Co-Published: Inorg. Mass Spectrom. ACS Central Science2 BBA — Mol. Cell Biol. ACS Catalysis4, Miller, S. Nature, Nature, Org Lett. ACS Catalysis1, ACS Comb. Tetrahedron Lett. Tetrahedron65, Tetrahedron64, Tetrahedron62, Biochemistry45, Fell for marketing tricks not at all. Wait for the unbiased reviews of the phone or try buy to experience it.
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Stress-induced hyperglycemia was associated with reduced hepatic insulin signaling and increased hepatic FOXO target gene expression while loss of FOXO13, and 4 in the liver attenuated hyperglycemia and prevented hyperinsulinemia.
Mechanistically, the loss of FOXO transcription factors mitigated the stress-induced hyperglycemia response by directly altering gene expression and glycogenolysis in the liver and indirectly suppressing lipolysis in adipose tissue. This study implicates FOXO transcription factors as a predominant driver of stress-induced hyperglycemia through means that include cross-talk between the liver and adipose, highlighting a novel mechanism underlying acute hyperglycemia and insulin resistance in stress.
September Abstract PDF Objective Protein disulfide isomerases PDIs are oxidoreductases that are involved in catalyzing the formation and rearrangement of disulfide bonds during protein folding.
We generated an ENU mouse model carrying a missense mutation PheSer in the second thioredoxin domain of the Pdia6 gene. Mice homozygous for the PheSer FS mutation were mildly hyperglycemic at weaning and subsequently became hypoinsulinemic and overtly diabetic at the adult stage. The data demonstrates that a global Pdia6 mutation renders mice hypoinsulinemic and hyperglycemic. September Abstract PDF Objective Activating brown adipose tissue BAT in humans has been proposed as a new treatment approach to combat obesity and its associated diseases since BAT participates in the regulation of energy homeostasis as well as glucose and lipid metabolism.
Genetic contributors driving brown adipogenesis in humans have not been fully understood. Profiling the gene expression of progenitor cells from subcutaneous and deep neck adipose tissue, we discovered new secreted factors with potential regulatory roles in white and brown adipogenesis. Among these, members of the latent transforming growth factor beta-binding protein LTBP family were highly expressed in brown compared to white adipocyte progenitor cells, suggesting these proteins to be capable of promoting brown adipogenesis.
September Abstract PDF Objective To improve understanding of mouse energy homeostasis and its applicability to humans, we quantitated the effects of housing density on mouse thermal physiology in both sexes. Littermate wild type and Brs3 null mice were single or group three per cage housed and studied by indirect calorimetry with continuous measurement of core body temperature, energy expenditure, physical activity, and food intake. In contrast, single housed females maintained a similar body temperature as group housed controls by increasing their metabolic rate.
Upon fasting, single housed mice had larger reductions in body temperature, with male mice having more torpor episodes of similar duration and female mice having a similar number of torpor episodes that lasted longer. Qualitatively, the effects of housing density on thermal physiology of Brs3 null mice generally mimicked the effects in controls. Single housing is more sensitive than group housing for detecting thermal physiology phenotypes.
Single housing increases heat loss and amplifies the effects of fasting or a cold environment. Male and female mice utilize different thermoregulatory strategies to respond to single housing.
August Abstract PDF The cycle of feeding and fasting is fundamental to life and closely coordinated with changes of metabolic programs. During extended starvation, ketogenesis coupled with fatty acid oxidation in the liver supplies ketone bodies to extrahepatic tissues as the major form of fuel. In this study, we demonstrated that PAQR9, a member of the progesterone and adipoQ receptor family, has a regulatory role on hepatic ketogenesis. The overall phenotype of the mice was not altered by Paqr9 deletion under normal chow feeding.
However, fasting-induced ketogenesis and fatty acid oxidation were attenuated by Paqr9 deletion. August Abstract PDF Objective Loss of FoxO1 signaling in response to metabolic stress contributes to the etiology of type II diabetes, causing the dedifferentiation of pancreatic beta cells to a cell type reminiscent of endocrine progenitors. Lack of methods to easily model this process in vitrohowever, have hindered progress into identification of key downstream targets and potential inhibitors.
