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Adipokines are a family of hormones and cytokines with both pro- and anti-inflammatory effects released into the circulation to exert their hormonal effects. Adipokines are closely involved in most metabolic pathways and play an important modulatory role in lipid and carbohydrate homeostasis as they are involved in the pathophysiology of most metabolic disorders. Incretin-based therapy is a newly introduced class of antidiabetic drugs that restores euglycemia through several cellular processes; however, its effect on adipokines expression/secretion is not fully understood. In this review, we propose that incretin-based therapy may function through adipokine modulation that may result in pharmacologic properties beyond their direct antidiabetic effects, resulting in better management of diabetes and diabetes-related complications.

Hepatocyte nuclear factor 4 alpha (HNF4) is required for hepatocyte differentiation and regulates expression of genes involved in lipid and carbohydrate metabolism including those that control VLDL secretion and gluconeogenesis. Whereas previous studies have focused on specific genes regulated by HNF4 in metabolism, its overall role in whole-body energy utilization has not been studied. In this study, we used indirect calorimetry to determine the effect of hepatocyte-specific HNF4 deletion (HNF4-KO) in mice on whole-body energy expenditure (EE) and substrate utilization in fed, fasted, and high-fat diet (HFD) conditions. HNF4-KO had reduced resting EE during fed conditions and higher rates of carbohydrate oxidation with fasting. HNF4-KO mice exhibited decreased body mass caused by fat mass depletion despite no change in energy intake and evidence of positive energy balance. HNF4-KO mice were able to upregulate lipid oxidation during HFD, suggesting that their metabolic flexibility was intact. However, only hepatocyte-specific HNF4-KO mice exhibited significant reduction in basal metabolic rate and spontaneous activity during HFD. Consistent with previous studies, hepatic gene expression in HNF4-KO supports decreased gluconeogenesis and decreased VLDL export and hepatic -oxidation in HNF4-KO livers across all feeding conditions. Together, our data suggest that deletion of hepatic HNF4 increases dependence on dietary carbohydrates and endogenous lipids for energy during fed and fasted conditions by inhibiting hepatic gluconeogenesis, hepatic lipid export, and intestinal lipid absorption resulting in decreased whole-body energy expenditure. These data clarify the role of hepatic HNF4 on systemic metabolism and energy homeostasis.

The sessile nature of plants' life is endowed with a highly evolved defense system to adapt and survive under environmental extremes. To combat such stresses, plants have developed complex and well-coordinated molecular and metabolic networks encompassing genes, metabolites, and acclimation responses. These modulate growth, photosynthesis, osmotic maintenance, and carbohydrate homeostasis. Under a given stress condition, sugars act as key players in stress perception, signaling, and are a regulatory hub for stress-mediated gene expression ensuring responses of osmotic adjustment, scavenging of reactive oxygen species, and maintaining the cellular energy status through carbon partitioning. Several sugar transporters are known to regulate carbohydrate partitioning and key signal transduction steps involved in the perception of biotic and abiotic stresses. Sugar transporters such as SUGARS WILL EVENTUALLY BE EXPORTED TRANSPORTER (SWEETs), SUCROSE TRANSPORTERS (SUTs), and MONOSACCHARIDE TRANSPORTERS (MSTs) are involved in sugar loading and unloading as well as long-distance transport (source to sink) besides orchestrating oxidative and osmotic stress tolerance. It is thus necessary to understand the structure-function relationship of these sugar transporters to fine-tune the abiotic stress-modulated responses. Advances in genomics have unraveled many sugars signaling components playing a key role in cross-talk in abiotic stress pathways. An integrated omics approach may aid in the identification and characterization of sugar transporters that could become targets for developing stress tolerance plants to mitigate climate change effects and improve crop yield. In this review, we have presented an up-to-date analysis of the sugar homeostasis under abiotic stresses as well as describe the structure and functions of sugar transporters under abiotic stresses.

With the extensive usage of gold nanoparticles (AuNPs) in various industrial sectors and biomedical applications, evaluation of their possible effects on human health becomes imperative. Therefore, the present study was aimed toward assessing the dose-dependent impact of AuNPs ingestion on metabolic homeostasis using Drosophila melanogaster as a model system. We found that larval ingestion of higher dose of AuNPs significantly reduced body weight. Further analysis of the crucial energy reservoir showed selective alteration in carbohydrate levels without any change in the lipid and protein levels. Transcriptional downregulation of glycogen synthase further supported impaired glycogen metabolism in flies supplemented with higher dose of AuNPs. Additionally, ingestion of higher dose of AuNPs in larvae results in significantly increased levels of reactive oxygen species (ROS) in the peripheral tissues, suggestive of stress condition. Our findings clearly imply that supplementing higher doses of AuNPs at an early developmental stage can potentially cause weight loss, impair glycogen metabolism, and elevate ROS production. Therefore, determination of a biologically effective dose is critical for the safety of mankind and vulnerable populations at the workplace.

Purpose: Non-alcoholic fatty liver (NAFL) is comorbid to obesity, metabolic syndrome and type 2 diabetes mellitus (T2DM). It is unclear whether NAFLD constitutes a direct risk factor for macrovascular disease in T2DM. This study aimed at revisiting the cardiometabolic traits linked to NADL and micro-/ macrovascular complications in a biethnic Caucasian and African cohort. Methods: Cross-sectional analysis of 568 of T2DM patients (515 Caucasians; 53 Africans) in whom the presence of NAFL was identified by ultrasonography and the cardiometabolic phenotype was exhaustively characterized, including carbohydrate homeostasis, comprehensive lipidogram including Lp(a), cumulative exposure to hyperglycemia, and prevalent micro/macrovascular complications. Results: FL was present in 73% of Caucasians and 36% of Africans (p − in both groups. A marked reduction in diabetic retinopathy (DR), ocular hypertonia and cataracts were found in FL+ of the two ethnicities. In FL+ Caucasians, relative risk of DR was −38%, cataracts −35%, and ocular hypertonia −42%. In FL+ Africans, risk of overall microangiopathy was −66% and that of DR −86%. Conclusions: An inverse association was observed between NAFL and the presence of diabetic retinopathy, cataract and ocular hypertonia. The ophthalmoprotection conferred by liver steatosis was found in Caucasians and Africans. Among the latter, hepatic steatosis was linked to lower lipoprotein(a) levels. There was no association between hepatic steatosis and prevalent macrovascular complications in neither of the two ethnic groups.

In recent years, the possibility of using intranasally administered insulin to treat Alzheimers disease and other cognitive disorders has been widely studied. At the same time, the possibility of its use in the treatment of diabetes mellitus is practically not investigated, which is due to the insufficient study of the molecular mechanisms of its action on the hormonal and metabolic status of the organism. The review discusses literature data and the results of our own research on the role of insulin in the central regulation of energy homeostasis, as well as on the experience of using intranasally administered insulin to correct eating disorders and metabolic and hormonal dysfunctions developing under conditions of experimental diabetes mellitus and metabolic syndrome. In studies involving healthy volunteers, various effects of intranasally administered insulin were shown, including effects on cognitive function, eating behavior and weight loss, and the gender specificity of its action was found. In the course of numerous studies of intranasally administered insulin in animal models of diabetes mellitus, not only stabilization of carbohydrate homeostasis was shown, but also a positive effect in the form of restoration of the functional activity of insulin signaling pathways in the hypothalamus and other parts of the brain. We have presented and analyzed data on the systemic effects of intranasally administered insulin in rodents with experimental models of diabetes mellitus, as well as in healthy individuals.В последние годы широко изучается возможность применения интраназально вводимого инсулина для лечения болезни Альцгеймера и других когнитивных расстройств. В то же время практически не исследуется возможность его применения в рамках терапии сахарного диабета, что во многом связано с недостаточной изученностью молекулярных механизмов его действия на гормональный и метаболический статусы организма. В обзоре обсуждаются данные литературы и результаты собственных исследований о роли инсулина в центральной регуляции энергетического гомеостаза, а также об опыте применения интраназально вводимого инсулина для коррекции нарушений пищевого поведения и метаболических и гормональных дисфункций, развивающихся в условиях экспериментального сахарного диабета и метаболического синдрома. В исследованиях с участием здоровых добровольцев были показаны различные эффекты интраназально вводимого инсулина, в том числе влияние на когнитивные функции, пищевое поведение и снижение массы тела, а также обнаружена гендерная специфичность его действия. В ходе многочисленных исследований интраназально вводимого инсулина на животных моделях сахарного диабета были показаны не только стабилизация углеводного гомеостаза, но и положительное действие в виде восстановления функциональной активности инсулиновых сигнальных путей в гипоталамусе и других отделах мозга. Нами представлены и проанализированы данные о системных эффектах интраназально вводимого инсулина у грызунов с экспериментальными моделями сахарного диабета, а также у здоровых индивидуумов.

