Metabolic Syndrome Phenotype Research Articles

Intestinal human carboxylesterase 2 (CES2) expression rescues drug metabolism and most metabolic syndrome phenotypes in global Ces2 cluster knockout mice.

Carboxylesterase 2 (CES2) is expressed mainly in liver and intestine, but most abundantly in intestine. It hydrolyzes carboxylester, thioester, and amide bonds in many exogenous and endogenous compounds, including lipids. CES2 therefore not only plays an important role in the metabolism of many (pro-)drugs, toxins and pesticides, directly influencing pharmacology and toxicology in humans, but it is also involved in energy homeostasis, affecting lipid and glucose metabolism. In this study we investigated the pharmacological and physiological functions of CES2. We constructed Ces2 cluster knockout mice lacking all eight Ces2 genes (Ces2-/- strain) as well as humanized hepatic or intestinal CES2 transgenic strains in this Ces2-/- background. We showed that oral availability and tissue disposition of capecitabine were drastically increased in Ces2-/- mice, and tissue-specifically decreased by intestinal and hepatic human CES2 (hCES2) activity. The metabolism of the chemotherapeutic agent vinorelbine was strongly reduced in Ces2-/- mice, but only marginally rescued by hCES2 expression. On the other hand, Ces2-/- mice exhibited fatty liver, adipositis, hypercholesterolemia and diminished glucose tolerance and insulin sensitivity, but without body mass changes. Paradoxically, hepatic hCES2 expression rescued these metabolic phenotypes but increased liver size, adipose tissue mass and overall body weight, suggesting a "healthy" obesity phenotype. In contrast, intestinal hCES2 expression efficiently rescued all phenotypes, and even improved some parameters, including body weight, relative to the wild-type baseline values. Our results suggest that the induction of intestinal hCES2 may combat most, if not all, of the adverse effects of metabolic syndrome. These CES2 mouse models will provide powerful preclinical tools to enhance drug development, increase physiological insights, and explore potential solutions for metabolic syndrome-associated disorders.

Associations of Adipokine Levels With Levels of Remnant Cholesterol: The Multi-Ethnic Study of Atherosclerosis.

The metabolic syndrome phenotype of individuals with obesity is characterized by elevated levels of triglyceride-rich lipoproteins and remnant particles, which have been shown to be significantly atherogenic. Understanding the association between adipokines, endogenous hormones produced by adipose tissue, and remnant cholesterol (RC) would give insight into the link between obesity and atherosclerotic cardiovascular disease. We studied 1791 MESA (Multi-Ethnic Study of Atherosclerosis) participants who took part in an ancillary study on body composition with adipokine levels measured (leptin, adiponectin, and resistin) at either visit 2 or visit 3. RC was calculated as non-high-density lipoprotein cholesterol minus low-density lipoprotein cholesterol, measured at the same visit as the adipokines, as well as subsequent visits 4 through 6. Multivariable-adjusted linear mixed-effects models were used to assess the cross-sectional and longitudinal associations between adipokines and log-transformed levels of RC. Mean±SD age was 64.5±9.6 years; mean±SD body mass index was 29.9±5.0 kg/m2; and 52.0% were women. In fully adjusted cross-sectional models that included body mass index, diabetes, low-density lipoprotein cholesterol, and lipid-lowering therapy, for each 1-unit increment in adiponectin, there was 14.6% (95% CI, 12.2-16.9) lower RC. With each 1-unit increment in leptin and resistin, there was 4.8% (95% CI, 2.7-7.0) and 4.0% (95% CI, 0.2-8.1) higher RC, respectively. Lower adiponectin and higher leptin were also associated with longitudinal increases in RC levels over median follow-up of 5 (interquartile range, 4-8) years. Lower adiponectin and higher leptin levels were independently associated with higher levels of RC at baseline and longitudinal RC increase, even after accounting for body mass index and low-density lipoprotein cholesterol.

Aldehydes alter TGF-β signaling and induce obesity and cancer

Obesity and fatty liver diseases-metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH)-affect over one-third of the global population and are exacerbated in individuals with reduced functional aldehyde dehydrogenase 2 (ALDH2), observed in approximately 560 million people. Current treatment to prevent disease progression to cancer remains inadequate, requiring innovative approaches. We observe that Aldh2-/- and Aldh2-/-Sptbn1+/- mice develop phenotypes of human metabolic syndrome (MetS) and MASH with accumulation of endogenous aldehydes such as 4-hydroxynonenal (4-HNE). Mechanistic studies demonstrate aberrant transforming growth factor β (TGF-β) signaling through 4-HNE modification of the SMAD3 adaptor SPTBN1 (β2-spectrin) to pro-fibrotic and pro-oncogenic phenotypes, which is restored to normal SMAD3 signaling by targeting SPTBN1 with small interfering RNA (siRNA). Significantly, therapeutic inhibition of SPTBN1 blocks MASH and fibrosis in a human model and, additionally, improves glucose handling in Aldh2-/- and Aldh2-/-Sptbn1+/- mice. This study identifies SPTBN1 as a critical regulator of the functional phenotype of toxic aldehyde-induced MASH and a potential therapeutic target.

