Featured Articles

Volume 16 | October 2018

Human metabolomics reveal daily variations under nutritional challengesMetabolomics is increasingly playing a role in tracking and diagnosing an individual’s health status. The identification of specific metabolomics ‘signatures’ in response to challenges such as a high fat diet, exercise, drug abuse, or diseases is important for the discovery of biomarkers. Sato, Parr, et al. analyzed the metabolome levels of human serum and skeletal muscle in the morning and evening in response to nutritional challenges in order to identify unique signatures. Their findings illustrate how the changes in metabolomics in response to nutritional challenges are dependent on the time of the day.

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AMPK activation negatively regulates GDAP1, which influences skeletal muscle Skeletal muscle is a major regulator of whole-body metabolic homeostasis. AMP-activated protein kinase (AMPK) is of particular importance for metabolic regulation in skeletal muscle. Transcriptomic studies reveal that ganglioside-induced differentiation-associated protein 1 (GDAP1) mRNA is inversely associated with AMPK activity. Lassiter et al. reveal a role for GDAP1 in modulating mitochondrial protein abundance, lipid oxidation, and nonmitochondrial respiration. Their results show that GDAP1 influences metabolic processes and circadian gene expression in skeletal muscle.

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Exercise-induced mechanisms promoting glycogen supercompensation in muscleThe majority of glycogen is stored in skeletal muscle and the “set-point” for glycogen concentration in human skeletal muscle appears to be tightly controlled. However, when a single bout of exercise is followed by intake of carbohydrates, the muscle cell favors glycogen synthesis far beyond resting levels. The molecular mechanisms of this phenomenon, known as glycogen supercompensation, are unknown. Hingst and colleagues used an invasive study in man and advanced muscle proteomics to come up with a model of the molecular mechanisms of glycogen supercompensation.

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Maternal exercise intervention in obese pregnancy improves offspring cardiovascular health The risk of cardiovascular disease is elevated in individuals whose mothers were obese during pregnancy. Disease risk could be reduced prior to birth through targeted interventions to the mother before and during pregnancy. However, the long-term results of lifestyle intervention trials in humans will only become available many years in the future. Therefore, Beeson, Blackmore, and colleagues used a murine model of maternal diet-induced obesity to test the effectiveness of exercise intervention during obese pregnancy at preventing programmed cardiovascular dysfunction in the adult offspring. They demonstrate that offspring cardiac hypertrophy and dysfunction can be programmed independently of hypertension by adverse intrauterine conditions.

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GLP-2 receptor signaling is dispensable for the metabolic benefits of vertical sleeve gastrectomyGlucagon-like peptide 2 (GLP-2), together with GLP-1, controls the absorption of nutrients through reduction of gut motility, upregulation of nutrient transport and via optimization of mucosal surface area and gut integrity. Patel, Yusta, et al. hypothesized that elevated levels of GLP-2 may contribute to the metabolic benefits arising following reduction of glucagon receptor (GCGR) signaling or metabolic surgery. However, their data using two different experimental models failed to demonstrate a key role for the GLP-2 receptor in regulation of glucose control or body weight evident after disruption of GCGR signaling, or following vertical sleeve gastrectomy.

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Reduction of lysophospholipids in the digestive tract promotes diabetes remissionThe most effective obesity intervention currently is bariatric surgery. A recent survey of metabolomic and lipidomic changes associated with bariatric surgery in humans revealed that successful diabetes remission is associated with reduced sphingomyelin and lysophospholipid levels. Cash et al. find that a 1B phospholipase A2 (PLA2G1B) intervention has similar metabolic benefits as bariatric surgery with normalization of plasma lipid, glucose, insulin, and trimethylamine N-oxide levels. PLA2G1B inhibitors may be an alternative option to bariatric surgery for management of obesity and obesity-related diseases.

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Co-storage and release of INSL5, GLP-1 and peptideYY from colonic cellsInsulin-like-5 (INSL5) is a peptide hormone found to be highly expressed in enteroendocrine cells also producing GLP-1 and PYY in the colon and rectum. However, INSL5 production is increased by calorie restriction, contrasting with plasma GLP-1 and PYY concentrations that are elevated after food ingestion. Whether INSL5 secretion is triggered by the same stimuli as GLP-1 and PYY is unknown. The opposing behaviors of these peptides could be explained at the level of tissue exposure or single cell responsiveness. Billing, Smith, Larraufie, Goldspink, and colleagues found that INSL5 is co-packaged with GLP-1 and PYY in secretory vesicles of colonic L-cells, and that all three peptides are co-released in response to a broad range of stimuli.

