Endocrine disrupting chemicals in mixture and obesity,diabetes and related metabolic disorders

Obesity and associated metabolic disorders represent a major societal challenge in health and quality of life with large psychological consequences in addition to physical disabilities. They are also one of the leading causes of morbidity and mortality. Although, different etiologic factors including excessive food intake and reduced physical activity have been well identified, they cannot explain the kinetics of epidemic evolution of obesity and diabetes with prevalence rates reaching pandemic proportions. Interestingly, convincing data have shown that environmental pollutants, specifically those endowed with endocrine disrupting activities, could contribute to the etiology of these multifactorial metabolic disorders. Within this review, we will recapitulate characteristics of endocrine disruption. We will demonstrate that metabolic disorders could originate from endocrine disruption with a particular focus on convincing data from the literature. Eventually, we will present how handling an original mouse model of chronic exposition to a mixture of pollutants allowed demonstrating that a mixture of pollutants each at doses beyond their active dose could induce substantial deleterious effects on several metabolic end-points. This proof-of-concept study, as well as other studies on mixtures of pollutants, stresses the needs for revisiting the current threshold model used in risk assessment which does not take into account potential effects of mixtures containing pollutants at environmental doses, e.g., the real life exposure. Certainly, more studies are necessary to better determine the nature of the chemicals to which humans are exposed and at which level, and their health impact. As well, research studies on substitute products are essential to identify harmless molecules.     

Lysine acetylation contributes to development,aflatoxin biosynthesis and pathogenicity in Aspergillus flavus

Aspergillus flavus is a pathogenic fungus that produces carcinogenic aflatoxins, posing a great threat to crops, animals and humans. Lysine acetylation is one of the most important reversible post-translational modifications and plays a vital regulatory role in various cellular processes. However, current information on the extent and function of lysine acetylation and aflatoxin biosynthesis in A. flavus is limited. Here, a global acetylome analysis of A. flavus was performed by peptide pre-fractionation, pan-acetylation antibody enrichment and liquid chromatography–mass spectrometry. A total of 1313 high-confidence acetylation sites in 727 acetylated proteins were identified in A. flavus. These acetylation proteins are widely involved in glycolysis/gluconeogenesis, pentose phosphate pathway, citric acid cycle and aflatoxin biosynthesis. AflO (O-methyltransferase), a key enzyme in aflatoxin biosynthesis, was found to be acetylated at K241 and K384. Deletion of aflO not only impaired conidial and sclerotial developments, but also dramatically suppressed aflatoxin production and pathogenicity of A. flavus. Further site-specific mutations showed that lysine acetylation of AflO could also result in defects in development, aflatoxin production and pathogenicity, suggesting that acetylation plays a vital role in the regulation of the enzymatic activity of AflO in A. flavus. Our findings provide evidence for the involvement of lysine acetylation in various biological processes in A. flavus and facilitating in the elucidation of metabolic networks.     

In-depth metabolic phenotyping of genetically engineered mouse models in obesity and diabetes

The world-wide prevalence of obesity and diabetes has increased sharply during the last two decades. Accordingly, the metabolic phenotyping of genetically engineered mouse models is critical for evaluating the functional roles of target genes in obesity and diabetes, and for developing new therapeutic targets. In this review, we discuss the practical meaning of metabolic phenotyping, the strategy of choosing appropriate tests, and considerations when designing and performing metabolic phenotyping in mice.     

Obestatin, obesity and diabetes

The high prevalence of obesity and diabetes will lead to higher rates of morbidity and mortality. It is well known that ghrelin plays a potential role in obesity and diabetes. Obestatin, a novel 23 amino acid amidated peptide encoded by the same gene that encodes ghrelin, was initially reported to have opposite actions to ghrelin in the regulation of food intake, emptying of the stomach and body weight. Recent work suggests that obestatin also regulate beta-cell survival and insulin secretion. The ghrelin-obestatin system is, therefore, a promising target for the developing of new drugs for the treatment of obesity and diabetes. This review summarizes the interrelationship between obestatin, obesity and diabetes.     

