Metabolic disorders articles within Nature Communications

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  • Article
    | Open Access

    Inherited disorders of neurotransmitter metabolism represent a group of rare neurometabolic diseases characterized by movement disorders and developmental delay. Here, the authors report a standardized evaluation of a registry of 275 patients from 42 countries, and highlight an evolving phenotypic spectrum of this disease group and factors influencing diagnostic processes.

    • Oya Kuseyri Hübschmann
    • , Gabriella Horvath
    •  & Thomas Opladen

  • Article
    | Open Access

    Lipid induced stress contributes to metabolic diseases. Here the authors identify small nucleolar RNA 73 (SNORA73) in a screen for genes that protect against lipotoxicity and show that deficiency of SNORA73 reprograms oxidative metabolism and protects against steatohepatitis in mice.

    • Arthur C. Sletten
    • , Jessica W. Davidson
    •  & Jean E. Schaffer

  • Article
    | Open Access

    Lipid accumulation in the liver leads to nonalcoholic fatty liver disease (NAFLD) that is a risk factor for developing hepatocellular carcinoma (HCC). Here, the authors show that activation of the translation initiation factor eIF6 promotes lipid accumulation in the liver and targeting eIF6 in murine models reduces NAFLD and associated HCC.

    • Alessandra Scagliola
    • , Annarita Miluzio
    •  & Stefano Biffo

  • Article
    | Open Access

    Genetic variants in CD36 have been associated with metabolic syndrome. Here, the authors found that lymphatic vessel integrity and lipid transport are influenced by CD36 expression, and lymphatic endothelial cell CD36 deficiency causes visceral obesity and insulin resistance, which are risk factors for metabolic syndrome and diabetes.

    • Vincenza Cifarelli
    • , Sila Appak-Baskoy
    •  & Nada A. Abumrad

  • Article
    | Open Access

    Leptin can rescue hyperglycemia in type 1 diabetes, but the underlying mechanisms for this effect are not clear. Here, the authors report that leptin action is mediated by inhibition of the heightened activity of arcuate GABA neurons in murine models of type 1 diabetes through restoring nutrient sensing.

    • Shengjie Fan
    • , Yuanzhong Xu
    •  & Qingchun Tong

  • Article
    | Open Access

    Mitochondrial diseases, including those caused by defects in complex III of the respiratory chain, lack curative treatments. Here the authors report that the small molecule pyocyanin has beneficial effects in cells derived from patients with complex III-deficiency as well as in fly and zebrafish genetic models with reduced complex III activity.

    • Roberta Peruzzo
    • , Samantha Corrà
    •  & Ildikò Szabò

  • Article
    | Open Access

    Phenylketonuria (PKU) is caused by autosomal recessive variants in phenylalanine hydroxylase (PAH) and can lead to neurotoxicity. Here the authors describe a mouse model of PKU based on a mutation in phenylalanine hydroxylase (R261Q) which replicates traits of this disease and shows a proteostasis defect and oxidative stress, implying a gain-of-function contribution to the disease phenotype.

    • Oscar Aubi
    • , Karina S. Prestegård
    •  & Aurora Martinez

  • Article
    | Open Access

    Nutritional modification including fasting has been shown to reduce cardiometabolic risk linked to western diet. Here the authors show implementation of fasting resulted in alterations to the intestinal microbiota, and circulating immune cells, improving blood pressure and body weight in patients with metabolic syndrome.

    • András Maifeld
    • , Hendrik Bartolomaeus
    •  & Sofia K. Forslund

  • Article
    | Open Access

    Treatments for Fabry disease, an inherited lysosomal disorder caused by the deficiency of the enzyme alpha-galactosidase A, are not fully efficacious. Here the authors report a single-arm phase I trial of gene therapy with autologous, lentivirus-transduced, hematopoietic cells that express alpha-galactosidase A to demonstrate that this approach is safe in five patients with Fabry disease.

    • Aneal Khan
    • , Dwayne L. Barber
    •  & Jeffrey A. Medin

  • Article
    | Open Access

    Adaptive thermogenesis is regulated by central neuronal circuits. Here, the authors show that microRNA-33 in the brain contributes to the maintenance of brown adipose tissue thermogenesis and whole-body energy balance via enhanced sympathetic nerve tone, and regulating the expression of GABAa receptor subunits.