Protective Effect of Tertiary Butylhydroquinone against Obesity-induced Skeletal Muscle Pathology in Post-weaning High Fat Diet Fed Rats.

Obesity deleteriously affects skeletal muscle functionality starting from infancy to adulthood, leading to dysfunctional skeletal muscle. This study, therefore, evaluated the protective action of tert-butylhydroquinone (tBHQ) against obesity-induced skeletal muscle pathology in high-fat diet (HFD) fed rats. Twenty post-weaning male albino rats were randomized into four groups of five rats each as: Group 1 (control), Group 2 (HFD), Group 3 (orlistat) and Group 4 (tBHQ). Group one received rat pellets for 12 weeks, while groups 2 to 4 received HFD for 12 weeks. At the end of week 8, obesity was confirmed with Lee Obesity Index and body mass index values of ≥ 303 and ≥ 0.68 gcm2, respectively. Group 3 was given oral administration of orlistat (10 mg/kg, once daily), while group 4 was given oral administration of tBHQ (25 mg/kg, once daily). Administration of orlistat and tBHQ commenced from week 9 to the end of the experiment. Chronic exposure of post-weaning rats to HFD led to their development of the metabolic syndrome phenotypes in adulthood, characterized by obesity, hyperglycemia, dyslipidaemia, hyperinsulinaemia, insulin resistance as well as induction of oxidative stress and alteration of skeletal muscle markers, which were mitigated following supplementation with orlistat and tBHQ. The study showed the anti-obesity potentials of tBHQ and its protective action against HFD obesity-induced skeletal muscular pathology.

High sucrose diet-induced abnormal lipid metabolism in mice is related to the dysbiosis of gut microbiota

Background & AimsExcess sucrose intake induces metabolic syndrome. In human, abnormal lipids metabolism like obesity, hyperlipidemia and fatty liver are induced. However, excess sucrose causes different phenotypes in different species. Based on our previous study, excess sucrose induced fatty liver and hyperlipidemia in rats. The phenotypes and mechanism of abnormal lipid metabolism in mice is unclear. We investigated the different phenotypes in 5 strains of mice and the relationship between gut microbiome and abnormal lipid metabolism in C57BL/6N mice. MethodsWe examined the effect of a high sucrose diet in 5 different strains of mice. Besides, to find out the relationship between gut microbiome and metabolic disorder induced by excess sucrose, C57BL/6N mice were fed with a high sucrose diet with or without antibiotics cocktail. ResultsA high sucrose diet induced obesity and fatty liver in inbred mice, whereas did not induce hyperlipidemia in all strains of mice. Moreover, a high sucrose diet changed the composition of gut microbiota in C57BL/6N mice. Antibiotics treatment alleviated the abnormal lipid metabolism induced by high sucrose diet by changing the composition of gut short chain fatty acids. ConclusionsThese results indicates that the phenotypes of metabolic syndrome are influenced by genetic factors. Furthermore, the dysbiosis of gut microbiome caused by excess sucrose may contribute to the development of abnormal lipid metabolism via its metabolites.

Family Disadvantage, Education, and Health Outcomes Among Black Youths Over a 20-Year Period

