and characteristics of mitochondrial dysfunction on FAOD and its contribution to the clinical phenotype.

Isotope and fatty acid trends along continental shelf depth gradients: Inshore versus offshore hydrological influences on benthic trophic functioning

Anthropogenic activities and land-based inputs into the sea may influence the trophic structure and functioning of coastal and continental shelf ecosystems, despite the numerous opportunities and services the latter offer to humans and wildlife. In addition, hydrological structures and physical dynamics potentially influence the sources of organic matter (e.g., terrestrial versus marine, or fresh material versus detrital material) entering marine food webs. Understanding the significance of the processes that influence marine food webs and ecosystems (e.g., terrestrial inputs, physical dynamics) is crucially important because trophic dynamics are a vital part of ecosystem integrity. This can be achieved by identifying organic matter sources that enter food webs along inshore–offshore transects. We hypothesised that regional hydrological structures over wide continental shelves directly control the benthic trophic functioning across the shelf. We investigated this issue along two transects in the northern ecosystem of the Bay of Biscay (north-eastern Atlantic). Carbon and nitrogen stable isotope analysis (SIA) and fatty acid analysis (FAA) were conducted on different complementary ecosystem compartments that include suspended particulate organic matter (POM), sedimentary organic matter (SOM), and benthic consumers such as bivalves, large crustaceans and demersal fish. Samples were collected from inshore shallow waters (at ∼1 m in depth) to more than 200 m in depth on the offshore shelf break. Results indicated strong discrepancies in stable isotope (SI) and fatty acid (FA) compositions in the sampled compartments between inshore and offshore areas, although nitrogen SI (δ15N) and FA trends were similar along both transects. Offshore the influence of a permanently stratified area (described previously as a “cold pool”) was evident in both transects. The influence of this hydrological structure on benthic trophic functioning (i.e., on the food sources available for consumers) was especially apparent across the northern transect, due to unusual carbon isotope compositions (δ13C) in the compartments. At stations under the cold pool, SI and FA organism compositions indicated benthic trophic functioning based on a microbial food web, including a significant contribution of heterotrophic planktonic organisms and/or of SOM, notably in stations under the cold pool. On the contrary, inshore and shelf break areas were characterised by a microalgae-based food web (at least in part for the shelf break area, due to slope current and upwelling that can favour fresh primary production sinking on site). SIA and FAA were relevant and complementary tools, and consumers better medium- to long-term system integrators than POM samples, for depicting the trophic functioning and dynamics along inshore–offshore transects over continental shelves.

Analgesic Effects of Fatty Acid Amide Hydrolase Inhibition in a Rat Model of Neuropathic Pain

Cannabinoid-based medicines have therapeutic potential for the treatment of pain. Augmentation of levels of endocannabinoids with inhibitors of fatty acid amide hydrolase (FAAH) is analgesic in models of acute and inflammatory pain states. The aim of this study was to determine whether local inhibition of FAAH alters nociceptive responses of spinal neurons in the spinal nerve ligation model of neuropathic pain. Electrophysiological studies were performed 14-18 days after spinal nerve ligation or sham surgery, and the effects of the FAAHinhibitor cyclohexylcarbamic acid 3-carbamoyl biphenyl-3-yl ester (URB597) on mechanically evoked responses of spinal neurons and levels of endocannabinoids were determined. Intraplantar URB597 (25 _g in 50 _l) significantly ( p _ 0.01) attenuated mechanically evoked responses of spinal neurons in sham-operated rats. Effects of URB597 were blocked by the cannabinoid 1 receptor (CB1 ) antagonist AM251 [N-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide] (30_g in50_l) and the opioid receptor antagonist naloxone. URB597 treatment increased levels of anandamide, 2-arachidonyl glycerol, and oleoyl ethanolamide in the ipsilateral hindpaw of shamoperated rats. Intraplantar URB597 (25 _g in 50 _l) did not, however, alter mechanically evoked responses of spinal neurons in spinal nerve ligated (SNL) rats or hindpaw levels of endocannabinoids. Intraplantar injection of a higher dose of URB597 (100 _g in 50 _l) significantly ( p_0.05) attenuated evoked responses of spinal neurons in SNL rats but did not alter hindpaw levels of endocannabinoids. Spinal administration of URB597 attenuated evoked responses of spinal neurons and elevated levels of endocannabinoids in shamoperated and SNL rats. These data suggest that peripheral FAAH activity may be altered or that alternative pathways of metabolism have greater importance in SNL rats.