The increasing burden of obesity worldwide and its effect on cardiovascular disease (CVD) risk is an opportunity for evaluation of preventive approaches. Both obesity and CVD have a genetic background and polymorphisms within genes which enhance expression of variant proteins that influence CVD in obesity. Genome-based prediction may therefore be a feasible strategy, but the identification of genetically driven risk factors for CVD manifesting as clinically recognized phenotypes is a major challenge. Clusters of such risk factors include hyperglycaemia, hypertension, ectopic liver fat, and inflammation. All involve multiple genetic pathways having complex interactions with variable environmental influences. The factors that make significant contributions to CVD risk include altered carbohydrate homeostasis, ectopic deposition of fat in muscle and liver, and inflammation, with contributions from the gut microbiome. A futuristic model depends on harnessing the predictive power of plausible genetic variants, phenotype reversibility, and effective therapeutic choices based on genotype-phenotype interactions. Inverting disease phenotypes into ideal cardiovascular health metrics could improve genetic and epigenetic assessment, and form the basis of a future model for risk detection and early intervention.

As a typical glycolytic inhibitor, 3-bromopyruvate (3-BrPA) has been extensively studied in cancer therapy in recent decades. However, few studies focused on 3-BrPA in regulating the growth and development of insects, and the relationship and regulatory mechanism between glycolysis and chitin biosynthesis remain largely unknown. The Hyphantria cunea, named fall webworm, is a notorious defoliator, which caused a huge economic loss to agriculture and forestry. Here, we investigated the effects of 3-BrPA on the growth and development, glycolysis, carbohydrate homeostasis, as well as chitin synthesis in H. cunea larvae. To elucidate the action mechanism of 3-BrPA on H. cunea will provide a new insight for the control of this pest. The results showed that 3-BrPA dramatically restrained the growth and development of H. cunea larvae and resulted in larval lethality. Meanwhile, we confirmed that 3-BrPA caused a significant decrease in carbohydrate, adenosine triphosphate (ATP), pyruvic acid (PA), and triglyceride (TG) levels by inhibiting glycolysis in H. cunea larvae. Further studies indicated that 3-BrPA significantly affected the activities of hexokinase (HK), phosphofructokinase (PFK), pyruvate kinase (PK), glucose 6-phosphate dehydrogenase (G6PDH) and trehalase, as well as expressions of the genes related to glycolysis, resulting in carbohydrate homeostasis disorder. Moreover, it was found that 3-BrPA enhanced 20-hydroxyecdysone (20E) signaling by upregulating HcCYP306A1 and HcCYP314A1, two critical genes in 20E synthesis pathway, and accelerated chitin synthesis by upregulating transcriptional levels of genes in the chitin synthesis pathway in H. cunea larvae. Taken together, our findings provide a novel insight into the mechanism of glycolytic inhibitor in regulating the growth and development of insects, and lay a foundation for the potential application of glycolytic inhibitors in pest control as well.

Biological age measures outperform chronological age in predicting various aging outcomes, yet little is known regarding genetic predisposition. We performed genome‐wide association scans of two age‐adjusted biological age measures (PhenoAgeAcceleration and BioAgeAcceleration), estimated from clinical biochemistry markers (Levine et al., 2018; Levine, 2013) in European‐descent participants from UK Biobank. The strongest signals were found in the APOE gene, tagged by the two major protein‐coding SNPs, PhenoAgeAccel—rs429358 (APOE e4 determinant) (p = 1.50 × 10−72); BioAgeAccel—rs7412 (APOE e2 determinant) (p = 3.16 × 10−60). Interestingly, we observed inverse APOE e2 and e4 associations and unique pathway enrichments when comparing the two biological age measures. Genes associated with BioAgeAccel were enriched in lipid related pathways, while genes associated with PhenoAgeAccel showed enrichment for immune system, cell function, and carbohydrate homeostasis pathways, suggesting the two measures capture different aging domains. Our study reaffirms that aging patterns are heterogeneous across individuals, and the manner in which a person ages may be partly attributed to genetic predisposition., A genome‐wide association study for differences in aging rates was performed in the UK Biobank sample using two previously established aging measures. Results suggest that one was associated with genes involved in lipid metabolism and blood pressure, while the other was associated with genes involved in immune functioning. APOE e4 was associated with faster aging in the measure reflecting lipid age, yet paradoxically, was associated with reduced aging in the measure reflecting immune functioning and inflammation.

Insulin plays a significant role in carbohydrate homeostasis as the blood glucose lowering hormone. Glucose-induced insulin secretion (GSIS) is augmented by glucagon-like peptide (GLP-1), a gastrointestinal peptide released in response to ingesting nutriments. The secretion of insulin and GLP-1 is mediated by the binding of nutrients to G protein-coupled receptors (GPCRs) expressed by pancreatic β-cells and enteroendocrine cells, respectively. Therefore, insulin secretagogues and incretin mimetics currently serve as antidiabetic treatments. This study demonstrates the potency of synthetic isoprenoid derivatives of lysophosphatidylcholines (LPCs) to stimulate GSIS and GLP-1 release. Murine insulinoma cell line (MIN6) and enteroendocrinal L cells (GLUTag) were incubated with LPCs bearing geranic acid (1-GA-LPC), citronellic acid (1-CA-LPC), 3,7-dimethyl-3-vinyloct-6-enoic acid (GERA-LPC), and (E)-3,7,11-trimethyl- 3-vinyldodeca-6,10-dienoic acid (1-FARA-LPC). Respective free terpene acids were also tested for comparison. Besides their insulin- and GLP-1-secreting capabilities, we also investigated the cytotoxicity of tested compounds, the ability to intracellular calcium ion mobilization, and targeted GPCRs involved in maintaining lipid and carbohydrate homeostasis. We observed the high cytotoxicity of 1-GERA-LPC and 1-FARA-LPC in contrast 1-CA-LPC and 1-GA-LPC. Moreover, 1-CA-LPC and 1-GA-LPC demonstrated the stimulatory effect on GSIS and 1-CA-LPC augmented GLP-1 secretion. Insulin and GLP-1 release appeared to be GPR40-, GPR55-, GPR119- and GPR120-dependent.

BackgroundGrapevines are commonly infected with one or more viruses causing a significant threat to the sustainability of quality wine grape production worldwide. The recently identified Grapevine red blotch disease (GRBD) significantly affects the yield and quality of wine grapes. It is largely unknown how the red blotch disease affects carbohydrate homeostasis and regulate the source-to-sink relationship in grapevines. We took an integrative approach to determine the consequences of viral infection in commercially grown, two popular wine grape cultivars from distinct locations in the eastern Washington.ResultsThe deep sequencing approach revealed that Grapevine red blotch virus (GRBV) was found in all symptomatic vines, while asymptomatic vines were free of this virus. Analysis of mature berries at commercial harvest in virus-infected vines indicated significant changes in the soluble sugar accumulation along with the increase in leaf sucrose and starch content. To follow up with the altered carbohydrate homeostasis, we analyzed cell wall components in winter canes of virus-infected vines and compared them to their virus-free counterparts. Major cell wall monosaccharide contents and total lignin content was not affected due to red blotch disease in either cultivar. However, high-resolution glycome profiling revealed consistent changes in loosely bound cell wall pectin matrices and tightly bound non-fucosylated xyloglucans in virus-infected vines. Furthermore, in cv. Syrah, co-infection with other viruses leads to additional cell wall compositional variations.ConclusionsThese changes highlighted that virus infection in woody perennial leads to detrimental adjustments in the soluble and storage carbohydrates, and in the cell wall layers that could be attributed to lower vine performance or vine decline in a relatively short time. The information gained from such qualitative cell wall structural fine-tuning could be used in assessing how viruses or other pathogenic agents affect perennial longevity.

The prototypical M13 peptidase, human Neprilysin, functions as a transmembrane “ectoenzyme” that cleaves neuropeptides that regulate e.g. glucose metabolism, and has been linked to type 2 diabetes. The M13 family has undergone a remarkable, and conserved, expansion in the Drosophila genus. Here, we describe the function of Drosophila melanogaster Neprilysin-like 15 (Nepl15). Nepl15 is likely to be a secreted protein, rather than a transmembrane protein. Nepl15 has changes in critical catalytic residues that are conserved across the Drosophila genus and likely renders the Nepl15 protein catalytically inactive. Nevertheless, a knockout of the Nepl15 gene reveals a reduction in triglyceride and glycogen storage, with the effects likely occurring during the larval feeding period. Conversely, flies overexpressing Nepl15 store more triglycerides and glycogen. Protein modeling suggests that Nepl15 is able to bind and sequester peptide targets of catalytically active Drosophila M13 family members, peptides that are conserved in humans and Drosophila, potentially providing a novel mechanism for regulating the activity of neuropeptides in the context of lipid and carbohydrate homeostasis.