Upward mobility (via educational attainment) is highly valued, but longitudinal associations with mental and physical health among Black youths are less understood. To examine associations of childhood family disadvantage and college graduation with adult mental and physical health in Black youths followed up into adulthood. This longitudinal, prospective cohort study of Black youths from the state of Georgia who were studied for 20 years (ages 11 to 31 years) was conducted between 2001 and 2022. Participants for this study were drawn from the Strong African American Healthy Adults Program. Data analysis was conducted from April 2023 to January 2024. Family economic disadvantage (measured during the adolescent years) and college graduation (indicating upward mobility). Primary outcomes included mental health, substance use, and physical health. Mental health included a composite of internalizing and disruptive problems (anxiety, depression, anger, aggressive behaviors, and emotional reactivity). Substance use included a composite of smoking, drinking, and drug use. Physical health included metabolic syndrome (MetS) and proinflammatory phenotypes (immune cells mounting exaggerated cytokine responses to bacterial challenge and being insensitive to inhibitory signals from glucocorticoids). Mental and physical health measures were taken at age 31 and during the adolescent years. Linear and logistic regression analyses, as well as mediated moderation analyses, were conducted. The study population consisted of 329 Black youths (212 women [64%]; 117 men [36%]; mean [SD] age at follow-up, 31 [1] years). Compared with those who did not graduate college, those who graduated from college had 0.14 SD fewer mental health problems (b = -1.377; 95% CI, -2.529 to -0.226; β = -0.137; P = .02) and 0.13 SD lower levels of substance use (b = -0.114; 95% CI, -0.210 to -0.018; β = -0.131; P = .02). Residualized change scores revealed that college graduates showed greater decreases from age 16 to 31 years in mental health problems (b = -1.267; 95% CI, -2.360 to -0.174; β = -0.133; P = .02) and substance use problems (b = -0.116; 95% CI, -0.211 to -0.021; β = -0.136; P = .02). For physical health, significant interactions between childhood family disadvantage and college completion emerged in association with MetS (OR, 1.495; 95% CI, 1.111-2.012; P = .008) and proinflammatory phenotype (b = 0.051; 95% CI, 0.003 to 0.099; β = 0.131; P = .04). Among youths growing up in disadvantaged households, college completion was associated with a 32.6% greater likelihood of MetS (OR, 3.947; 95% CI, 1.003-15.502; P = .049) and 0.59 SD more proinflammatory phenotype (mean difference, 0.249, 95% CI, 0.001 to 0.497; P = .049). Conversely, among those from economically advantaged backgrounds, college completion was correlated with lower MetS and less proinflammatory phenotype. Findings held after controlling for body mass index at age 19 years. In this longitudinal cohort study of Black youths, graduating from college was associated with an adult profile of better mental health but poorer physical health among those from economic disadvantage. These findings suggest that developing interventions that foster healthy outcomes across multiple life domains may be important for ensuring that striving for upward mobility is not accompanied by unintended cardiometabolic risk.

Adverse Metabolic Phenotypes in Parenterally Fed Neonatal Pigs Do Not Persist into Adolescence

BackgroundNutrition during fetal and neonatal life is an important determinant for the risk of adult-onset diseases, especially type 2 diabetes and obesity. ObjectivesWe aimed to determine whether total parenteral nutrition (TPN) compared with enteral formula feeding [enteral nutrition (EN)] in term piglets during the first 2 wk after birth would increase the long-term (5-mo) development of metabolic syndrome phenotypes with adverse glucose homeostasis, fatty liver disease, and obesity. MethodsNeonatal female pigs were administered TPN (n = 12) or fed enterally with a liquid enteral milk-replacer formula (EN, n = 12) for 14 d. After transitioning TPN pigs to enteral feeding of liquid formula (days 15–26), both groups were adapted to a solid high-fat diet (30% of the total diet) and sucrose (20% of the total diet) diet (days 27–33), which was fed until the end of the study (140 d). Body composition was measured by dual-energy X-ray absorptiometry at 14, 45, and 140 d. Serum biochemistry and glucose-insulin values (after a fasting intravenous glucose tolerance test) were obtained at 140 d. Liver and muscle were analyzed for insulin receptor signaling and triglycerides. ResultsBody weight was similar, but percent fat was higher, whereas percent lean and bone mineral density were lower in TPN than in EN pigs (P < 0.01) at 45 d of age but not at 140 d. At 140 d, there were no differences in serum markers of liver injury or lipidemia. Intravenous glucose tolerance test at 140 d showed a lower (P < 0.05) AUC for both glucose and insulin in TPN than in EN pigs, but the ratio of AUCs of insulin and glucose was not different between groups. ConclusionsAdministration of TPN during the neonatal period increased adipose deposition that transiently persisted in early adolescence when challenged with a high-fat diet but was not sustained or manifested as glucose intolerance.