Comparison of prophylactic and therapeutic use of short-chain fatty acid enemas in diversion colitis: a study in Wistar rats

OBJECTIVES: To study the effect of short-chain fatty-acids on atrophy and inflammation of excluded colonic segments before and after the development of diversion colitis. INTRODUCTION: Diversion colitis is a chronic inflammatory process affecting the dysfunctional colon, possibly evolving with mucous and blood discharge. The most favored hypotheses to explain its development is short-chain fatty-acid deficiency in the colon lumen. METHODS: Wistar rats were submitted to colostomy with distal colon exclusion. Two control groups (A1 and B1) received rectally administered physiological saline, whereas two experimental groups (A2 and B2) received rectally administered short-chain fatty-acids. The A groups were prophylactically treated (5th to 40th days postoperatively), whereas the B groups were therapeutically treated (after post-operative day 40). The mucosal thickness of the excluded colon was measured histologically. The inflammatory reaction of the mucosal lamina propria and the lymphoid tissue response were quantified through established scores. RESULTS: There was a significant thickness recovery of the colonic mucosa in group B2 animals (p = 0.0001), which also exhibited a significant reduction in the number of eosinophilic polymorphonuclear cells in the lamina propria (p = 0.0126) and in the intestinal lumen (p = 0.0256). Group A2 showed no mucosal thickness recovery and significant increases in the numbers of lymphocytes (p = 0.0006) and eosinophilic polymorphonuclear cells in the lamina propria of the mucosa (p = 0.0022). CONCLUSION: Therapeutic use of short-chain fatty-acids significantly reduced eosinophilic polymorphonuclear cell numbers in the intestinal wall and in the colonic lumen; it also reversed the atrophy of the colonic mucosa. Prophylactic use did not impede the development of mucosal atrophy

Adding value to the meat of spent laying hens manufacturing sausages with a healthy appeal

The aim of this study was to evaluate the viability of the use of spent laying hens' meat in the manufacturing of mortadella-type sausages with healthy appeal by using vegetable oil instead of animal fat. 120 Hy-line® layer hens were distributed in a completely randomized design into two treatments of six replicates with ten birds each. The treatments were birds from light Hy-line® W36 and semi-heavy Hy-line® Brown lines. Cold carcass, wing, breast and leg fillets yields were determined. Dry matter, protein, and lipid contents were determined in breast and leg fillets. The breast and legg fillets of three replicates per treatment were used to manufacture mortadella. After processing, sausages were evaluated for proximal composition, objective color, microbiological parameters, fatty acid profile and sensory acceptance. The meat of light and semi-heavy spent hens presented good yield and composition, allowing it to be used as raw material for the manufacture of processed products. Mortadellas were safe from microbiological point of view, and those made with semi-heavy hens fillets were redder and better accepted by consumers. Values for all sensory attributes were evaluated over score 5 (neither liked nor disliked). Both products presented high polyunsaturated fatty acid contents and good polyunsaturated to saturated fatty acid ratio. The excellent potential for the use of meat from spent layer hens of both varieties in the manufacturing of healthier mortadella-type sausage was demonstrated.

Dietary proteins and atherosclerosis.

More than one hundred years ago the "protein hypothesis" of the pathogenesis of atherosclerosis and its association with cardiovascular disease was put forward on the basis of animal experiments; however, it has so far never been verified in humans. This theory was soon replaced by the "lipid hypothesis", which was confirmed in humans as of 1994. Epidemiological ecological studies in the 1960 s showed significant associations between dietary animal protein and mortality from cardiovascular disease. However, animal protein intake was also significantly correlated with saturated fatty acid and cholesterol intake. In the last decades two prospective cohort studies demonstrated a decreased cardiovascular risk in women during high- versus low-protein intake when adjusting for other dietary factors (e. g., saturated fats) and other cardiovascular risk factors. A direct cholesterol lowering effect of proteins has not been shown. Despite earlier research indicating that soy protein has cardioprotective effects as compared to other proteins, these observations have not been confirmed by randomized placebo-controlled trials. However, most experts recommend the consumption of foods rich in plant proteins as alternatives to meat and dairy products rich in saturated fat and containing cholesterol. There are no scientific arguments to increase the daily protein intake to more than 20 % of total energy intake as recommended by the guidelines, in order to improve cardiovascular health.

PPARβ/δ activation blocks lipid-induced inflammatory pathways in mouse heart and human cardiac cells.

Owing to its high fat content, the classical Western diet has a range of adverse effects on the heart, including enhanced inflammation, hypertrophy, and contractile dysfunction. Proinflammatory factors secreted by cardiac cells, which are under the transcriptional control of nuclear factor-κB (NF-κB), may contribute to heart failure and dilated cardiomyopathy. The underlying mechanisms are complex, since they are linked to systemic metabolic abnormalities and changes in cardiomyocyte phenotype. Peroxisome proliferator-activated receptors (PPARs) are transcription factors that regulate metabolism and are capable of limiting myocardial inflammation and hypertrophy via inhibition of NF-κB. Since PPARβ/δ is the most prevalent PPAR isoform in the heart, we analyzed the effects of the PPARβ/δ agonist GW501516 on inflammatory parameters. A high-fat diet induced the expression of tumor necrosis factor-α, monocyte chemoattractant protein-1, and interleukin-6, and enhanced the activity of NF-κB in the heart of mice. GW501516 abrogated this enhanced proinflammatory profile. Similar results were obtained when human cardiac AC16 cells exposed to palmitate were coincubated with GW501516. PPARβ/δ activation by GW501516 enhanced the physical interaction between PPARβ/δ and p65, which suggests that this mechanism may also interfere NF-κB transactivation capacity in the heart. GW501516-induced PPARβ/δ activation can attenuate the inflammatory response induced in human cardiac AC16 cells exposed to the saturated fatty acid palmitate and in mice fed a high-fat diet. This is relevant, especially taking into account that PPARβ/δ has been postulated as a potential target in the treatment of obesity and the insulin resistance state.