The projected impact of global warming on coffee production may require the heat-adapted genotypes in the next decades. To identify thermotolerance cellular strategies, we compared the effect of elevated temperature on two commercialCoffea arabicaL. genotypes exploring leaf physiology, transcriptome and carbohydrate/protein composition. Growth temperatures were 23/19°C (day/night), as optimal condition (OpT), and 30/26°C (day/night) as a possible warmer scenario (WaT). The cv. Acauã showed lower levels of leaf temperature under both conditions compared to cv. Catuaí, whereas slightly or no differences for other leaf physiological parameters. Therefore, to explore thermoregulatory pathways the leaf transcriptome was examined using RNAseq. Genotypes showed a marked number of differentially-expressed genes (DEGs) under OpT, however DEGs strongly decrease in both at WaT condition indicating a transcriptional constraint. DEGs responsive to WaT revealed shared and genotype-specific genes mostly related to carbohydrate metabolism. Under OpT, leaf starch content was greater in cv. Acauã although the levels of leaf starch, sucrose, and leaf protein decreased in both genotypes as WaT was imposed. These findings indicate that genotypes with a greater capacity to maintain carbohydrate homeostasis under temperature fluctuations could be more thermotolerant and which may be useful in breeding for a changing climate.HIGHLIGHTIn response to warming, transcriptional differences decrease in coffee genotypes hampering breeding programs. Differences in gene expression and sugar levels confirm intraspecific variation associating thermotolerance to maintenance of energetic homeostasis.

Diabetes mellitus is a chronic, life-threatening metabolic disorder that occurs worldwide. Despite an increase in the knowledge of the risk factors that are associated with diabetes mellitus, its worldwide prevalence has continued to rise; thus, necessitating more research into its aetiology. Recent researches are beginning to link a dysregulation of the circadian rhythm to impairment of intermediary metabolism; with evidences that circadian rhythm dysfunction might play an important role in the aetiology, course or prognosis of some cases of diabetes mellitus. These evidences thereby suggest possible relationships between the circadian rhythm regulator melatonin, and diabetes mellitus. In this review, we discuss the roles of the circadian rhythm in the regulation of the metabolism of carbohydrates and other macronutrients; with emphasis on the importance of melatonin and the impacts of its deficiency on carbohydrate homeostasis. Also, the possibility of using melatonin and its analogs for the “prophylaxis” or management of diabetes mellitus is also considered.

Nowadays, an acute myocardial infarction is one of the leading causes of mortality among the population. The EHS-DH registry data clearly illustrate the association between the comorbidities and high mortality following acute myocardial infarction during a year period of follow up. The pronounced influence of carbohydrate metabolism disturbances on the survival of such patients has already been reported. The aim of the study was to analyze the immune inflammation relationships based on assessing calprotectin and the parameters of lipid and carbohydrate metabolism, to evaluate the presence and nature of the relationship between these parameters and carbohydrate metabolism parameters based on the study of blood glucose, insulin and insulin resistance (by the indices HOMA, QUICKI, Caro), anthropometric indicators and inflammatory indicators (monocyte and neutrophile levels). Materials and methods. The study included 64 patients (mean age 65, 31 ± 1.62 years) with acute myocardial infarction and concomitant diabetes mellitus type 2. The design of the study included the primary laboratory investigation of patients during the first day since the onset of acute myocardial infarction with the elevation of the ST segment before the initiation of thrombolytic therapy or percutaneous intervention. The direct correlation between the calprotectin concentration and the HOMA insulin resistance index (R = 0.52; p 0.05 and R = 0.18; p> 0.05, respectively). Conclusions. The increase in the body mass index and the activity of serum monocytes and neutrophils is associated with high concentrations of calprotectin that is accompanied by disturbances of carbohydrate homeostasis towards the growth of insulin resistance and changes of lipidograms of proatherrogenic nature.

Sugars are important energy sources, but high sugar intake poses a metabolic challenge and leads to diseases. Drosophila melanogaster is a generalist fruit breeder that encounters high levels of dietary sugars in its natural habitat. Consequently, Drosophila displays adaptive responses to dietary sugars, including highly conserved and unique metabolic adaptations not described in mammals. Carbohydrate homeostasis is maintained by a network comprising intracellular energy sensors, transcriptional regulators, and hormonal and neuronal mechanisms that together coordinate animal behavior, gut function, and metabolic flux. Here we give an overview of the physiological responses associated with sugar intake and discuss some of the emerging themes and applications of the Drosophila model in understanding sugar sensing and carbohydrate metabolism.

Bile acid receptors regulate lipid homeostasis, carbohydrate homeostasis, drug metabolism, energy consumption and inflammatory responses in response to bile acids and drugs. Cardiovascular diseases such as atherosclerosis and vascular calcification are major complications in patients with diabetes mellitus, chronic kidney disease, dyslipidemia and aging. Cardiovascular complications have a risk of mortality and morbidity worldwide. Bile acid modulators including agonists and antagonists are effective at treating cardiovascular diseases and improving outcomes. In this chapter, we summarize basic bile acid receptor signaling and functions, and effects of bile acid receptor modulations in the development of cardiovascular diseases.

Methylmercury (MeHg) is a well-known neurotoxicant; however, its role in metabolic diseases has been gaining wider attention. We have previously shown that MeHg causes metabolic alterations in Caenorhabditis elegans, leading to decreased nicotinamide adenine dinucleotide cofactor, mitochondrial dysfunction, and oxidative stress. We were, therefore, interested in whether MeHg also affects nutrient metabolism, particularly lipid homeostasis, which may contribute to the development of metabolic conditions such as obesity or metabolic syndrome (MS). RNA from wild-type worms exposed to MeHg was collected immediately after treatment and used for gene expression analysis by DNA microarray. MeHg differentially regulated 215 genes, 17 genes involved in lipid homeostasis, and 12 genes involved in carbohydrate homeostasis. Of particular interest was cebp-1, the worm ortholog to human C/EBP, a pro-adipogenic transcription factor implicated in MS. MeHg increased the expression of cebp-1 as well as pro-adipogenic transcription factors sbp-1 and nhr-49, triglyceride synthesis enzyme acl-6, and lipid transport proteins vit-2 and vit-6. Concurrent with the altered gene expression, MeHg increased triglyceride levels, lipid storage, and feeding behaviors. Worms expressing mutant cebp-1 were protected from MeHg-induced alterations in lipid content, feeding behaviors, and gene expression, highlighting the importance of this transcription factor in the worm’s response to MeHg. Taken together, our data demonstrate that MeHg induces biochemical, metabolic, and behavioral changes in C. elegans that can lead to metabolic dysfunction.

The ability to accurately predict complex trait phenotypes from genetic and genomic data are critical for the implementation of personalized medicine and precision agriculture; however, prediction accuracy for most complex traits is currently low. Here, we used data on whole genome sequences, deep RNA sequencing, and high quality phenotypes for three quantitative traits in the ∼200 inbred lines of the Drosophila melanogaster Genetic Reference Panel (DGRP) to compare the prediction accuracies of gene expression and genotypes for three complex traits. We found that expression levels (r = 0.28 and 0.38, for females and males, respectively) provided higher prediction accuracy than genotypes (r = 0.07 and 0.15, for females and males, respectively) for starvation resistance, similar prediction accuracy for chill coma recovery (null for both models and sexes), and lower prediction accuracy for startle response (r = 0.15 and 0.14 for female and male genotypes, respectively; and r = 0.12 and 0.11, for females and male transcripts, respectively). Models including both genotype and expression levels did not outperform the best single component model. However, accuracy increased considerably for all the three traits when we included gene ontology (GO) category as an additional layer of information for both genomic variants and transcripts. We found strongly predictive GO terms for each of the three traits, some of which had a clear plausible biological interpretation. For example, for starvation resistance in females, GO:0033500 (r = 0.39 for transcripts) and GO:0032870 (r = 0.40 for transcripts), have been implicated in carbohydrate homeostasis and cellular response to hormone stimulus (including the insulin receptor signaling pathway), respectively. In summary, this study shows that integrating different sources of information improved prediction accuracy and helped elucidate the genetic architecture of three Drosophila complex phenotypes.

The insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1-R) play key roles in growth, regulation of nutrient metabolism and carbohydrate homeostasis. Insulin-like molecules in prokaryotes and other early life have been reported. However, an account of metabolic effects of insulin, transcriptomic evidence of expression of glucose transporting channels (GLUT) and homology modelling of IR and IGF1-R like proteins in unicellular life-forms have yet to be established. Acanthamoeba spp. has existed for about 2 billion years and is one of the earliest mitochondriate unicellular eukaryotic cells on Earth. Despite Acanthamoeba spp. being grown in a medium called peptone-yeast-glucose (PYG) for over 50 years, the mechanism and regulation of glucose uptake by IR or IGF1-R molecules in this microbe has not yet been reported. Several methods were utilized to validate the effects of insulin on trophozoites of A. castellanii, including: growth assays with insulin, estimation of glucose and potassium (K+) entry into the cell, and histology showing anabolic effects on proteins. Bioinformatic computational tools and homology modeling demonstrated the involvement of IR like proteins, GLUT, and adapter proteins in mediating the IR cascade. Growth assays showed proliferative effects in a dose range of 2.98–5.97 µmol/mL of insulin. After insulin exposure, A. castellanii trophozoites displayed enhanced Periodic acid-Sciff (PAS) staining. Amino acid sequence similarities and homology modelling revealed ACA1_163470 in Acanthamoeba spp. to be a homolog of human-IR. Acanthamoeba protein ACA1_336150 shares similarities with IGF1-R. Additionally, some proteins like ACA1_060920 have attributes of GLUT like channels on homology modelling and show similarity with human GLUT. Knowledge of IR and insulin effects in Acanthamoeba spp. contributes to its biology and advances current understanding behind the evolution of IR and IGF1-R signalling cascade.