    • Takahiro Horie
    • , Tetsushi Nakao
    •  & Koh Ono

  • Article
    | Open Access

    Metabolites are indicators of health and disease; genetic studies can reveal variants influencing their levels. Here, the authors investigate the contribution of rare, exonic variants on the levels of urine metabolites and generate predictions on metabolic consequences underlying metabolic disease.

    • Yurong Cheng
    • , Pascal Schlosser
    •  & Anna Köttgen

  • Article
    | Open Access

    Some cholesterol-lowering drugs can increase the risk of type 2 diabetes, but the mechanism behind this is not fully understood. Here the authors show that there is a single genetic regulatory module that influences both cholesterol levels and glucose levels, providing a link between cholesterol levels and diabetes.

    • Ariella T. Cohain
    • , William T. Barrington
    •  & Eric E. Schadt

  • Article
    | Open Access

    Current therapeutic strategies for vitamin D-induced hypercalcemia are poorly efficient. Here the authors identify a new interaction between the vitamin D receptor (VDR) and WBP4 controlling the subcellular localization of VDR and show that ZK168281, a VDR antagonist, enhances the interaction between VDR and WBP4 blunting VDR signalling and normalizing calcium levels in vitamin D-intoxicated mice.

    • Daniela Rovito
    • , Anna Y. Belorusova
    •  & Daniel Metzger

  • Article
    | Open Access

    Propionic acidemia is a serious pediatric inherited disorder with no effective treatments. Here the authors demonstrate that delivering dual mRNAs as an enzyme replacement approach can be used as an effective therapy in a mouse model of propionic acidemia, with potential applicability to chronically administer multiple mRNAs in other genetic disorders.

    • Lei Jiang
    • , Ji-Sun Park
    •  & Lin T. Guey

  • Article
    | Open Access

    Insulinomas are rare, benign beta cell tumours which overproduce insulin and have been associated to epigenetic alterations. Here the authors characterise insulinoma methylomes, finding changes in promoter methylation and chromatin structure proposed to drive the pathological expression of insulin.

    • Esra Karakose
    • , Huan Wang
    •  & Luca Lambertini

  • Article
    | Open Access

    Time restricted feeding has several health benefits. Here the authors perform a randomised cross-over study with 11 men with overweight/obesity to investigate how time restricted feeding affects skeletal muscle and serum, and report that it does not affect the core circadian machinery, but modifies periodicity in amino acid related metabolites and transporters.

    • Leonidas S. Lundell
    • , Evelyn B. Parr
    •  & John A. Hawley

  • Article
    | Open Access

    Gut microbiome alterations have been linked to inflammatory bowel disease (IBD) and obesity. Here, the authors characterize the metagenomes of four large human cohorts and perform co-abundance network analysis showing that dysbiosis in disease is marked by the altered co-abundance relationships, suggesting that pathway coabundance networks are more heterogeneous than species network.

    • Lianmin Chen
    • , Valerie Collij
    •  & Jingyuan Fu

  • Article
    | Open Access

    Defective rhythmic metabolism is associated with high-fat diet feeding and obesity. The authors show that the clock gene BMAL1 drives paraventricular hypothalamic neuron activity via rhythmic GABAergic neurotransmission, and that this mediates diurnal metabolism and diet-induced obesity.

    • Eun Ran Kim
    • , Yuanzhong Xu
    •  & Qingchun Tong

  • Article
    | Open Access

    Adipose tissue expansion occurs via enlargement of adipocytes as well as the generation of new fat cells, the latter being associated with more favorable metabolic outcomes. Here, the authors show that activation of adipocyte Piezo1 results in release of FGF1 and stimulates the differentiation of adipocyte precursor cells.

    • ShengPeng Wang
    • , Shuang Cao
    •  & Stefan Offermanns

  • Article
    | Open Access

    Beta-adrenergic stimulation of brown adipose tissue leads to thermogenesis via the activating transcription factor 2 (ATF2) mediated expression of the thermogenic genes Ucp1 and Pgc-1α. Here, the authors show that the scaffold protein p62 regulates brown adipose tissue function through modifying ATF2 genomic binding and subsequent Ucp1 and Pgc-1α induction.