Mutated CYP17A1 promotes atherosclerosis and early-onset coronary artery disease

BackgroundCoronary artery disease (CAD) is a multi-factor complex trait and is heritable, especially in early-onset families. However, the genetic factors affecting the susceptibility of early-onset CAD are not fully characterized.MethodsIn the present study, we identified a rare nonsense variant in the CYP17A1 gene from a Chinese Han family with CAD. To validate the effect of this variation on atherosclerosis and early-onset coronary artery disease, we conducted studies on population, cells, and mice.ResultsThe mutation precisely congregated with the clinical syndrome in all the affected family members and was absent in unaffected family members and unrelated controls. Similar to the human phenotype, the CYP17A1-deficient mice present the phenotype of metabolic syndrome with hypertension, increased serum glucose concentration, and presentation of central obesity and fatty liver. Furthermore, CYP17A1 knockout mice or CYP17A1 + ApoE double knockout mice developed more atherosclerotic lesions than wild type (WT) with high fat diary. In cell models, CYP17A1 was found to be involved in glucose metabolism by increasing glucose intake and utilization, through activating IGF1/mTOR/HIF1-α signaling way, which was consistent in CYP17A1 knockout mice with impaired glucose tolerance and insulin resistance.ConclusionsThrough our study of cells, mice and humans, we identified CYP17A1 as a key protein participating in the pathophysiology of the atherosclerotic process and the possible mechanism of CYP17A1 C987X mutation induced atherosclerosis and early-onset CAD involving glucose homeostasis regulation was revealed.4TTV6qaEtBhVuN78SSsyWiVideo

MATERNAL PROTEIN MALNUTRITION DURING LACTATION PREDISPOSES TO A METABOLIC SYNDROME PHENOTYPE IN MALE WISTAR RATS

Maternal nutritional insults during lactation can modulate the offspring phenotype associatedwith the risk of non-communicable diseases at different stages of ontogenetic development.The aim of this research was to analyze biometric and biochemical parameters of male Wistarrats, born to dams fed a low-protein diet in the first two-thirds of lactation. Therefore, themothers received ad libitum a normal (NP, 23%) or low-protein (LP, 4%) diet, originatingtwo experimental groups that were evaluated at 14 days old (NP-14 and LP-14). The resultsshowed that the LP-14 offspring male rats had lower body weight (p&amp;lt;0.0001), reduced liver(p&amp;lt;0.0001) and higher brown fat deposits (p&amp;lt;0.0001), compared to the equivalent control.They also exhibited hyperglycemia (p&amp;lt;0.05), hypercholesterolemia (p&amp;lt;0.0001), and increasedserum β-hydroxybutyrate (p&amp;lt;0.0001), contrasting with reduced triglycerides (p&amp;lt;0.05) levels.We conclude that maternal exposure to a low-protein diet during lactation was able toprogram 14-day-old male neonates to develop a metabolic syndrome phenotype, probably dueto restriction of body and visceral growth in these animals.

Abstract #1401109: Quetiapine-induced Hypoglycemia in an Elderly Non-diabetic Patient with Dementia

Quetiapine is a second-generation antipsychotic agent (SGA) widely prescribed for the treatment of psychotic and mood disorders. In elderly patients, quetiapine is often used to treat psychotic symptoms associated with dementia. A metabolic syndrome phenotype of weight gain, hyperglycemia, and hyperlipidemia is a potential adverse effect of SGA’s, though hypoglycemia caused by SGA’s is documented. We report a case of quetiapine-induced hypoglycemia in a non-diabetic patient. A 79-year-old male with Lewy body dementia was admitted to hospital for management of a myocardial infarction. The patient had no history of diabetes mellitus, renal failure, or hepatic insufficiency, and nobody living with the patient was treated for diabetes. Plasma glucose on admission was 84 mg/dL. Quetiapine was started to control delirium, but within 24 h the patient had worsening confusion and a capillary blood glucose (CBG) measurement of 52 mg/dL. Symptoms improved with administration of dextrose, and the patient ultimately required a 10% dextrose infusion to maintain CBG’s >80 mg/dL. An ACTH-stimulation test (30 min stimulated cortisol 24.8 μg/dL, expected >18) and hypoglycemic medications panel (sulfonylureas and meglitinides) were unremarkable. Quetiapine was stopped, and hypoglycemia resolved. No hypoglycemia occurred during a subsequent 48-h diagnostic fast followed by a mixed meal tolerance test. Due to the patient’s advanced age and comorbidities, it was decided not re-challenge with quetiapine and observe for recurrence of hypoglycemia. Hypoglycemia is a rare complication of SGA’s, and diagnosis may be delayed or missed in patients with baseline confusion or agitation. In addition to quetiapine, there are case reports of hypoglycemia occurring during treatment with risperidone, olanzapine, aripiprazole, and paliperidone. Clozapine and olanzapine increase insulin release from isolated pancreatic islets in vitro, though quetiapine did not demonstrate this effect. However, endogenous hyperinsulinemia has been documented in case reports of quetiapine-induced hypoglycemia. The physiologic pathway by which SGA’s increase insulin release is unknown; some authors have focused on the antagonism of M1 muscarinic receptors, but the muscarinic M1 receptor antagonist pirenzepine has been demonstrated to reduce insulin secretion induced by the muscarinic receptor agonist carbachol from isolated rat pancreatic islets in vitro. Though the mechanism by which hypoglycemia occurs is unclear, this case demonstrates that hypoglycemia should be considered in patients with worsening mental status during treatment with SGA’s.