Liver plays a key role in controlling body carbohydrate homeostasis by switching between accumulation and production of glucose and this way maintaining constant level of glucose in blood. Increased blood glucose level triggers release of insulin from pancreatic β-cells. Insulin represses hepatic glucose production and increases glucose accumulation. Insulin resistance is the main cause of type 2 diabetes and hyperglycemia. Currently thiazolidinediones (TZDs) targeting transcriptional factor PPARγ are used as insulin sensitizers for treating patients with type 2 diabetes. However, TZDs are reported to be associated with cardiovascular and liver problems and stimulate obesity. Thus, it is necessary to search new approaches to improve insulin sensitivity. A promising candidate is transcriptional factor Prep1, as it was shown earlier it could affect insulin sensitivity in variety of insulin-sensitive tissues. The aim of the present study was to evaluate a possible involvement of transcriptional factor Prep1 in control of hepatic glucose accumulation and production. We created mice with liver-specific Prep1 knockout and discovered that hepatocytes derived from these mice are much more sensitive to insulin, comparing to their WT littermates. Incubation of these cells with 100 nM insulin results in almost complete inhibition of gluconeogenesis, while in WT cells this repression is only partial. However, Prep1 doesn't affect gluconeogenesis in the absence of insulin. Also, we observed that nuclear content of gluconeogenic transcription factor FOXO1 was greatly reduced in Prep1 knockout hepatocytes. These findings suggest that Prep1 may control hepatic insulin sensitivity by targeting FOXO1 nuclear stability.

Human exposure to bisphenol A (BPA) could favor obesity and related metabolic disorders such as hepatic steatosis. Investigations in rodents have shown that these deleterious effects are observed not only when BPA is administered during the adult life but also with different protocols of perinatal exposure. Whether perinatal BPA exposure could pose a risk in human is currently unknown, and thus appropriate in vitro models could be important to tackle this major issue. Accordingly, we determined whether long-term BPA treatment could induce steatosis in human HepaRG cells by using a protocol mimicking perinatal exposure. To this end, the kinetics of expression of seven proteins differentially expressed during liver development was determined during a 4-week period of cell culture required for proliferation and differentiation. By analogy with data reported in rodents and humans, our results indicated that the period of cell culture around day 15 and day 18 after seeding could be considered as the "natal" period. Consequently, HepaRG cells were treated for 3 weeks with BPA (from 0.2 to 2000 nM), with a treatment starting during the proliferating period. BPA was able to induce steatosis with a nonmonotonic dose response profile, with significant effects on neutral lipids and triglycerides observed for the 2 nM concentration. However, the expression of many enzymes involved in lipid and carbohydrate homeostasis was unchanged in exposed HepaRG cells. The expression of other potential BPA targets and enzymes involved in BPA biotransformation was also determined, giving answers as well as new questions regarding the mechanisms of action of BPA. Hence, HepaRG cells provide a valuable model that can prove useful for the toxicological assessment of endocrine disruptors on hepatic metabolisms, in particular in the developing liver. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1024-1036, 2017.

Aging is a complex phenomenon caused by the time-dependent loss of cellular homeodynamics and consequently of physiological organismal functions. This process is affected by both genetic and environmental (e.g., diet) factors, as well as by their constant interaction. Consistently, deregulation of nutrient sensing and signaling pathways is considered a hallmark of aging. Nutrigenomics is an emerging scientific discipline that studies changes induced by diet on the genome and thus it considers the intersection of three topics, namely health, diet, and genomics. Model organisms, such as the fruit fly Drosophila melanogaster, have been successfully used for in vivo modeling of higher metazoans aging and for nutrigenomic studies. Drosophila is a well-studied organism with sophisticated genetics and a fully annotated sequenced genome, in which ~ 75% of human disease-related genes have functional orthologs. Also, flies have organs/tissues that perform the equivalent functions of most mammalian organs, while discrete clusters of cells maintain insect carbohydrate homeostasis in a way similar to pancreatic cells. Herein, we discuss the mechanistic connections between nutrition and aging in Drosophila, and how this model organism can be used to study the effect of different diets (including natural products and/or their derivatives) on higher metazoans longevity. Electronic supplementary material The online version of this article (10.1186/s12263-019-0638-6) contains supplementary material, which is available to authorized users.

Angiopoietin-like 3 (ANGPTL3) is a regulator of plasma triglyceride (TRG) levels due to its inhibitory action on the activity of lipoprotein lipase (LPL). ANGPTL3 is proteolytically cleaved by proprotein convertases to generate an active N-terminal domain, which forms a complex with ANGPTL8 orchestrating LPL inhibition. ANGPTL3-4-8 mouse model studies indicate that these three ANGPTL family members play a significant role in partitioning the circulating TRG to specific tissues according to nutritional states. Recent data indicate a positive correlation of ANGPTL3 with plasma glucose, insulin, and homeostatic model assessment of insulin resistance (HOMA-IR) in insulin-resistant states. The aim of this review is to critically present the metabolic effects of ANGPTL3, focusing on the possible mechanisms involved in the dysregulation of carbohydrate homeostasis by this protein. Heterozygous and homozygous carriers of ANGPTL3 loss-of-function mutations have reduced risk for type 2 diabetes mellitus. Suggested mechanisms for the implication of ANGPTL3 in carbohydrate metabolism include the (i) increment of free fatty acids (FFAs) owing to the enhancement of lipolysis in adipose tissue, which can induce peripheral as well as hepatic insulin resistance; (ii) promotion of FFA flux to white adipose tissue during feeding, leading to the attenuation of de novo lipogenesis and decreased glucose uptake and insulin sensitivity; (iii) induction of hypothalamic LPL activity in mice, which is highly expressed throughout the brain and is associated with enhanced brain lipid sensing, reduction of food intake, and inhibition of glucose production (however, the effects of ANGPTL3 on hypothalamic LPL in humans need more clarification); and (iv) upregulation of ANGPTL4 expression (owing to the plasma FFA increase), which possibly enhances insulin resistance due to the selective inhibition of LPL in white adipose tissue leading to ectopic lipid accumulation and insulin resistance. Future trials will reveal if ANGPTL3 inhibition could be considered an alternative therapeutic target for dyslipidemia and dysglycemia.

Apolipoprotein CIII (ApoCIII), a small protein that resides on the surface of lipoprotein particles, is a key regulator of triglyceride metabolism. The inhibition of lipoprotein lipase (LPL), the increased assembly and secretion of very low-density lipoproteins (VLDL) and the decreased reuptake of triglyceride-rich lipoproteins (TRLs) by the liver are mechanisms associating elevated serum ApoCIII levels and hypertriglyceridemia. ApoCIII concentration is high in individuals with diabetes mellitus, indicating a possible positive correlation with impairment of glucose metabolism. The aim of this review (based on a Pubmed search until August 2018) is to present the possible mechanisms linking ApoCIII and deterioration of carbohydrate homeostasis. ApoCIII enhances pancreatic β-cells apoptosis via an increase of the cytoplasmic Ca2+ levels in the insulin-producing cells. In addition, overexpression of ApoCIII enhances non-alcoholic fatty liver disease and exacerbates inflammatory pathways in skeletal muscles, affecting insulin signalling and thereby inducing insulin resistance. Moreover, recent studies reveal a possible mechanism of body weight increase and glucose production through a potential ApoCIII-induced LPL inhibition in the hypothalamus. Also, the presence of ApoCIII on the surface of high-density lipoprotein particles is associated with impairment of their antiglycemic and atheroprotective properties. Modulating ApoCIII may be a potent therapeutic approach to manage hypertriglyceridemia and improve carbohydrate metabolism.