We therefore aimed to establish such an in vitro cellular dedifferentiation model and apply it to identify novel agents involved in the maintenance of beta cell identity. The murine beta cell line, Min6, was used for primary experiments and high content screening.
Screens encompassed a library of small molecule drugs representing the chemical and target space of all FDA-approved small molecules with an automated immunofluorescence read-out. Validation experiments were performed in a murine alpha cell line as well as in primary murine and human diabetic islets.
Developmental effects were studied in zebrafish and C. We show that short-term pharmacological FoxO1 inhibition can model beta cell dedifferentiation by downregulating beta-cell specific transcription factors, resulting in the aberrant expression of progenitor genes and the alpha cell marker glucagon.
From a high content screen, we identified loperamide as a small molecule that can prevent FoxO inhibitor-induced glucagon expression and further stimulate insulin protein processing and secretion by altering calcium levels, intracellular pH and FoxO1 localization. Our study provides novel models, molecular targets and drug candidates for studying and preventing beta cell dedifferentiation.
However, the response of mice with genetic depletion of MCA to an obesogenic diet has not been evaluated. We measured BA composition from a pool of liver, gallbladder, and intestine, as well as weekly body weight, food intake, lean and fat mass, systemic glucose homeostasis, energy expenditure, intestinal lipid absorption, fecal lipid, and energy content.
MCA does not protect against diet-induced obesity but may protect against liver injury. August Abstract PDF Background The discovery of insulin in and its near-immediate clinical use initiated a century of innovation. Advances extended across a broad front from stabilizing formulations of animal insulins to the frontiers of synthetic peptide chemistry and in turn from the advent of recombinant DNA manufacture to structure-based protein analog design.
In each case a creative interplay was observed between pharmaceutical applications and then-emerging principles of protein science; indeed, translational objectives contributed to a growing molecular understanding of protein structure, aggregation and misfolding. Crystallization of insulin was exploited both as a step in manufacturing and as a means to obtain protracted action. Forty years ago, the confluence of recombinant human insulin with techniques for site-directed mutagenesis initiated the present era of insulin analogs.
Variant or modified insulins were developed that exhibit improved prandial or basal pharmacokinetic PK properties. Next-generation insulin analog design seeks to explore new frontiers, including glucose-responsive insulins, organ-selective analogs and biased agonists tailored to address yet-unmet clinical needs.
In the coming decade we envision ever-more powerful scientific synergies at the interface of structural biology, molecular physiology and therapeutics. In contrast, LEAP2 reduces acyl-ghrelin-induced food intake and GH secretion and is elevated in obesity but lower upon fasting.
In particular, LEAP2 may serve to dampen acyl-ghrelin action in the setting of obesity, which is associated with ghrelin resistance. Here, we sought to determine the metabolic effects of genetic LEAP2 deletion. Food intake, GH secretion, and cellular activation c-fos induction in different brain regions following s. In particular, acyl-ghrelin acutely stimulated food intake at a dose of 0. Acyl-ghrelin induced a LEAP2 deletion raised body weight by These genotype-dependent differences were not observed in high-fat diet-exposed males or in female and male mice exposed long-term to standard chow diet.
LEAP2 deletion sensitizes both lean and obese mice to the acute effects of administered acyl-ghrelin on food intake and GH secretion. LEAP2 deletion increases body weight in females chronically fed high-fat diet as a result of lowered energy expenditure, reduced locomotor activity, and increased food intake.
Furthermore, in female mice, LEAP2 deletion increases body length and exaggerates the hepatic fat accumulation normally associated with chronic high-fat diet feeding. August Abstract PDF Objective Salsalate is a prodrug of salicylate that lowers blood glucose in people with type 2 diabetes. Reductions in atherosclerosis by salsalate were associated with reduced macrophage proliferation, reduced plaque lipid content and reduced serum cholesterol. Since rapidly-proliferating macrophages are a hallmark of atherosclerosis, these data indicate further evaluation of salsalate as a potential therapeutic agent for treating atherosclerotic cardiovascular disease.