Ob-stopping obesity, metabolic and immune-mediated disorders

Despite its physiological importance, no part of human leptin receptor (ObR) has been structurally characterized before. In this issue of Structure, Carpenter et?al. report the crystal structure of the leptin-binding domain of human ObR in complex with the Fab fragment of an ObR-blocking monoclonal antibody (9F8 mAb).     

Lysine acetylation stabilizes SP2 protein in the silkworm Bombyx mori

Lysine acetylation (Kac) is a vital post-translational modification that plays an important role in many cellular processes in organisms. In the present study, the nutrient storage proteins in hemolymph were first found to be highly acetylated—particularly SP2 protein, which contains 20 potential Kac sites. Further results confirmed that lysine acetylation could stabilize and up-regulate the protein level of anti-apoptosis protein SP2, thereby improving the survival of H₂O₂-treated BmN cells and suppressing the apoptosis induced by H₂O₂. The potential mechanism involved in the inhibition of ubiquitin-mediated proteasomal degradation by crosstalk between lysine acetylation and ubiquitination. Our results showed that the increase in the acetylation level by TSA could decrease the ubiquitination and improve the protein level of SP2, indicating that lysine acetylation could influence the SP2 protein level through competition between ubiquitination and the suppression of ubiquitin-mediated proteasomal degradation, thereby stabilizing the protein. SP2 is a major nutrient storage protein from hemolymph for amino acid storage and utilization. The crosstalk between lysine acetylation and ubiquitination of SP2 might imply an important role of lysine acetylation for nutrient storage and utilization in silkworm.     

Polyamine acetylation modulates polyamine metabolic flux, a prelude to broader metabolic consequences

Recent studies suggest that overexpression of the polyamine-acetylating enzyme spermidine/spermine N(1)-acetyltransferase (SSAT) significantly increases metabolic flux through the polyamine pathway. The concept derives from the observation that SSAT-induced acetylation of polyamines gives rise to a compensatory increase in biosynthesis and presumably to increased flow through the pathway. Despite the strength of this deduction, the existence of heightened polyamine flux has not yet been experimentally demonstrated. Here, we use the artificial polyamine precursor 4-fluoro-ornithine to measure polyamine flux by tracking fluorine unit permeation of polyamine pools in human prostate carcinoma LNCaP cells. Conditional overexpression of SSAT was accompanied by a massive increase in intracellular and extracellular acetylated spermidine and by a 6-20-fold increase in biosynthetic enzyme activities. In the presence of 300 microM 4-fluoro-ornithine, SSAT overexpression led to the sequential appearance of fluorinated putrescine, spermidine, acetylated spermidine, and spermine. As fluorinated polyamines increased, endogenous polyamines decreased, so that the total polyamine pool size remained relatively constant. At 24 h, 56% of the spermine pool in the induced SSAT cells was fluorine-labeled compared with only 12% in uninduced cells. Thus, SSAT induction increased metabolic flux by approximately 5-fold. Flux could be interrupted by inhibition of polyamine biosynthesis but not by inhibition of polyamine oxidation. Overall, the findings are consistent with a paradigm whereby flux is initiated by SSAT acetylation of spermine and particularly spermidine followed by a marked increase in key biosynthetic enzymes. The latter sustains the flux cycle by providing a constant supply of polyamines for subsequent acetylation by SSAT. The broader metabolic implications of this futile metabolic cycling are discussed in detail.     