Hepatocyte Nuclear Factor 4 alpha (HNF4α) is required for hepatocyte differentiation and regulates expression of genes involved in lipid and carbohydrate metabolism including those that control VLDL secretion and gluconeogenesis. Whereas previous studies have focused on specific genes regulated by HNF4α in metabolism, its overall role in whole body energy utilization has not been studied. In this study, we used indirect calorimetry to determine the effect of hepatocyte-specific HNF4α deletion (HNF4α-KO) in mice on whole body energy expenditure (EE) and substrate utilization in fed, fasted, and high fat diet (HFD) conditions. HNF4α-KO had reduced resting EE during fed conditions and higher rates of carbohydrate oxidation with fasting. HNF4α-KO mice exhibited decreased body mass caused by fat mass depletion despite no change in energy intake and evidence of positive energy balance. HNF4α-KO mice were able to upregulate lipid oxidation during HFD suggesting that their metabolic flexibility was intact. However, only hepatocyte specific HNF4α-KO mice exhibited significant reduction in basal metabolic rate and spontaneous activity during HFD. Consistent with previous studies, hepatic gene expression in HNF4α-KO supports decreased gluconeogenesis and decreased VLDL export and hepatic β-oxidation in HNF4α-KO livers across all feeding conditions. Together, our data suggest deletion of hepatic HNF4α increases dependence on dietary carbohydrates and endogenous lipids for energy during fed and fasted conditions by inhibiting hepatic gluconeogenesis, hepatic lipid export, and intestinal lipid absorption resulting in decreased whole body energy expenditure. These data clarify the role of hepatic HNF4α on systemic metabolism and energy homeostasis.

Newborns with intrauterine growth-restriction are at increased risk of mortality and life-long comorbidities. Insulin-like growth factor-II (IGF2) deficiency in humans, as well as in mice, leads to intrauterine growth restriction and decreased neonatal glycogen stores. The present study aims to further characterize the metabolic and transcriptional consequences of Igf2 deficiency in the newborn. We found that, despite being born significantly smaller than their wild-type ( Igf2+/+) littermates, brain size was preserved in Igf2 knockout ( Igf2−/−), consistent with nutritional deficiency. Histological and triglyceride analyses of newborn livers revealed that Igf2−/−mice are born with hepatic steatosis. Gene expression analysis in Igf2−/−newborn livers showed an alteration of genes known to be dysregulated in chronic caloric restriction, including the most upregulated gene, serine dehydratase. Multiple genes connected with lipid metabolism and/or hepatic steatosis were also upregulated. Ingenuity Pathway Analysis confirmed that the biological functions most altered in livers of Igf2−/−newborns are related to lipid metabolism, with the top upstream regulator predicted to be the peroxisome proliferator-activated receptor alpha, a master regulator of hepatic lipid and carbohydrate homeostasis. Together, our data indicate that Igf2 deficiency leads to a newborn phenotype strongly reminiscent of nutritional deficiency, including growth retardation, increased brain/body weight ratio, hepatic steatosis, and characteristic changes in hepatic gene expression. We propose that in addition to its growth factor proliferating functions, Igf2 may also regulate growth by altering the expression of genes that control nutrient metabolism in the newborn.

The Transforming growth factor beta (TGF-β) family of secreted proteins regulates a variety of key events in normal development and physiology. In mammals, this family, represented by 33 ligands, including TGF-β, activins, nodal, bone morphogenetic proteins (BMPs), and growth and differentiation factors (GDFs), regulate biological processes as diverse as cell proliferation, differentiation, apoptosis, metabolism, homeostasis, immune response, wound repair, and endocrine functions. In Drosophila, only 7 members of this family are present, with 4 TGF-β/BMP and 3 TGF-β/activin ligands. Studies in the fly have illustrated the role of TGF-β/BMP ligands during embryogenesis and organ patterning, while the TGF-β/activin ligands have been implicated in the control of wing growth and neuronal functions. In this review, we focus on the emerging roles of Drosophila TGF-β/activins in inter-organ communication via long-distance regulation, especially in systemic lipid and carbohydrate homeostasis, and discuss findings relevant to metabolic diseases in humans.

Clinical trials and meta-analyses have shown that statins can dose dependently increase the incidence of new-onset diabetes mellitus (DM) especially in patients with underlying abnormalities of carbohydrate homeostasis. Mendelian randomization studies support these findings since genetic variants in the gene encoding the target of statins, the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, are associated with increased incidence of new-onset DM, suggesting that the so-called diabetogenic effect of statins is an "on-target effect" possibly related to their main mechanism of action, that is the increased low-density lipoprotein (LDL) receptor expression. Additionally, Mendelian randomization studies have shown that genetic variants as proxies of other drugs that increase LDL receptor expression (ezetimibe and proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors) also increase the risk of new-onset DM. This concept is supported by the fact of decreased DM prevalence in patients with familial hypercholesterolemia who have decreased LDL receptor expression. In contrast, hypolipidemic drugs, such as the cholesteryl ester transfer protein inhibitors, that decrease LDL cholesterol without directly interfering with the LDL receptor expression do not seem to detrimentally affect carbohydrate homeostasis. However, the clinical trials of ezetimibe and PCSK9 inhibitors have not shown an increased DM risk, possibly suggesting that other potential non-well-defined "off-target effects" of hypolipidemic drugs may affect carbohydrate homeostasis. Thus, the long-term effect of hypolipidemic drugs on DM risk depends not only on their final mechanism of hypolipidemic action but also on other "on-target" and "off-target" effects of these drugs.

Economically important plant species, such as Eucalyptus globulus, are often rooting recalcitrant. We have previously shown that far-red light enrichment applied to E. globulus donor-plants improved microcutting rooting competence and increased rooting zone/shoot carbohydrate ratio. To better understand this developmental response, the relative expression profiles of genes involved in auxin signaling (ARF6, ARF8, AGO1), biosynthesis (YUC3) and transport (AUX1, PIN1, PIN2); sucrose cleavage (SUS1, CWINV1), transport (SUC5), hexose phosphorylation (HXK1, FLN1) and starch biosynthesis (SS3) were quantified during adventitious rooting of E. globulus microcuttings derived from donor plants exposed to far-red or white light. Expression of auxin transport-related genes increased in the first days of root induction. Far-red enrichment of donor plants induced ARF6, ARF8 and AGO1 in microcuttings. The first two gene products could activate GH3 and other rooting related genes, whereas AGO1 deregulation of the repressor ARF17 may relief rooting inhibition. Increased sink strength at the basal stem with sucrose unloading in root tissue mediated by SUC and subsequent hydrolysis by SUS1 were also supported by gene expression profile. Fructose phosphorylation and starch biosynthesis could also contribute to proper carbon allocation at the site of rooting, as evidenced by increased expression of related genes. These data are in good agreement with increased contents of hexoses and starch at the cutting base severed from far-red exposed donor plants. To sum up, pathways integrating auxin and carbohydrate metabolism were activated in microcuttings derived from donor plants exposed to far red light enrichment, thereby improving rooting response in E. globulus.

SummaryFibroblast growth factor 15 (FGF15) has been proposed as a postprandial hormone that signals from intestine to liver to regulate bile acid and carbohydrate homeostasis. However, detecting FGF15 in blood using conventional techniques has proven difficult. Here, we describe a stable isotope standards and capture by anti-peptide antibodies (SISCAPA) assay that combines immuno-enrichment with selected reaction monitoring (SRM) mass spectrometry to overcome this issue. Using this assay, we show that FGF15 circulates in plasma in an FXR and circadian rhythm-dependent manner at concentrations that activate its receptor. Consistent with the proposed endocrine role for FGF15 in liver, mice lacking hepatocyte expression of the obligate FGF15 co-receptor, β-Klotho, have increased bile acid synthesis and reduced glycogen storage despite having supraphysiological plasma FGF15 concentrations. Collectively, these data demonstrate that FGF15 functions as a hormone and highlight the utility of SISCAPA-SRM as a sensitive assay for detecting low-abundance proteins in plasma.

Purpose Previous studies have shown that several components of the metabolic syndrome, such as hypertension, obesity or imbalanced lipid and carbohydrate homeostasis, are associated with the sympathetic nervous system overactivity. Therefore, the inhibition of the adrenergic nervous system seems to be a reasonable and appropriate therapeutic approach for the treatment of metabolic disturbances. It has been suggested that non-selective adrenoceptor antagonists could be particularly beneficial, since $\alpha$1-adrenoceptor antagonists can improve disrupted lipid and carbohydrate profiles, while the inhibition of the $\alpha$2-adrenoceptor may contribute to body weight reduction. The aim of the present study was to investigate the metabolic benefits deriving from administration of a non-selective $\alpha$-adrenoceptor antagonist from the group of pyrrolidin-2-one derivatives. The aim of the present study was to investigate the potential metabolic benefits deriving from chronic administration o a non-selective $\alpha$-adrenoceptor antagonist, from the group of pyrrolidin-2-one derivatives. Methods The $\alpha$1- and $\alpha$2-adrenoreceptor affinities of the tested compound-1-(3-(4-(o-tolyl)piperazin-1-yl)propyl) pyrrolidin-2-one had been investigated previously by means of the radioligand binding assay. In the present study, we extended the pharmacological profile characteristics of the selected molecule by additional intrinistic activity assays. Next, we investigated the influence of the tested compound on body weight, hyperglycemia, hypertriglyceridemia, blood pressure in the animal model of obesity induced by a highfat diet, and additionally we measured the spontaneous activity and body temperature. Results The intrinistic activity studies revealed that the tested compound is a potent, non-selective antagonist of $\alpha$1B and $\alpha$2A-adrenoceptors. After the chronic administration of the tested compound, we observed reduced level of triglycerides and glucose in the rat plasma. Interestingly, the tested did not reduce the body weight and did not influence the blood pressure in normotensive animals. Additionally, the administration of the tested compound did not change the animals' spontaneous activity and body temperature. Conclusion Non-selective $\alpha$-adrenoceptor antagonist seems to carry potential benefits in the improvement of the reduction of elevated glucose and triglyceride level. The lack of influence on blood pressure suggests that compounds with such a pharmacological profile may be particulary beneficial for the patients with disturbed lipid and carbohydrate profile, who do not suffer from hypertension. These results are particulary valuable, since currently there are no safe $\alpha$2A-adrenoceptor antagonist drugs available in clinical use with the ability to modulate hyperglycemia that would not affect blood pressure.