The increase in body temperature is generally interpreted as hyperthermia, i. Here we examine an alternative hypothesis: that FGF21 has Peris Scope direct pyrexic effect, i. FGF21 increases body temperature independently of any effect on energy expenditure. Despite not increasing energy expenditure in all these models, FGF21 always increased body temperature.
The effect of FGF21 on body temperature was more not less, as expected in hyperthermia pronounced at lower ambient temperatures. Effects on body temperature and energy expenditure were temporally distinct daytime Peris Scope nighttime.
In mice lacking UCP1, FGF21 did not increase energy expenditure but nonetheless increased body temperature by reducing heat loss, through e. The effect of FGF21 on body temperature is independent of UCP1 and can be achieved in the absence of any change in energy expenditure. Since elevated body temperature is a primary effect of FGF21 and may be achieved without increasing energy expenditure, only limited body weight-lowering effects of FGF21 may be expected.
August Abstract PDF Objective It was reported that chemerin as an adipocyte-secreted protein could regulate bone resorption and bone formation. However, the specific molecular and gene mechanism of the chemerin role is unclear. The results showed that the bone mineral density and volume score, the trabecular thickness, the weight and bone formation marker BALP increased, but Tb.
Moreover, knockdown of chemerin using RNA interference inhibited osteoblastogenesis genes and enhanced osteoclastogenesis genes in Mc3t3-E1 and Raw The maintenance of low chemerin level may be a potential strategy to prevent and treat osteoporosis. Given the potential of newly created insulin-producing cells as a treatment or even cure of type 1 diabetes T1D and possibly in severe cases of type 2 diabetes T2Dmultiple academic and commercial laboratories are attempting to derive surrogate glucose-responsive, insulin-producing cells.
August Abstract PDF. August Abstract PDF Objective Homo- or heterodimerization of G protein—coupled receptors GPCRs generally affects the normal functioning of these receptors and mediates the responses to a variety of physiological stimuli in vivo. It is well known that melanocortin-3 receptor MC3R and melanocortin-4 receptor MC4R are key regulators of appetite and energy homeostasis in the central nervous system.
Our objective is to analyze single cell RNA-seq datasets of the hypothalamus to explore and identify novel GPCR partners of MC3R and MC4R and examine the pharmacological effect on the downstream signal transduction and membrane translocation of melanocortin receptors.
We conducted an integrative analysis of multiple single cell RNA-seq datasets to reveal the expression pattern and correlation of GPCR families in the mouse hypothalamus. The emerging GPCRs with important metabolic functions were selected for cloning and co-immunoprecipitation validation. This work represented the first large-scale screen for the functional GPCR complex of central melanocortin receptors and defined a composite metabolic regulatory GPCR network of the hypothalamic nucleuses.
NCOR1, both in vitro and in vivo specifically regulates thyroid hormone TH action in the context of individual organs such as the liver, and systemically in the context of the hypothalamic-pituitary-thyroid HPT axis. In contrast, selective deletion of SMRT in the liver or other parts has shown that it plays very little role in TH signaling.
Metabolic parameters, gene expression, and thyroid function tests were analyzed. Surprisingly, adult mice that acquired NCOR1 and SMRT deletion rapidly became hypoglycemic and hypothermic and perished within ten days of deletion of both corepressors. Additionally, alterations in lipogenesis, beta oxidationalong with hepatic triglyceride and glycogen levels suggested defects in hepatic metabolism.
Hepatosteatosis rapidly developed along with alterations in hepatic metabolism suggesting a contribution to the dramatic phenotype from liver injury. August Abstract PDF Background In mammals, modifications to cytosine bases, particularly in cytosine-guanine CpG dinucleotide contexts, play a major role in shaping the epigenome. The canonical epigenetic mark is 5-methylcytosine 5mCbut oxidized versions of 5mC, including 5-hydroxymethylcytosine 5hmCare now known to be important players in epigenomic dynamics.
Understanding the functional role of these modifications in gene regulation, normal development, and pathological conditions requires the ability to localize these modifications in genomic DNA. The classical approach for sequencing cytosine modifications has involved differential deamination via the chemical sodium bisulfite ; however, bisulfite is destructive, limiting its utility in important biological or clinical settings Peris Scope detection of low frequency populations is critical.