Functional activity of the adrenal glands in type 2 diabetes patients with different hormonal and metabolic phenotypes

Background. Clinical trials showed a number of additional phenotypes of metabolic syndrome. All of them differ in the type of metabolic disorders and the composition of subcutaneous and visceral adipose tissue. Some of phenotypes have a number of clinical and metabolic similarities with endogenous or exogenous hypercorticism syndromes. The purpose was to characterize the functional activity of the adrenal glands in type 2 diabetes depending on the phenotypic features: the degree of general obesity and the level of visceral fat. Material and methods. Our trial included 89 patients with type 2 diabetes (46 men and 43 women) aged 32 to 85 years. The examination included evaluation of anthropometric parameters, body composition by the bioelectrical impedance method, assessment of the lipid and carbohydrate metabolism, the level of cortisol, dehydroepiandrosterone sulfate (DHEAS) in blood serum, and the activity of 11-beta-hydroxysteroid dehydrogenase (11β-HSD) enzyme. Results. Insulin and C-peptide levels were significantly lower in the non-obese group. The cortisol/DHEAS ratio was elevated in both subgroups with high levels of visceral fat as possible marker of imbalance of anabolic and catabolic hormones. In addition, the concentration of the cortisol, measured in the blood serum of the patients after waking up, was within the normal range. However, the average value in both groups was closer to its upper ranges. This may suggest the presence of subclinical hypercortisolism caused by an increased activity of 11β-HSD, which contributes to the local production of cortisol in visceral adipose tissue. Conclusions. The hormonal and metabolic changes that we found in our groups of patients with type 2 diabetes may indicate anabolic-catabolic imbalance, which is manifested both in the features of the topography of adipose tissue and in changes of metabolic processes, i.e. form the special metabolic phenotype with a catabolic or anabolic axis. Detection the subgroups at high risk allows to develop pathogenetic approaches to the most targeted comprehensive correction of existing violations.

Inhibition of Na/K-ATPase signaling Attenuates Steatohepatitis and Atherosclerosis in Mice Fed a Western Diet.

We have previously reported that the α1 subunit of sodium-potassium adenosine triphosphatase (Na/K-ATPase), acts as a receptor and an amplifier for reactive oxygen species, in addition to its distinct pumping function. On this background, we speculated that the blockade of Na/K-ATPase-induced ROS amplification with a specific peptide, pNaKtide, might attenuate the development of steatohepatitis. To test this hypothesis, pNaKtide was administered to a murine model of NASH: the C57Bl6 mouse fed a "western" diet containing high amounts of fat and fructose. The administration of pNaKtide reduced obesity as well as hepatic steatosis, inflammation and fibrosis. Of interest, we also noted a marked improvement in mitochondrial fatty acid oxidation, insulin sensitivity, dyslipidemia and aortic streaking in this mouse model. To further elucidate the effects of pNaKtide on atherosclerosis, similar studies were performed in ApoE knockout mice also exposed to the western diet. In these mice, pNaKtide not only improved steatohepatitis, dyslipidemia, and insulin sensitivity but also ameliorated significant aortic atherosclerosis. Collectively, this study demonstrates that the Na/K-ATPase/ROS amplification loop contributes significantly to the development and progression of steatohepatitis and atherosclerosis. Furthermore, this study presents a potential treatment, the pNaKtide, for the metabolic syndrome phenotype.

Periodontal treatment and microbiome-targeted therapy in management of periodontitis-related nonalcoholic fatty liver disease with oral and gut dysbiosis.