The sessile lifestyle of higher plants is accompanied by their remarkable ability to tolerate unfavorable environmental conditions. This is because, during evolution, plants developed a sophisticated repertoire of molecular and metabolic reactions to cope with changing biotic and abiotic challenges. In particular, the abiotic factors light intensity and ambient temperature are characterized by altering their amplitude within comparably short periods of time and are causative for onset of dynamic plant responses. These rapid responses in plants are also classified as 'acclimation reactions' which differ, due to their reversibility and duration, from non-reversible 'adaptation reactions'. In this review, we demonstrate the remarkable importance of stress-induced changes in carbohydrate homeostasis of plants exposed to high light or low temperatures. These changes represent a co-ordinated process comprising modifications of (i) the concentrations of selected sugars; (ii) starch turnover; (iii) intracellular sugar compartmentation; and (iv) corresponding gene expression patterns. The critical importance of these individual processes has been underlined in the recent past by the analyses of a large number of mutant plants. The outcome of these analyses raised our understanding of acclimation processes in plants per se but might even become instrumental to develop new concepts for directed breeding approaches with the aim to increase abiotic stress tolerance of crop species, which in most cases have high stress sensitivity. The latter direction of plant research is of special importance since abiotic stress stimuli strongly impact on crop productivity and are expected to become even more pronounced because of human activities which alter environmental conditions rapidly.

Cholesteryl ester transfer protein (CETP) inhibitors significantly increase serum high-density lipoprotein cholesterol (HDL) cholesterol levels and decrease low-density lipoprotein cholesterol (LDL) cholesterol concentration. However, three drugs of this class failed to show a decrease of cardiovascular events in high-risk patients. A new CETP inhibitor, anacetrapib, substantially increases HDL cholesterol and apolipoprotein (Apo) AI levels with a profound increase of large HDL2 particles, but also pre-β HDL particles, decreases LDL cholesterol levels mainly due to increased catabolism of LDL particles through LDL receptors, decreases lipoprotein a (Lp(a)) levels owing to a decreased Apo (a) production and, finally, decreases modestly triglyceride (TRG) levels due to increased lipolysis and increased receptor-mediated catabolism of TRG-rich particles. Interestingly, anacetrapib may be associated with a beneficial effect on carbohydrate homeostasis. Furthermore, the Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification (REVEAL) trial showed that anacetrapib administration on top of statin treatment significantly reduces cardiovascular events in patients with atherosclerotic vascular disease without any significant increase of adverse events despite its long half-life. Thus, anacetrapib could be useful for the effective management of dyslipidemias in high-risk patients that do not attain their LDL cholesterol target or are statin intolerable, while its role in patients with increased Lp(a) levels remains to be established.

Hypoglycemia in the neonatal period is one of the urgent problems of pediatric endocrinology. The main factors that lead to disruption of carbohydrate homeostasis are generally known, but the issues of neonatal hypoglycemia continue to be actively studied. In the last few years, the effect of low blood glucose on brain neurons has been studied, the issues of glycemia monitoring in the first days of life have been outlined, and strategies for managing newborns with hypoglycemic syndrome are being discussed.Гипогликемии в периоде новорожденности являются одной из актуальных проблем детской эндокринологии. Основные факторы, приводящие к нарушению гомеостаза углеводов, в целом известны, однако вопросы неонатальных гипогликемий продолжают активно изучаться. В последние годы исследуется влияние низкого уровня глюкозы крови на нейроны головного мозга, дискутируются вопросы мониторинга гликемии в первые дни жизни, обсуждается тактика ведения новорожденных с гипогликемическим синдромом.

The HSD11B1 gene encodes the type 1 isoform of the 11-β-hydroxysteroid dehydrogenase that is responsible for the regeneration of glucocorticoids from hormonally-inactive metabolites into active forms in a tissue-specific manner. Altered activity of the enzyme, and certain genetic variants of the HSD11B1 gene, has been associated with various metabolic morbidities. In this study, our aim was to systematically test the potential role of the HSD11B1's single nucleotide polymorphisms (SNPs) in polycystic ovary syndrome (PCOS). Nine HSD11B1 SNPs were selected and genotyped using Taqman SNP assays on real-time PCR in a group of PCOS patients (n = 58) and in age-matched healthy controls (n = 64). Genotype-phenotype correlations were determined and haplotype analysis was performed. An in silico prediction for potential transcription factor binding sites was also performed. Of the 5 promoter SNPs, 3 (rs760951; rs4844880; rs3753519) were less frequent in the PCOS group compared to healthy controls. SNPs rs4844880 and rs3753519 were in a complete linkage and the mutant haplotype (AA) was less frequent in the PCOS group. No association between HSD11B1 variants and clinical, pathological findings was observed in patients, but in healthy women the rs4844880 and the AA haplotype were associated with higher levels of homeostasis model assessment of beta cell function. The polymorphic form of the rs4844880 was predicted to bind Pbx-1. Promoter SNPs of the HSD11B1 gene might exert a potential genetic protective role against the development of PCOS, possibly via their beneficial effect on carbohydrate homeostasis due to facilitation of insulin efflux from pancreatic beta-cells.

Statins are the cornerstone of lipid-lowering treatment in patients with or without type 2 diabetes. Prospective randomized clinical trials and meta-analyses have shown that the statin-mediated decrease in plasma low-density lipoprotein cholesterol (LDL-C) is associated with a significant decrease in cardiovascular (CV) morbidity and mortality. Furthermore, high-intensity statin treatment in high-risk individuals is followed by a significantly greater decrease in CV events compared with moderate dose statin treatment. However, the majority of high-risk individuals do not attain the LDL-C targets set by the guidelines even if high-intensity statin therapy is used. This is especially relevant in diabetic patients who need aggressive lipid management to decrease macrovascular complications. To further decrease this residual CV risk associated with suboptimal reduction in LDL-C levels, combination lipid-lowering treatment (eg, statin þ ezetimibe) is an attractive option. Ezetimibe targets the Niemann-Pick C1-like 1 (NPC1L1) protein and thus decreases cholesterol absorption from the gastrointestinal tract leading to a further fall in plasma LDL-C concentration by 20% to 25% when added to ongoing statin therapy. The recently published results of the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) study showed, for the first time, that the additional ezetimibe-induced decrease in LDL-C levels (compared with simvastatin monotherapy) is associated with a significant further decrease in major CV events in very high-risk patients with acute coronary syndrome. Thus, the IMPROVE-IT trial confirms the LDL-C story. A lower LDL-C concentration is better for the reduction in CV events. These findings also refute any hypothesis that focuses on LDL-C–independent pleiotropic effects of statins. Additionally, a recently published meta-analysis of randomized controlled trials showed that adding ezetimibe to statin therapy not only decreases LDL-C concentration but also reduces CV events (relative risk: 0.92, P 1⁄4 .004). The IMPROVE-IT trial showed that elderly individuals and diabetic patients gain greater benefit from the addition of ezetimibe (Table 1). Interestingly, the addition of ezetimibe to ongoing statin therapy may induce a greater reduction in plasma LDL-C levels in diabetic patients compared with nondiabetic individuals. It is worth mentioning that the incidence of side effects (including cancer) in the IMPROVE-IT trial was not different between the statin and the statin þ ezetimibe combination groups. This finding not only confirms the long-term safety of ezetimibe but also that of very low LDL-C levels. Furthermore, recently published Mendelian randomization studies have also confirmed the benefits of decreased cholesterol absorption, which is associated with reduction in LDL-C concentration, in terms of CV disease. These studies showed that genetic polymorphisms of the NPC1L1 gene, which can be used as a proxy of ezetimibe therapy that targets the NPC1L1 protein, are not only associated with a reduction in LDL-C levels but also with a reduction in CV events (Table 2). Thus, combination therapy of statins with ezetimibe is a reasonable, effective, and safe option to treat diabetic dyslipidemia. Nowadays, fixed-dose combinations of a statin with ezetimibe are currently, or awaiting to be, marketed. The fixed-dose atorvastatin þ ezetimibe combination is especially attractive, since it can substantially increase adherence to statin therapy, while atorvastatin (the most commonly used statin in many countries) has the unique properties of lower renal excretion and fewer interactions with other commonly used drugs compared with simvastatin. Further analysis of the results of the IMPROVE-IT trial will clarify the role of ezetimibe (and of statin þ ezetimibe combination therapy) in carbohydrate homeostasis. Some recently published preliminary data hint that ezetimibe might favorably affect insulin resistance and carbohydrate metabolism, in part due to its ability to stimulate intestinal glucagon-like peptide 1 secretion via the mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase signaling pathway. It is worth mentioning that ezetimibe can also exhibit pleiotropic effects