Additionally, bisulfite fails to resolve 5mC from 5hmC. To summarize how enzymatic rather than chemical approaches can be leveraged to localize and resolve different cytosine modifications in a non-destructive manner. Nature offers a suite of enzymes with biological roles in cytosine modification in organisms spanning from bacteriophages to mammals. These enzymatic activities include methylation by DNA methyltransferasesoxidation of 5mC by TET family enzymes, hypermodification of 5hmC by glucosyltransferasesand the generation of transition mutations from cytosine to uracil by DNA deaminases.
Here, we describe how insights into the natural reactivities of these DNA-modifying enzymes can be leveraged to convert them into powerful biotechnological tools. Application of these enzymes in sequencing can be accomplished by relying on their natural activity, exploiting their ability to discriminate between cytosine modification states, reacting them with functionalized substrate analogs to introduce chemical handles, or engineering the DNA-modifying enzymes to take on new reactivities.
We describe how these enzymatic reactions have been combined and permuted to localize DNA modifications with high specificity and without the destructive limitations posed by chemical methods for epigenetic sequencing.
July Abstract PDF The discovery of insulin years ago and its application to the treatment of human disease in the years since have marked a major turning point in the history of medicine.
The availability of purified insulin allowed for the establishment of its physiological role in the regulation of blood glucose and ketonesthe determination of its amino acid sequenceand the solving of its structure.
Over the last 50 years, the function of insulin has been applied into the discovery of the insulin receptor and its signaling cascade to reveal the role of impaired insulin signaling—or resistance—in the progression of type 2 diabetes.
It has also become clear that insulin signaling can impact not only classical insulin-sensitive tissues, but all tissues of the body, and that in many of these tissues the insulin signaling cascade regulates unexpected physiological functions.
Despite these remarkable advances, much remains to be learned about both insulin signaling and how to use this molecular knowledge to advance the treatment of type 2 diabetes and other insulin-resistant states. As the century unfolded and the autoimmune nature of type 1 diabetes was recognised, a darker side of insulin emerged.
Autoimmunity to insulin was found to be an early marker of risk for type 1 diabetes in young children. In humans, it remains unclear if autoimmunity to insulin is primarily due to a defect in the beta cell itself or to dysregulated immune activation. Conversely, it may be secondary to beta-cell damage from an environmental agent e. Nevertheless, direct, interventional studies in non-obese diabetic NOD mouse models of type Peris Scope diabetes point to a critical role for pro insulin as a primary autoantigen that drives beta cell pathology.
Modelled on Koch's postulates for the pathogenicity of an infectious agent, evidence for a pathogenic role of pro insulin as an autoantigen in type 1 diabetes, particularly applicable to the NOD mouse model, is reviewed.
Evidence in humans remains circumstantial. Additionally, as pro insulin is a target of autoimmunity in type 1 diabetes, its application as a therapeutic tool to elicit antigen-specific immune tolerance is assessed. July Abstract PDF. June Abstract PDF Background While insulin has been central to the pathophysiology and treatment of patients with diabetes for the last years it has only been since that genetic variation in the INS gene has been recognised as a major cause of monogenic diabetes.
Both dominant and recessive mutations in the INS gene are now recognised as important causes of neonatal diabetes and offer important insights both into the structure and function of insulin. It is also recognised that in rare cases, mutations in the INS gene can present in patients with diabetes diagnosed outside the first year of life. This review examines the genetics and clinical features of monogenic diabetes resulting from INS gene mutations from the first description in and includes information from patients from families diagnosed in Exeter with INS gene mutations.
We discuss the implications for diagnosing and treating this subtype of monogenic diabetes. The dominant mutations in the INS gene typically affect the secondary structure of the insulin protein usually by disrupting the 3 disulfide bonds in mature insulin. The resulting misfolded protein results in ER stress and beta-cell destruction. In contrast recessive INS gene mutations typically result in no functional protein being produced as a result of reduced insulin biosynthesis or loss-of-function mutations of the insulin protein.
There are clinical differences between the two genetic aetiologies, between the specific mutations, and finally variation within patients with identical mutations. May Abstract PDF Background A strong association of obesity and insulin resistance with increased circulating levels of branched-chain and aromatic amino acids and decreased glycine levels has been recognized in human subjects for decades.