A growing body of evidence from multiple areas proposes that periodontal disease, accompanied by oral inflammation and pathological changes in the microbiome, induces gut dysbiosis and is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A subgroup of NAFLD patients have a severely progressive form, namely nonalcoholic steatohepatitis (NASH), which is characterized by histological findings that include inflammatory cell infiltration and fibrosis. NASH has a high risk of further progression to cirrhosis and hepatocellular carcinoma. The oral microbiota may serve as an endogenous reservoir for gut microbiota, and transport of oral bacteria through the gastro-intestinal tract can set up a gut microbiome dysbiosis. Gut dysbiosis increases the production of potential hepatotoxins, including lipopolysaccharide, ethanol, and other volatile organic compounds such as acetone, phenol and cyclopentane. Moreover, gut dysbiosis increases intestinal permeability by disrupting tight junctions in the intestinal wall, leading to enhanced translocation of these hepatotoxins and enteric bacteria into the liver through the portal circulation. In particular, many animal studies support that oral administration of Porphyromonas gingivalis, a typical periodontopathic bacterium, induces disturbances in glycolipid metabolism and inflammation in the liver with gut dysbiosis. NAFLD, also known as the hepatic phenotype of metabolic syndrome, is strongly associated with metabolic complications, such as obesity and diabetes. Periodontal disease also has a bidirectional relationship with metabolic syndrome, and both diseases may induce oral and gut microbiome dysbiosis with insulin resistance and systemic chronic inflammation cooperatively. In this review, we will describe the link between periodontal disease and NAFLD with a focus on basic, epidemiological, and clinical studies, and discuss potential mechanisms linking the two diseases and possible therapeutic approaches focused on the microbiome. In conclusion, it is presumed that the pathogenesis of NAFLD involves a complex crosstalk between periodontal disease, gut microbiota, and metabolic syndrome. Thus, the conventional periodontal treatment and novel microbiome-targeted therapies that include probiotics, prebiotics and bacteriocins would hold great promise for preventing the onset and progression of NAFLD and subsequent complications in patients with periodontal disease.

Distribution of allele and genotype frequencies for the IL5 rs2069812 polymorphism in occupational asthma according to its phenotype

Molecular genotyping opens up fresh opportunities to search for a more targeted and personalized approach to treating occupational asthma (OA) and to developing an individual strategy for its prevention. Objective. To determine genetic risk markers for OA under the influence of sensitizers, by assessing IL5 rs2069812 polymorphic variants. Subjects and methods. The investigation enrolled 170 patients with different OA phenotypes. The patients were divided into groups according to the OA phenotype: 1) 42 patients with an allergic OA phenotype; 2) 36 patients with a non-allergic OA phenotype; 3) 58 patients with an OA + occupational chronic obstructive pulmonary disease (COPD) phenotype; 4) 34 patients with an OA + metabolic syndrome (MS) phenotype. A control group included 50 healthy individuals. IL5 rs2069812 polymorphisms were determined as part of the study of genetic predisposition to OA. Phenol chloroform extraction was used to isolate DNA from peripheral lymphocyte samples. Genotyping was done by real-time polymerase chain reaction with primers and probes designed using the PrimerQuest program (Integrated DNA Technologies, Inc., USA). Results. The genetic markers for OA were found for the first time after exposure to sensitizers, IL5 rs2069812 polymorphic variants, which can recommend that this genetic marker should be identified during thorough periodic medical examinations in individuals with clinical, functional, and immunological changes upon occupational exposure to sensitizing and irritating substances. Conclusion. The identified marker profiles of the genotypes of OA can optimize an approach to diagnosing, treating, and preventing this disease, and expanding the range of criteria for predicting its course. When a polymorphism in the IL5 gene is detected using a molecular genetic study, the patient needs to be registered for follow-up, repeated respiratory function tests once every six months, thorough periodic medical examinations in a specialized center of occupational pathology, by obligatorily attracting a pulmonologist, an allergist/immunologist, and an occupational pathologist, as well as extensive functional and immunological studies once every two years.

Untargeted metabolomics and phenotype data indicate the therapeutic and prophylactic potential of Lysimachia candida Lindl. towards high-fat high-fructose-induced metabolic syndrome in rats.

The present study evaluated the therapeutic potential of the medicinal plant Lysimachia candida Lindl. against metabolic syndrome in male SD rats fed with a high-fat high-fructose (HFHF) diet. Methanolic extract of Lysimachia candida Lindl. (250 mg kg-1 body weight p.o.) was administrated to the HFHF-fed rats daily for 20 weeks. Blood samples were collected, and blood glucose levels and relevant biochemical parameters were analysed and used for the assessment of metabolic disease phenotypes. In this study, Lysimachia candida decreased HFHF diet-induced phenotypes of metabolic syndrome, i.e., obesity, blood glucose level, hepatic triglycerides, free fatty acids, and insulin resistance. Liquid chromatography-mass spectrometry-based metabolomics was done to study the dynamics of metabolic changes in the serum during disease progression in the presence and absence of the treatment. Furthermore, multivariate data analysis approaches have been employed to identify metabolites responsible for disease progression. Lysimachia candida Lindl. plant extract restored the metabolites that are involved in the biosynthesis and degradation of amino acids, fatty acid metabolism and vitamin metabolism. Interestingly, the results depicted that the treatment with the plant extract restored the levels of acetylated amino acids and their derivatives, which are involved in the regulation of beta cell function, glucose homeostasis, insulin secretion, and metabolic syndrome phenotypes. Furthermore, we observed restoration in the levels of indole derivatives and N-acetylgalactosamine with the treatment, which indicates a cross-talk between the gut microbiome and the metabolic syndrome. Therefore, the present study revealed the potential mechanism of Lysimachia candida Lindl. extract to prevent metabolic syndrome in rats.