Glyoxalase in diabetes, obesity and related disorders

Diabetes was the first disease state where evidence emerged for increased formation of methylglyoxal. Metabolism of methylglyoxal by the glyoxalase system has been linked to the development of vascular complications of diabetes - nephropathy, retinopathy, neuropathy and cardiovascular disease. Increased formation of methylglyoxal in hyperglycaemia associated with diabetes and down regulation of glyoxalase 1 by inflammatory signalling in vascular cells leads to a marked increased modification of proteins by methylglyoxal to form advanced glycation endproducts at the sites of vascular complications. Hotspot protein targets of methylglyoxal that suffer functional impairment - the dicarbonyl proteome - likely play a key role in the mechanisms underlying the development of vascular complications in diabetes: particularly modification of integrin binding sites in extracellular matrix proteins leading to endothelial cell shedding and anoikis, modification of mitochondrial proteins and increased formation of reaction oxygen species, and modification of apolipoprotein B100 of low density lipoprotein leading to its increased atherogenicity. Some current therapeutic agents counter partially dysfunctional metabolism of methylglyoxal by the glyoxalase system in diabetes - including the recent development of high dose thiamine therapy for early stage diabetic nephropathy. Further pharmacologic strategies are required to overcome the down regulation of glyoxalase1 in diabetes. The glyoxalase system is likely to be a continuing and future focus for research on clinical biomarkers and therapeutic development for respectively assessment of metabolic control and prevention of vascular complications in diabetes and obesity.     

Inflammation, obesity, and the metabolic syndrome.

Adipose tissue expresses cytokines which inhibit insulin signalling pathways. Obesity also results in impairment of endothelium-dependent vasodilatation to insulin. We have previously suggested that adipocytokines might contribute to the coexistence of insulin resistance and endothelial dysfunction. However, the adipocytokine best characterised as causing insulin resistance is tumour necrosis factor-alpha (TNF-alpha), a molecule which under normal circumstances circulates in low concentrations. We propose a vasoregulatory role for local deposits of fat around blood vessels, which may contribute both to insulin action and to vascular endothelial dysfunction. In particular, we propose that the localised fat depot around the origin of skeletal muscle arterioles may play a physiological role in blood flow distribution. Isolated rat arterioles are under dual regulation by insulin, which activates both endothelin-1 mediated vasoconstriction and nitric oxide mediated vasodilatation. In obese rat arterioles, insulin-stimulated nitric oxide synthesis is impaired, resulting in unopposed vasoconstriction. We propose this to be the consequence of production of TNF-alpha from the fat surrounding the vessel origin - a depot to which we ascribe a specialist vasoregulatory role. We suggest that this cytokine accesses the nutritive vascular tree to inhibit insulin-mediated capillary recruitment - a mechanism we term 'vasocrine' signalling. We also suggest a homology between periarteriolar fat and both periarterial and visceral fat, which may, through outside-to-inside signalling, play a direct role in producing the inflammatory changes found in atherosclerotic plaques, so explaining relationships between visceral fat, insulin resistance, and vascular disease.     

Maternal obesity and diabetes induces latent metabolic defects and widespread epigenetic changes in isogenic mice

Intrauterine nutrition can program metabolism, creating stable changes in physiology that may have significant health consequences. The mechanism underlying these changes is widely assumed to involve epigenetic changes to the expression of metabolic genes, but evidence supporting this idea is limited. Here we have performed the first study of the epigenomic consequences of exposure to maternal obesity and diabetes. We used a mouse model of natural-onset obesity that allows comparison of genetically identical mice whose mothers were either obese and diabetic or lean with a normal metabolism. We find that the offspring of obese mothers have a latent metabolic phenotype that is unmasked by exposure to a Western-style diet, resulting in glucose intolerance, insulin resistance and hepatic steatosis. The offspring show changes in hepatic gene expression and widespread but subtle alterations in cytosine methylation. Contrary to expectation, these molecular changes do not point to metabolic pathways but instead reside in broadly developmental ontologies. We propose that, rather than being adaptive, these changes may simply produce an inappropriate response to suboptimal environments; maladaptive phenotypes may be avoidable if postnatal nutrition is carefully controlled.     