    • Katrin Fischer
    • , Anna Fenzl
    •  & Timo D. Müller

  • Article
    | Open Access

    The HNF4α gene contains two promoters, which are thought to be active in the fetal and adult liver, the latter contributing to hepatic glucose production. Here the authors show that the fetal isoform of HNF4a is induced in mouse livers upon fasting and in type-2 diabetes in a manner regulated by TET3.

    • Da Li
    • , Tiefeng Cao
    •  & Yingqun Huang

  • Article
    | Open Access

    A difference in the survival of respiratory chain complex III deficient Bcs1lp.S78G mice was observed between two congenic mouse strains. Here the authors show how in one of the strains the combined effects of a spontaneously arising non-pathogenic variant and the disease-causing Bcs1lp.S78G mutation exacerbate CIII deficiency and disease progression.

    • Janne Purhonen
    • , Vladislav Grigorjev
    •  & Jukka Kallijärvi

  • Article
    | Open Access

    Human antigen R (HuR) is a RNA-binding protein. Here the authors investigate its role in adipose tissue and find that it protects mice from diet-induced obesity, prevents adipocyte hypertrophy, and promotes lipolysis, which may at least in part be due to HuR-dependent ATGL mRNA stability regulation demonstrated in-vitro.

    • Jingyuan Li
    • , Li Gong
    •  & Wencheng Zhang

  • Article
    | Open Access

    Type-2 innate lymphoid cells (ILC2s) are an immune population secreting Th2 cytokines playing a role in the regulation of adipose metabolic homeostasis. Here the authors show that engagement of GITR, a member of the TNF superfamily, in activated ILC2s is protective against insulin resistance in both a preventive and a therapeutic manner in the context of obesity.

    • Lauriane Galle-Treger
    • , Ishwarya Sankaranarayanan
    •  & Omid Akbari

  • Article
    | Open Access

    Substrate reduction therapies (SRT) are a promising therapeutic approach for monogenic inherited metabolic diseases. Here the authors evaluate the therapeutic potential of an in vivo CRISPR/Cas9-mediated SRT to treat primary hyperoxaluria type I and demonstrate its safety and efficacy.

    • Nerea Zabaleta
    • , Miren Barberia
    •  & Juan R. Rodriguez-Madoz

  • Article
    | Open Access

    Obesity is associated with low-grade chronic inflammation. Here the authors show that the activation of anti-inflammatory M2a-subtype macrophages requires the IL4/Irs2/Akt pathway. Due to decreased Irs2 expression this pathway is impaired in obese mice thus leading to a defect in M2a activation.

    • Tetsuya Kubota
    • , Mariko Inoue
    •  & Takashi Kadowaki

  • Article
    | Open Access

    Tobacco smoking and cold exposure are environmental modulators of human energy metabolism suppressing appetite and increasing energy expenditure, respectively. Here, the authors develop a novel pharmacological strategy in which they simultaneously mimic the metabolic benefits of both phenomena through small-molecule combination therapy, and show that this treatment improves metabolic health of obese mice.

    • Christoffer Clemmensen
    • , Sigrid Jall
    •  & Matthias H. Tschöp

  • Article
    | Open Access

    Patients with mutations in the ASL gene present with argininosuccinic aciduria characterised by hyperammonaemia and cognitive impairment. Here, the authors show that cerebral disease involves neuronal nitrosative/oxidative stress that is not induced by hyperammonaemia, and that it can be reversed using AAV-ASL directed to liver and brain in mice.

    • Julien Baruteau
    • , Dany P. Perocheau
    •  & Simon N. Waddington

  • Article
    | Open Access

    Acid ceramidase (aCDase) hydrolyzes lysosomal membrane ceramide into sphingosine and its dysfunction leads to a variety of disease phenotypes. Here, the authors present structures of aCDase in its proenzyme and autocleaved forms, which provides insight into its mechanism of action.

    • Ahmad Gebai
    • , Alexei Gorelik
    •  & Bhushan Nagar

  • Article
    | Open Access

    Beige adipocytes can arise from transdifferentiation of mature white adipocytes. Here the authors identify CDK6 as a key molecule involved in the white-to-beige adipocyte transdifferentiation and, therefore, as a regulator of organismal energy homeostasis in mice.