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Intestinal bitter taste receptor activation alters hormone secretion and imparts metabolic benefitsExtracts of the hops plant have been shown to reduce weight and improve glucose homeostasis in rodents and humans. Thus, it is of considerable interest to identify the molecular mechanisms that mediate these benefits. A promising candidate is signaling via bitter taste receptors present in extraoral tissues, particularly the gastrointestinal (GI) tract. Kok et al. demonstrate that specific modulation of bitter taste receptor signaling in extraoral tissues improves multiple features of metabolic disease. In the gut, bitter taste agonism alters enteroendocrine hormone secretion. Therefore, bitter taste agonists may prove useful in conditions characterized by insulin resistance, dyslipidemia, and inflammation

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PID1 regulates endocytosis of postprandial triglyceride-rich lipoproteinsThe accumulation of plasma triglyceride-rich lipoproteins (TRL) and their remnants is an important risk factor for cardiovascular disease. The LDLR-related protein 1 (LRP1) is an important endocytic receptor that is especially relevant for the uptake of postprandial TRL remnants. The protein phosphotyrosine interacting domain containing 1 (PID1) is an intracellular binding partner of LRP1. Fischer, Albers, and colleagues show that PID1 serves as an intracellular retention adaptor protein for LRP1 in hepatocytes. By controlling LRP1 localization, PID1 determines hepatic clearance and consequently plasma levels of pro-atherogenic TRL remnants in the postprandial phase.

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Intracellular lipids are an independent cause of liver injury and chronic kidney diseaseThe rise in global epidemics of obesity and type 2 diabetes in westernized countries contributes to a worrying increase in the incidence of non-alcoholic fatty liver disease and chronic kidney disease. A common metabolic feature of these complications is ectopic lipid accumulation, which is suspected to induce organ damage and dysfunction. Monteillet, Gjorgjieva, et al. show that the development of these hepatic and renal diseases is mainly initiated by altered lipid metabolism resulting in lipid accumulation, independently of excessive glycogen contents in these organs.

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Neuronal modulation of brown adipose activity through perturbation of white adipocyte lipogenesisAdipocytes of different types (white, brown or beige) may interconvert and change their behavior depending on local sympathetic nerve activity. De novo lipogenesis (DNL) within adipocytes may be linked to control of local sympathetic nerve activity. Guilherme, Pedersen, et al. investigated the role of DNL in adipose tissue under extreme temperature conditions. Their data indicate that DNL activity in white adipocytes can initiate long distance signaling to brown adipose tissue that enhances its thermoregulation program.

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FGF21 regulates insulin sensitivity following chronic stressProlonged exposure to stress and posttraumatic stress disorders (PTSD) increase the risk for developing type 2 diabetes, cardiovascular disease, and premature death. Adaptive mechanisms and associated biomarkers need to be explored in order to develop therapeutic options for the prevention of stress-induced insulin resistance. Jelenik, Dille, Müller-Lühlhoff, Kabra, et al. identify a molecular network in which fibroblast growth factor 21 (FGF21) regulates late-onset metabolic responses to stress and may account for the physiological memory mechanism to achieve metabolic homeostasis again.

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Loss of Tbk1 kinase activity protects from metabolic dysfunctionA primary pathology of obesity and metabolic disorders is the induction of chronic low-grade inflammation. TANK binding kinase 1 (TBK1) is a non-canonical activator of nuclear factor kappa B (NF-κB) that is thought to play an important role in obesity-associated inflammation. Cruz et al. studied the function of TBK1 using a Tbk1 mutant mouse that harbors two copies of a null Tbk1 allele. They report that these mice are resistant to high fat diet-induced weight gain and pancreatic islet hyperplasia and hypertrophy. This suggests that TBK1 can be a therapeutic target in the prevention and treatment of type 2 diabetes and obesity.