Restriction of dietary methionine by 80% slows the progression of aged-related diseases and prolongs lifespan in rodents. A salient feature of the methionine restriction phenotype is the significant reduction of adipose tissue mass, which is associated with improvement of insulin sensitivity. These beneficial effects of MR involve a host of metabolic adaptations leading to increased mitochondrial biogenesis and function, elevated energy expenditure, changes of lipid and carbohydrate homeostasis, and decreased oxidative damage and inflammation. This review summarizes observations from MR studies and provides insight about potential mediators of tissue-specific responses associated with MR's favorable metabolic effects that contribute to health and lifespan extension.

Accessions of Arabidopsis thaliana originating from climatically different habitats show different levels of cold acclimation when exposed to low temperatures. The central carbohydrate metabolism plays a crucial role during this acclimation. Subcellular distribution of carbohydrates over the compartments cytosol, vacuole and plastids, and putative interactions of the compartments, are analyzed in three differentially cold-tolerant accessions of Arabidopsis thaliana, originating from the Iberian Peninsula (C24), Russia (Rschew) and Scandinavia (Tenela), respectively. Subcellular carbohydrate concentrations were determined by applying the nonaqueous fractionation technique. Mathematical modeling and steady-state simulation was used to analyse the metabolic homeostasis during cold exposure. In all accessions, the initial response to cold exposure was a significant increase of plastidial and cytosolic sucrose concentrations. Raffinose accumulated in all cellular compartments of cold-tolerant accessions with a delay of 3 d, indicating that raffinose accumulation is a long-term component of cold acclimation. Minimal rates of metabolite transport permitting steady-state simulations of metabolite concentrations correlated with cold tolerance, indicating an important role of subcellular re-distribution of metabolites during cold acclimation. A highly regulated interplay of enzymatic reactions and intracellular transport processes appears to be a prerequisite for maintaining carbohydrate homeostasis during cold exposure and allowing cold acclimation in Arabidopsis thaliana.

Dyslipidemia is a frequent component of the metabolic disorder of diabetic patients contributing to organ damage. Herein, in low-density lipoprotein receptor–deficient hyperlipidemic and streptozotozin-induced diabetic mice, hyperglycemia and hyperlipidemia acted reciprocally, accentuating renal injury and altering renal function. In hyperglycemic-hyperlipidemic kidneys, the accumulation of Tip47-positive lipid droplets in glomeruli, tubular epithelia, and macrophages was accompanied by the concomitant presence of the oxidative stress markers xanthine oxidoreductase and nitrotyrosine, findings that could also be evidenced in renal biopsy samples of diabetic patients. As liver X receptors (LXRα,β) regulate genes linked to lipid and carbohydrate homeostasis and inhibit inflammatory gene expression in macrophages, the effects of systemic and macrophage-specific LXR activation were analyzed on renal damage in hyperlipidemic-hyperglycemic mice. LXR stimulation by GW3965 up-regulated genes involved in cholesterol efflux and down-regulated proinflammatory/profibrotic cytokines, inhibiting the pathomorphology of diabetic nephropathy, renal lipid accumulation, and improving renal function. Xanthine oxidoreductase and nitrotyrosine levels were reduced. In macrophages, GW3965 or LXRα overexpression significantly suppressed glycated or acetylated low-density lipoprotein–induced cytokines and reactive oxygen species. Specifically, in mice, transgenic expression of LXRα in macrophages significantly ameliorated hyperlipidemic-hyperglycemic nephropathy. The results demonstrate the presence of lipid droplet–induced oxidative mechanisms and the pathophysiologic role of macrophages in diabetic kidneys and indicate the potent regulatory role of LXRs in preventing renal damage in diabetes.

The oyster insulin-related peptide (oIRP) is known in other organisms to play important roles in growth control and carbohydrate homeostasis. Polymorphisms of the oIRP gene were evaluated for associations with growth performance of 271 Crassostrea gigas individuals from a diallel cross among three strains of C. gigas. Thirty-one single nucleotide polymorphisms (SNPs) were revealed in 1.5 kb of the oIRP gene, and six of them were significantly associated with growth performance (P < 0.05), particularly for T1358G and G1437A which were highly correlated with all the five growth traits (shell height, shell length, shell width, body mass and soft-tissue mass) (P < 0.01). Moreover, haplotypes analysis revealed that H7 (ATGTGA) and H8 (ATGTTA) might be the most advantageous haplotypes for growth traits. The results demonstrated that the oIRP gene could influence growth performance of C. gigas and have potential applications in future genetic improvement of C. gigas.

The purpose of the present study is to compare the effects of four different breads (one commercial par-baked wheat bread, three sourdough breads prepared with commercial wheat flour, organic wheat flour, organic einkorn flour) in 16 healthy subjects. The primary outcome of this randomized cross-over trial was evaluating intra-individual changes in glycemic areas-under-the-curve (AUCs) after 50g carbohydrate portions of each bread; secondary outcomes were changes in insulin, fatty free acids (FFA), triglyceride, acylated ghrelin and satiety AUCs. Blood samples and satiety ratings were collected every 30-min for 2-h after the consumption of each bread. The einkorn flour showed the lowest amylase activity, the commercial flour the highest; commercial bread had the highest carbohydrate content and the lowest dietary fiber content. Glucose AUCs were significantly lower after the consumption of sourdough breads made with organic (12,754±1433mg/dL×h) and einkorn flour (12,216±1210mg/dL×h), with respect to the commercial bread (13,849±2193mg/dL×h). Insulin AUCs decreased after the consumption of all sourdough breads when compared to commercial bread. FFA and triglyceride AUCs did not differ by kind of breads. Median ghrelin AUC was significantly lower and satiety higher after the einkorn bread (3710pg/mL×h; 3225±2414, respectively) than after commercial bread consumption (4140pg/mL×h; 1706±1766, respectively), but not with other sourdough breads. In conclusion, the use of sourdough may improve the nutritional features of breads; einkorn bread induced the least disturbance in carbohydrate homeostasis and the greater satiety. If confirmed by further research, these results might have implications in the approach towards chronic dysmetabolic diseases.

Clinical findings and data obtained in animal models indicate that nutrient uptake and exposure to environmental agents during pregnancy may affect fetal/newborn gestational programming, thereby resulting in obesity and/or obesity-related disorders in offspring. Human amniotic mesenchymal stem cells (hA-MSCs) differentiate into adipocytes and are thus a suitable model to investigate adipocyte functions in obesity. The aim of this study was to elucidate the miRNome of hA-MSCs and its contribution to obesity in pregnancy. To this aim we used the following: (i) high-resolution small RNA sequencing to characterize the microRNA (miRNA) profiles of hA-MSCs of 13 obese (Ob-) and 7 control (Co-) pregnant women at delivery; (ii) multiple-method integrated bioinformatics to predict the metabolic pathways potentially miRNA deregulated in Ob-hA-MSCs; and (iii) microarray mRNA expression profiling to verify obese-associated mRNA alterations. In summary, 12 miRNAs were differentially expressed between Ob-hA-MSCs and Co-hA-MSCs, with a multiple-methods bioinformatic consensus on miR-138-5p and miR-222-3p, which were overexpressed in Ob-hA-MSCs versus Co-hA-MSCs. The top 20 significant pathways predicted to be deregulated through miR-138-5p and/or miR-222-3p/target interaction included fat cell differentiation and deposits, lipid/carbohydrate homeostasis, response to stress, metabolic syndrome, heart disease, and ischemia. In conclusion, our finding of miR-138-5p/miR-222-3p overexpression in Ob-hA-MSCs, together with the transcriptomic data, suggests that these miRNAs in obese pregnancy could derange metabolic pathways previously found impaired in tissues from obese adults or in obesity-associated disorders and concur to modify gestational programming as has been demonstrated in animal models. This raises the possibility of using diet-based strategies to normalize the perinatal miRNome in obesity.