    • Xiaoli Hou
    • , Yongzhao Zhang
    •  & Miaofen G. Hu

  • Article
    | Open Access

    Adipocyte hyperplasia is thought to have beneficial metabolic effects in obesity, but definitive evidence is lacking. Here, Shao et al. promote de novo formation of adipocytes in visceral white adipose tissue (WAT) of adult mice through inducible overexpression of Pparg in Pdgfrβ+ preadipocytes and show that this protects from pathological WAT remodeling.

    • Mengle Shao
    • , Lavanya Vishvanath
    •  &  Rana K. Gupta

  • Article
    | Open Access

    The activity of protein tyrosine phosphatase PTP1B, a major metabolic regulator, depends on its oxidation state. Here the authors identify and characterize a small molecule that targets the oxidized, inactive form of PTP1B, suggesting a new therapeutic approach to diabetes and obesity.

    • Navasona Krishnan
    • , Christopher A. Bonham
    •  & Nicholas K. Tonks

  • Article
    | Open Access

    CREB-regulated transcription coactivator 2, CRTC2, has been associated with regulation of glucose and lipid homeostasis. Here Han et al. show that Creb/Crtc2 modulates lipid and glucose metabolism by inhibiting the expression of mi-R34 that, in turn, represses the expression of Sirt1 and PPARα and consequently Fgf21 levels.

    • Hye-Sook Han
    • , Byeong Hun Choi
    •  & Seung-Hoi Koo

  • Article
    | Open Access

    The vitamin D receptor/retinoid X receptor-α heterodimer (VDRRXRα) regulates bone mineralization. Here the authors employ hydrogen/deuterium exchange (HDX) mass spectrometry to study the conformational dynamics of VDRRXRα and give mechanistic insights into how VDRRXRα controls the transcriptional activity of specific genes.

    • Jie Zheng
    • , Mi Ra Chang
    •  & Patrick R. Griffin

  • Article
    | Open Access

    The NRF2 transcription factor regulates the response to stress in mammalian cells. Here, the authors show that activating mutations in NRF2, commonly found in cancer cells, are found in four patients with a multisystem disorder characterized by immunodeficiency and neurological symptoms.

    • Peter Huppke
    • , Susann Weissbach
    •  & Jutta Gärtner

  • Article
    | Open Access

    Hunter syndrome is a lysosomal storage disease caused by mutations in the enzyme iduronate-2-sulfatase (IDS). Here, the authors present the IDS crystal structure and give mechanistic insights into mutations that cause Hunter syndrome.

    • Mykhaylo Demydchuk
    • , Chris H. Hill
    •  & Randy J. Read

  • Article
    | Open Access

    The enzyme Atgl participates in the breakdown of lipids in adipose tissue. Here the authors show that pharmacological inhibition of Atgl reduces weight gain and improves metabolic health in mice fed a high-fat diet, without causing adverse effects in cardiac muscle associated with genetic depletion ofAtgl.

    • Martina Schweiger
    • , Matthias Romauch
    •  & Rudolf Zechner

  • Article
    | Open Access

    High levels of homocysteine in cells are linked to pathological states. Here, the authors report that homocysteine inactivates catalase by modifying the heme group, impairing cellular redox homeostasis, and show that this modification occurs in cancer cells and in a cellular model of Parkinson’s disease.

    • Dominique Padovani
    • , Assia Hessani
    •  & Isabelle Artaud

  • Article
    | Open Access

    Iron overload can be either hereditary or acquired via transfusions, and current treatments include the use of iron chelators that have adverse effects in some patients. Here the authors modify siderocalin to enhance iron excretion in urine, and demonstrate therapeutic efficacy in iron overload mouse models.

    • Jonathan Barasch
    • , Maria Hollmen
    •  & Andong Qiu

  • Article
    | Open Access

    PI3K is activated as a result of insulin receptor (IR) signalling. Here the authors show that activation of specific class III PI3Ks in response to insulin promotes IR endocytosis and lysosomal degradation, providing negative feedback on IR signalling by reducing the time IR is activated.

    • Ivan Nemazanyy
    • , Guillaume Montagnac
    •  & Ganna Panasyuk

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