More recently, human metabolomic and genetic studies have confirmed and expanded upon these observations, accompanied by a surge in preclinical studies that have identified mechanisms involved in perturbation of amino acid homeostasis, how these events are connected to dysregulated glucose and lipid metabolism, and how elevations in branched-chain amino acids BCAA may participate in development of insulin resistance, type 2 diabetes T2D and other cardiometabolic diseases and conditions.
In human cohorts, BCAA and related metabolites are now well established as among the strongest biomarkers of obesity, insulin resistance, T2D, and cardiovascular diseases.
These and other emergent links between BCAA, glucose and lipid metabolism motivate ongoing studies of possible causal actions of BCAA and related metabolites in development of cardiometabolic diseases. May Abstract PDF Background Insulin's discovery years ago and its ongoing use since that time to treat diabetes belies the molecular complexity of its structure and that of its receptor. Advances in single-particle cryo-electron microscopy have over the past three years revolutionized our understanding of the atomic detail of insulin-receptor interactions.
This review describes the three-dimensional structure of insulin and its receptor and details on how they interact. This review also highlights the current gaps in our structural understanding of the system. A near-complete picture has been obtained of the hormone receptor interactions, providing new insights into the kinetics of the interactions and necessitating a revision of the extant two-site cross-linking model of hormone receptor engagement.
How insulin initially engages the receptor and the receptor's traversed trajectory as it undergoes conformational changes associated with activation remain areas for future investigation.
April Abstract PDF Background Insulin has been demonstrated to exert direct and indirect effects on vascular tissues. In this review, we summarize the current understanding of insulin's physiological and pathophysiological actions and associated signaling pathways in vascular cells, mainly in endothelial cells EC and vascular smooth muscle cells VSMCand how these Peris Scope lead to selective insulin resistance.
We also describe insulin's potential new signaling and biological effects derived from animal studies and cultured capillary and arterial EC, VSMC, and pericytes.
We will not provide a detailed discussion of insulin's effects on the myocardiuminsulin's structure, or its signaling pathways' various steps, since other articles in this issue discuss these areas in depth.
Insulin mediates many important functions on vascular cells via its receptors and signaling cascades. Its direct actions on EC and VSMC are important for transporting and communicating nutrients, cytokines, hormones, and other signaling molecules. These vascular actions are also important for regulating systemic fuel metabolism and energetics.
Inhibiting or enhancing these pathways leads to selective insulin resistance, exacerbating the development of endothelial dysfunctionatherosclerosisrestenosispoor wound healing, and even myocardial dysfunction. Targeted therapies to improve selective insulin resistance in EC and VSMC are thus needed to specifically mitigate these pathological processes. We now know that the insulin receptor is present throughout the brain and serves important functions in whole body metabolism and brain function.
While brain insulin signaling plays only a small role in central nervous system glucose regulation, it has a significant impact on the metabolic health of the brain. Normal insulin signaling is important for mitochondrial functioning and normal food intake.
Brain insulin resistance contributes to obesity and may also play an important role in neurodegeneration. February Abstract PDF The th anniversary of the discovery of insulin in Toronto in is an important moment in medical and scientific history.
The demonstration that an extract of dog pancreas reproducibly lowered blood glucose, initially in diabetic dogs and then in humans with type 1 diabetes, was a medical breakthrough that changed the course of what was until then a largely fatal disease.
Over the ensuing years, research on insulin has advanced on many fronts, producing insights that have transformed our understanding of diabetes and our approach to its treatment.
However, research on insulin had another consequence of far broader scientific significance, serving as a pacesetter and catalyst to bioscience research across many fields. Some of this was directly insulin-related and was also recognized by the Nobel Prize. Equally important, however, was research stimulated by the discovery of insulin that has profoundly influenced biomedical research, sometimes also recognized by the Nobel Prize and sometimes without this recognition.
In this paper, we review some of the most notable examples of both insulin-related and insulin-stimulated research to illustrate the impact of this discovery on the course of modern bioscience. In this section authors briefly report on their work recently published in Molecular Metabolism.
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