Lysine acetylation is a widespread protein modification for diverse proteins in Arabidopsis

Lysine acetylation (LysAc), a form of reversible protein posttranslational modification previously known only for histone regulation in plants, is shown to be widespread in Arabidopsis (Arabidopsis thaliana). Sixty-four Lys modification sites were identified on 57 proteins, which operate in a wide variety of pathways/processes and are located in various cellular compartments. A number of photosynthesis-related proteins are among this group of LysAc proteins, including photosystem II (PSII) subunits, light-harvesting chlorophyll a/b-binding proteins (LHCb), Rubisco large and small subunits, and chloroplastic ATP synthase (β-subunit). Using two-dimensional native green/sodium dodecyl sulfate gels, the loosely PSII-bound LHCb was separated from the LHCb that is tightly bound to PSII and shown to have substantially higher level of LysAc, implying that LysAc may play a role in distributing the LHCb complexes. Several potential LysAc sites were identified on eukaryotic elongation factor-1A (eEF-1A) by liquid chromatography/mass spectrometry and using sequence- and modification-specific antibodies the acetylation of Lys-227 and Lys-306 was established. Lys-306 is contained within a predicted calmodulin-binding sequence and acetylation of Lys-306 strongly inhibited the interactions of eEF-1A synthetic peptides with calmodulin recombinant proteins in vitro. These results suggest that LysAc of eEF-1A may directly affect regulatory properties and localization of the protein within the cell. Overall, these findings reveal the possibility that reversible LysAc may be an important and previously unknown regulatory mechanism of a large number of nonhistone proteins affecting a wide range of pathways and processes in Arabidopsis and likely in all plants.     

Endoplasmic reticulum stress, obesity and diabetes

The endoplasmic reticulum (ER) stress response, also commonly known as the unfolded protein response (UPR), is an adaptive response used to align ER functional capacity with demand. It is activated in various tissues under conditions related to obesity and type 2 diabetes. Hypothalamic ER stress contributes to inflammation and leptin/insulin resistance. Hepatic ER stress contributes to the development of steatosis and insulin resistance, and components of the UPR regulate liver lipid metabolism. ER stress in enlarged fat tissues induces inflammation and modifies adipokine secretion, and saturated fats cause ER stress in muscle. Finally, prolonged ER stress impairs insulin synthesis and causes pancreatic β cell apoptosis. In this review, we discuss ways in which ER stress operates as a common molecular pathway in the pathogenesis of obesity and diabetes.     

Adipocyte/macrophage fatty acid binding proteins control integrated metabolic responses in obesity and diabetes

Fatty acid binding proteins (FABPs) are cytosolic fatty acid chaperones whose biological role and mechanisms of action are not well understood. Here, we developed mice with targeted mutations in two related adipocyte FABPs, aP2 and mal1, to resolve their role in systemic lipid, glucose, and energy metabolism. Mice lacking aP2 and mal1 exhibited a striking phenotype with strong protection from diet-induced obesity, insulin resistance, type 2 diabetes, and fatty liver disease. These mice have altered cellular and systemic lipid transport and composition, leading to enhanced insulin receptor signaling, enhanced muscle AMP-activated kinase (AMP-K) activity, and dramatically reduced liver stearoyl-CoA desaturase-1 (SCD-1) activity underlying their phenotype. Taken together with the previously reported strong protection against atherosclerosis, these results demonstrate that adipocyte/macrophage FABPs have a robust impact on multiple components of metabolic syndrome, integrating metabolic and inflammatory responses in mice and constituting a powerful target for the treatment of these diseases.     

Neurotensin in diabetes and obesity

Basal and postprandial concentrations of immunoreactive neurotensin were measured in insulin dependent diabetic patients and lean and obese noninsulin dependent diabetic patients when partially withdrawn from subcutaneous (s.c.) insulin treatment and again when near normoglycemia had been achieved from insulin infusion by an artificial endocrine pancreas (AEP). Neither basal nor postprandial neurotensin differed among the 3 groups of diabetic patients during s.c. insulin treatment nor from weight matched nondiabetic subjects. In addition, AEP resulted in no significant change in postprandial neurotensin responses. No differences in neurotensin levels were observed between lean and obese nondiabetic subjects. In contrast to observations in experimental diabetes, these observations do not support the presence of an abnormality of neurotensin in human diabetes.     

Lysine acetylation restricts mutant IDH2 activity to optimize transformation in AML cells

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