Фенотип формирования метаболического синдрома в перименопаузальной когорте женщин без дисгликемии в зависимости от наличия артериальной гипертензии

Introduction. The high incidence of arterial hypertension (AH) in the population, its close association with menopause and disorders of carbohydrate metabolism with an emphasis on the predictive role of fasting glycemia (FG) for type 2 diabetes mellitus draws attention to the phenotype of the formation of metabolic syndrome (MS) in perimenopause depending on the presence of hypertension without dysglycemia. Aim of the research. To evaluate the associations between blood pressure (BP) levels and FG during the formation of insulin resistant menopausal MS in a cohort of normoglycemic women aged 35–59 years with AH and normotensive. Materials and methods. In the perimenopausal cohort of women aged 35–59 years without dysglycemia (n = 88), 58 women had hypertension, 30 were normotensive. The following were determined: body mass index (BMI), waist circumference (WC), levels of BP, triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), insulin, follicle-stimulating hormone (FSH) and estradiol, FG, TyG and HOMA2 family (HOMA2-IR and HOMA2-%B) indices. Using SPSS (version 17), we estimated the median (25; 75%); intergroup differences according to the Mann-Whitney test; then, the correlation analyses were carried out: according to Spearman (R) and partial (Rpc) to level the influence of age. Results. Significant associations of systolic BP (SBP) and FG levels, direct and mediated through lipid (TG and HDL-C) and anthropometric (WC) parameters of MS, were revealed with most of the correlations being only partially age-dependent. Among these parameters, the mediators of insulin resistance, the associations of SBP and FG with WC are the most pronounced; it is WC that stably correlates with insulin resistance indices, more specifically with TyG. The correlations of TG levels with HDL-C (R = –0.564; p &lt; 0.001) are also relevant when the influence of age is leveled (Rpc = –0.477; p &lt; 0.001); with them, as well as with the levels of insulin and the duration of postmenopause, FG correlates. BP levels, especially systolic, form correlations with insulin resistance indices, more stable with non-insulin TyG index, in contrast to age-dependent relationships with HOMA2-IR. Conclusion. The extensiveness of the revealed correlations between BP and FG levels with markers and factors for the formation of menopausal MS, including the relation of BP with HOMA2-IR indices and especially TyG, reflects its insulin resistant pathogenetic basis. Along with this, significant stable correlations of the duration of postmenopause with FG reflect a high risk of progression to dysglycemia in the analyzed phenotype of metabolic syndrome and allow us to consider menopause as a unique factor contributing to the rapid clustering of MS in women, determining the interest in clarifying its formation trajectories.

Abstract 122: Effect Of Tie2-cre Endothelial Caveolin-1 Deficiency Mice On Murine Cardiovascular And Metabolic Phenotypes