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Individual islet respirometry reveals functional diversity within the islet populationPancreatic islets rely on mitochondrial respiration to secrete insulin. Islets and β-cells within islets are known to show remarkable variability in glucose sensitivity, size, architecture, and cell composition. Islet heterogeneity seems to play a critical role in pathogenesis of metabolic disease. However, the high-throughput study of individual islet oxygen consumption has not been possible so far. Taddeo et al. have established a non-invasive method that enables high-throughput measurement of oxygen consumption in large-sized individual islets from mice and humans. This is possible using a special microplate. The authors found heterogeneous glucose sensitivity in large individual islets. Their method might accelerate islet research and help elucidate mechanisms underlying the metabolic heterogeneity in pancreatic islets.

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TGF-β receptor 1 regulates progenitors that promote browning of white fatBeige (or brite) adipocytes have therapeutic potential to combat metabolic diseases. They appear in response to cold exposure or upon stimulation by β-adrenergic pathways and might be derived from specialized progenitors. Wankhade et al. describe an important role of transforming growth factor β receptor I (TβRI) in regulating glucose and energy homeostasis via targeting of putative beige stem cells in white fat. These progenitor cells express key beige/brown signature markers and upon transplantation demonstrate the capacity to undergo beige adipogenesis.

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Cartilage oligomeric matrix protein is expressed in adipose tissue and regulates adipogenesisRemodeling of the extracellular matrix (ECM) is crucial for adipogenesis. Cartilage oligomeric matrix protein (COMP) exhibits a striking depot-specific expression pattern between subcutaneous abdominal and gluteal adipose tissue (AT). Denton and colleagues report that COMP expression in abdominal and gluteal AT as well as circulating COMP levels are positively correlated with adiposity but not with regional AT distribution. Also, exogenous COMP protein promoted adipogenesis. These results highlight the important yet poorly understood role of the ECM in AT.

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Metabolic syndrome and adipose tissue inflammation in obese Göttingen minipigsIn obesity, a deeper understanding of inflammatory triggers and mechanisms may uncover novel therapeutic targets for treatment. In this respect, animal models are important for increasing our knowledge of pathological processes and assessment of drug candidates. Rodent models are the first-line option for pharmacological evaluation, but their predictive value for drug efficacy and safety in humans is limited. Given the strong similarity of human anatomy and physiology to pigs, these can serve as a model bridging the gap between mouse and man. Renner, Blutke, and colleagues have established a diet-induced obesity (DIO) model in Göttingen minipigs (GM). Munich DIO-GM showed phenotypic signatures representative of the metabolic syndrome, as well as extensive fat tissue inflammation.

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Chronic D-serine supplementation impairs insulin secretionSerine racemase (SRR) catalyzes the conversion from L-serine to D-serine, an important co-agonist of N-methyl-D-aspartate (NMDA) receptors. SRR was recently suggested to regulate insulin secretion from pancreatic beta cells. Suwandhi et al. report positive and negative consequences of long-term treatment with D-serine. Importantly, it impairs glucose tolerance due to impaired insulin secretion from pancreatic beta cells. This depends on increased sympathetic activity in the islets of Langerhans rather than direct action on beta cells. Thus, alterations in D-serine levels could contribute to the development of T2D through the modulation of insulin secretion, especially in genetically predisposed subjects.

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The role of kidney in the coordination of glucose production during fastingGluconeogenesis is performed in three organs: liver, kidney, and intestine. While the liver is the main producer of glucose at the onset of fasting, gluconeogenesis from the kidney and intestine becomes increasingly important during prolonged fasting. Kaneko et al. find that a diminution of renal gluconeogenesis promotes a novel repartition of glucose production during fasting, featured by increased intestinal gluconeogenesis that leads to sparing glycogen stores in the liver. Their data shed light on the inter-organ crosstalk among glucose-producing organs, which might take place in the situations of deficient renal glucose production, such as chronic kidney disease.

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The 60 Second Metabolist
In this section authors briefly report on their work recently published in Molecular Metabolism.

Watch the most recent interview by clicking the video still. The link "referring article" directs you to this author's publication.



Jørgen Wojtaszewski, Janne Hingst
University of Copenhagen, Denmark
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