Diabetes mellitus (DM) is a serious and growing worldwide health problem and is associated with se- vere acute and chronic complications that negatively influence both quality of life and survival of affected individuals. It is a heterogeneous deregulation of car- bohydrate metabolism. The liver is a central regulator of carbohydrate homeostasis and releases glucose according to metabolic demands. In the last years, the liver injury has been recognized as a major complica- tion of DM. In fact, evidence suggests that in diabetic patients, the mortality rate due to liver cirrhosis is even higher than that due to cardiovascular disease and it has been suggested that there is a two-fold in- creased risk of liver disease in diabetic patients. Among the different types of diabetes, we analyze type 1 dia- betes mellitus as a chronic disorder and an inflam- matory process, which is also associated with in- creased risk of chronic liver injury. Animal models have contributed extensively to the study of diabetes, and it is well established that administration of a unique dose of streptozotocin (STZ) induces insulin- dependent type 1 diabetes mellitus. We analyzed the contribution of Tumor Necrosis Factor alpha (TNF-α) intracellular pathway and oxidative stress in the de- velopment of apoptosis in the liver of streptozotocin- induced diabetic animals. In this review, we describe the role of upstream mediators of the interaction be- tween TNF-α and its receptor, TNF-R1, by assessing the ability of the in vivo treatment with etanercept (TNF-α blocking antibody) to protect against TNF-α- induced apoptosis. Also, we studied the role of iNOS- induction in the TNF-α-induced liver apoptosis by type 1 diabetes, by treatment of diabetic rats with aminoguanidine (selective iNOS inhibitor), which blocked the induction of apoptosis. Interestingly, iNOS inhibition significantly reduced TNF-α levels, evidencing an interaction between TNF-α and iNOS activity. On the other hand, we found that the ad- ministration of antioxidants/hydroxyl radical scaven- gers (Tempol and Desferal) prevented oxidative stress by reducing the effects of hydroxyl radical production and both lipid peroxidation (LPO) levels and apop- tosis. Taken together, our studies support that, at least in part, the hydroxyl radical acts as a reactive inter- mediate, which leads to liver apoptosis in a model of STZ-mediated hyperglycemia. Conclusion and Future: The relevance of the present review is to provide fur- ther knowledge about the mechanisms which may contribute to the disease process in the liver during the course of an inflammatory process as it is type 1 diabetes. Regulation of hepatic TNF-α levels and oxi- dative stress in the diabetic state could be of thera- peutic relevance for the improvement or delay of the hepatic complications linked to chronic hyperglycemia. Fil: Frances, Daniel Eleazar Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina Fil: Ingaramo, Paola Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina Fil: Ronco, Maria Teresa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina Fil: Carnovale, Cristina Ester. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Fisiología Experimental (i); Argentina

Background Most recently, a novel myokine, named irisin, was identified in human that expressed by skeletal muscle after exercise. Irisin increases energy expenditure by turning white adipose tissue into brown adipose tissue. Thus improves carbohydrate homeostasis in humans. Irisin is considered as a potential biomarker for obesity and metabolic syndrome. In recent years, numerous studies have been conducted about irisin with adults, although number of studies with newborns is limited. Objective To evaluate cord blood irisin level with small gestational age (SGA) and appropriate gestational age (AGA) in term newborns. Methods A cross-sectional study of 34 AGA and 34 SGA term newborns who were born in (1–30) December 2015 in Fatih University Hospital. Estimated fetal weight were calculated using the Hadlock formula by gynecologists to pregnant women in second trimester. All the babies were classified at birth as SGA or AGA. SGA was defined according to the Lubchenco scale for gender and gestational age. We collected umbilical cord blood at the time of delivery. Cord blood irisin levels were measured using commercial enzyme-linked immunosorbent assays in our hospital laboratory. Results Cord blood irisin levels were significantly lower in SGA group [median 30 (25 ± 8) ng/ml] than in AGA group [median 40 (39 ± 13) ng/ml, p 0.05). Mothers with gestational diabetes, hypertension, asthma, chronic disease, use of drug or a history of smoking exposure were excluded from the study. When the study data were evaluated, Yates Continuity Correction and Fisher’s exact tests were used in descriptive statistical methods and for comparison of qualitative data. Conclusion Our results support the idea that irisin have a physiologic role in neonates. Low level of irisin is associated with the impaired carbohydrate metabolism in term infants with SGA. However, further studies with larger series are warranted to confirm this.

Introduction The causal role of sympathetic nervous system in the development of metabolic disorders has not been clearly defined. The aim of the study was to determine if a chronic increase of the sympathetic nervous activity can induce and/or accelerate the development of glucose metabolism disorders. For that purpose, we used a transgenic mouse model, in which the gene encoding for the reuptake norepinephrine transporter (NET) has been deleted; these animals display increased urinary catecholamine levels. Methods Carbohydrate homeostasis (intraperitoneal glucose tolerance test, IPGTT, insulin tolerance test, ITT, insulin rates) was studied in heterozygous NET knockout mice (±) or wild-type mice (+/+) at 10, 20 and 25 weeks old. Mice were then fed either with normal chow or 30% w/v fructose in drinking water; glucose metabolism was assessed again after 15 weeks of such diet. Results Heterozygous mice displayed glucose intolerance already at 10 weeks old (area under the curve of the IPGTT (AUC; %) = 24859 vs 18016, p=0.004); similar results were obtained at 25 weeks old, i.e, just before starting the fructose diet: AUC = 24524 vs 20573, p=0.005 for ± and +/+ mice respectively. Moreover sensibility to insulin seemed to be diminished in ± mice compared to +/+ mice (insulin rate = 1.12 vs 0.86 μg/L and HOMAIR= 11.1 vs 8.4). Heterozygous animals were also much more sensitive to high fructose, since a 20% increase in the AUC of the IPGTT was obtained at the end of the high fructose diet, compared to the 2% increase in +/+ mice. This was associated with a decrease of insulin sensibility (HOMA-IR of ± mice = 11.1 vs 18.1, p=0.01, before and after fructose diet respectively). Conclusion Our data show that constitutive chronic sympathetic hyperactivity can induce the early development of carbohydrate metabolism disorders. Moreover, it seems to represent a major factor of susceptibility to diet-induced metabolic dysfunction. The author hereby declares no conflict of interest

Central carbohydrate metabolism of Arabidopsis thaliana is known to play a crucial role during cold acclimation and the acquisition of freezing tolerance. During cold exposure, many carbohydrates accumulate and a new metabolic homeostasis evolves. In the present study, we analyse the diurnal dynamics of carbohydrate homeostasis before and after cold exposure in three natural accessions showing distinct cold acclimation capacity. Diurnal dynamics of soluble carbohydrates were found to be significantly different in cold-sensitive and cold-tolerant accessions. Although experimentally determined maximum turnover rates for sucrose phosphate synthase in cold-acclimated leaves were higher for cold-tolerant accessions, model simulations of diurnal carbohydrate dynamics revealed similar fluxes. This implied a significantly higher capacity for sucrose synthesis in cold-tolerant than cold-sensitive accessions. Based on this implication resulting from mathematical model simulation, a critical temperature for sucrose synthesis was calculated using the Arrhenius equation and experimentally validated in the cold-sensitive accession C24. At the critical temperature suggested by model simulation, an imbalance in photosynthetic carbon fixation ultimately resulting in oxidative stress was observed. It is therefore concluded that metabolic capacities at least in part determine the ability of accessions of Arabidopsis thaliana to cope with changes in environmental conditions.

The aim of this study was to determine the effects of chronic waterborne copper (Cu) exposure on the acute stress-induced cortisol response and associated physiological consequences in rainbow trout (Oncorhynchus mykiss). Trout were exposed to 30 μg Cu/L in moderately hard water (120 mg/L as CaCO(3)) for 40 days, following which time the acute cortisol response was examined with a series of stressors. At 40 days, a 65% increase in Cu was observed in the gill, but no accumulation was observed in the liver, brain or head kidney. Stressors such as air exposure or confinement did not elicit an increase in circulating cortisol levels for Cu-exposed fish, in contrast to controls. However, this inhibitory effect on the acute cortisol response appeared to have few implications on the ability of Cu-exposed fish to maintain ion and carbohydrate homeostasis. For example, plasma Na(+), Ca(2+) and glucose levels as well as hepatic glycogen levels were the same post-stress in control and Cu-exposed fish. Trout were also challenged with exposure to 50% seawater for 48 h, where Cu-exposed trout maintained plasma Na(+), glucose and hepatic glycogen levels. However, Cu-exposed fish experienced decreased plasma K(+) levels throughout the Cu exposure and stress tests. In conclusion, chronic Cu exposure resulted in the abolition of an acute cortisol response post-stress. There was no Cu accumulation in the hypothalamus-pituitary-interrenal axis (HPI axis) suggesting this was not a direct toxic effect of Cu on the cortisol regulatory pathway. However, the lack of an acute cortisol response in Cu-exposed fish did not impair the ability of the fish to maintain ion and carbohydrate homeostasis. This effect on cortisol may be a strategy to reduce costs during the chronic stress of Cu exposure, and not endocrine disruption as a result of toxic injury.