In humans, caveolin-1 (cav-1) gene polymorphisms confer a metabolic syndrome (MetS) phenotype and higher aldosterone (Aldo) levels. Further, global cav-1 knock out (KO) mice recapitulate the MetS phenotype, with both cardiovascular (CV) and metabolic dysfunction. We have shown that vascular dysfunction in the cav-1 KO is dissociated from the metabolic phenotype and is mediated by an endothelial crosstalk between cav-1 and the Aldo-mineralocorticoid receptor (MR) signaling pathway. Hence, we hypothesized endothelial cav-1 deficiency in mice is a major contributor to CV (but not metabolic) dysfunction.To assess this hypothesis, we generated Tie-2 mediated endothelium-specific cav-1 KO (ECKO) and appropriate genetic wild type (WT) control mice and studied their metabolic and CV traits in response to 1) changes in dietary salt intake (0.03% (LS) vs. 1.6% Na + (HS)) and 2) 3-weeks of Aldo infusion (200μg/kg/day) during sodium loading. Our results showed no difference in glucose, lipids and HOMA-IR in ECKO vs. WT mice, irrespective of the dietary intervention. However, on a HS (but not a LS) diet, ECKO vs. WT mice displayed similar CV dysfunction as previously shown in the full cav-1 KO: increased Aldo levels (73.7±11.1 vs 47.8±4.7ng/dl, p&lt;0.05) and systolic BP (116.4±1.5 vs111±1.4 mmHg, p&lt;0.015). Further, ECKO vs. WT mice had increased cardiac MR, eNOS, PAI-1 and CD68 expression (p&lt;0.05 for each) as well as left ventricular hypertrophy (echocardiogram, p&lt;0.05). In addition, 3-week HS diet led to higher albuminuria (p&lt;0.05) and kidney/body weight ratios in ECKO vs. WT (7.2±0.2 vs 6.3±0.1). Surprisingly, as compared to placebo, Aldo infusion induced significant CV and renal damage only in the WT, but not in the ECKO. However, as compared to WT, Aldo infused ECKO had increased cardiac hypertrophy (5.9±0.2 vs 5.2±0.1) and molecular markers noted above (p&lt;0.05 for each).In conclusion, lack of endothelial cav-1 in the mouse segregated the metabolic and CV phenotypes, and the associated CV phenotype resembles that described for the global cav-1 KO. Further, the CV and renal damage in the ECKO at baseline cannot be further enhanced by Aldo infusion. These data confirm our hypothesis that endothelial cav-1 is a major player in CV but not metabolic homeostasis.

Microbiota imbalance induced by dietary sugar disrupts immune-mediated protection from metabolic syndrome

How intestinal microbes regulate metabolic syndrome is incompletely understood. We show that intestinal microbiota protects against development of obesity, metabolic syndrome, and pre-diabetic phenotypes by inducing commensal-specific Th17 cells. High-fat, high-sugar diet promoted metabolic disease by depleting Th17-inducing microbes, and recovery of commensal Th17 cells restored protection. Microbiota-induced Th17 cells afforded protection by regulating lipid absorption across intestinal epithelium in an IL-17-dependent manner. Diet-induced loss of protective Th17 cells was mediated by the presence of sugar. Eliminating sugar from high-fat diets protected mice from obesity and metabolic syndrome in a manner dependent on commensal-specific Th17 cells. Sugar and ILC3 promoted outgrowth of Faecalibaculum rodentium that displaced Th17-inducing microbiota. These results define dietary and microbiota factors posing risk for metabolic syndrome. They also define a microbiota-dependent mechanism for immuno-pathogenicity of dietary sugar and highlight an elaborate interaction between diet, microbiota, and intestinal immunity in regulation of metabolic disorders.

Reduced leukocyte mitochondrial copy number in metabolic syndrome and metabolically healthy obesity.

ObjectiveThis study aimed to investigate the associations between peripheral blood leukocyte mitochondrial copy number, metabolic syndrome, and adiposity-related body composition phenotypes in a high prevalence population.MethodsA single center cross-sectional study was conducted, consisting of 521 middle-aged subjects of Maltese-Caucasian ethnicity. Participants were stratified according to the presence of metabolic syndrome and different metabolic health definitions based on NCEP-ATP III criteria. Relative leukocyte mitochondrial DNA copy number was determined by quantitative polymerase chain reaction and corrected for leukocyte and platelet count. The associations between mitochondrial copy number and metabolic syndrome components was evaluated and adjusted for age and gender.ResultsSignificant negative correlations between mtDNA copy number and BMI, waist circumference, triglyceride levels, fasting plasma glucose, HbA1c, HOMA-IR and hsCRP were observed, along with a positive correlation with HDL-C levels. Mitochondrial copy number was lower in individuals with metabolic syndrome. When compared to metabolically healthy normal weight subjects, a reduction in mtDNA copy number was observed in both the metabolically healthy and unhealthy obese categories.ConclusionOur data supports the association between reduced leukocyte mtDNA copy number, obesity, and metabolic syndrome. This investigation expands on the spectrum of associations between mtDNA copy number and metabolic phenotypes in different populations and underpins the role of mitochondrial dysfunction in the development and progression of metabolic syndrome and its components.

Efficacy and safety of guanabenz acetate treatment for non-alcoholic fatty liver disease: a study protocol for a randomised investigator-initiated phase IIa study

IntroductionNon-alcoholic fatty liver disease (NAFLD) is a metabolic syndrome phenotype in the liver and thus obviously associated with metabolic abnormalities, including insulin resistance-related to hyperglycaemic and hyperlipidaemia. The prevalence of...