publication

Role for the obesity-related FTO gene in the cellular sensing of amino acids

Role for the obesity-related FTO gene in the cellular sensing of amino acids

Summary:
SNPs in the first intron of FTO (fat mass and obesity associated) are strongly associated with human obesity. While it is not yet formally established that this effect is mediated through the actions of the FTO protein itself, loss of function mutations in FTO or its murine homologue Fto result in severe growth retardation, and mice globally overexpressing FTO are obese. The mechanisms through which FTO influences growth and body composition are unknown. We describe a role for FTO in the coupling of amino acid levels to mammalian target of rapamycin complex 1 signaling. These findings suggest that FTO may influence body composition through playing a role in cellular nutrient sensing.

Authors:
Pawan Gulati, Man Ka Cheunga, Robin Antrobus, Chris D. Church, Heather P. Harding, Yi-Chun Loraine Tung, Debra Rimmington, Marcella Ma, David Ron, Paul J. Lehner, Frances M. Ashcroft, Roger D. Cox, Anthony P. Coll, Stephen O’Rahilly, and Giles S. H. Yeo

Journal:
Proc. Natl. Acad. Sci. U.S.A. 12;110(7):2557-62.

PubMed Link:

http://www.ncbi.nlm.nih.gov/pubmed/23359686

Role for the obesity-related FTO gene in the cellular sensing of amino acids

Translational regulation shapes the molecular landscape of complex disease phenotypes

Translational regulation shapes the molecular landscape of complex disease phenotypes

Summary:
The extent of translational control of gene expression in mammalian tissues remains largely unknown. Here we perform genome-wide RNA sequencing and ribosome profiling in heart and liver tissues to investigate strain-specific translational regulation in the spontaneously hypertensive rat (SHR/Ola). For the most part, transcriptional variation is equally apparent at the translational level and there is limited evidence of translational buffering. Remarkably, we observe hundreds of strain-specific differences in translation, almost doubling the number of
differentially expressed genes. The integration of genetic, transcriptional and translational data sets reveals distinct signatures in 30UTR variation, RNA-binding protein motifs and miRNA expression associated with translational regulation of gene expression. We show that a large number of genes associated with heart and liver traits in human genome-wide association studies are primarily translationally regulated. Capturing interindividual differences in the translated genome will lead to new insights into the genes and regulatory pathways underlying disease phenotypes.

Authors:
Sebastian Schafer, Eleonora Adami, Matthias Heinig, Katharina E. Costa Rodrigues, Franziska Kreuchwig, Jan Silhavy, Sebastiaan van Heesch, Deimante Simaite, Nikolaus Rajewsky,
Edwin Cuppen, Michal Pravenec, Martin Vingron, Stuart A. Cook & Norbert Hubner

Journal:
Nat Commun. (2015) 26(6): 7200.

PubMed Link:

http://www.ncbi.nlm.nih.gov/pubmed/26007203

Hypothalamic POMC neurons promote cannabinoid-induced feeding

Hypothalamic POMC neurons promote cannabinoid-induced feeding

Summary:
Hypothalamic pro-opiomelanocortin (POMC) neurons promote satiety. Cannabinoid receptor 1 (CB1R) is critical for central regulation of food intake. We interrogated whether CB1R-controlled feeding is paralleled by decreased activity of POMC neurons. Chemical promotion of CB1R activity increased feeding, and strikingly, CB1R activation also promoted neuronal activity of POMC cells. This paradoxical increase in POMC activity was crucial for CB1R-induced feeding, because Designer-Receptors-Exclusively-Activated-by-Designer-Drugs (DREADD)-mediated inhibition of POMC neurons diminished, while DREADD-mediated activation of POMC neurons enhanced CB1R-driven feeding. The Pomc gene encodes both the anorexigenic peptide, α-melanocyte-stimulating hormone (α-MSH), and the peptide, β-endorphin. CB1R activation selectively increased β-endorphin but not α-MSH release in the hypothalamus, and, systemic or hypothalamic administration of the opioid receptor antagonist, naloxone, blocked acute CB1R-induced feeding. These processes involved mitochondrial adaptations, which, when blocked, abolished CB1R-induced cellular responses and feeding. Together, these results unmasked a previously unsuspected role of POMC neurons in promotion of feeding by cannabinoids.

Authors:
Marco Koch, Luis Varela, Jae Geun Kim, Jung Dae Kim, Francisco Hernandez, Stephanie E Simonds, Carlos M Castorena, Claudia R Vianna, Joel K Elmquist, Yury M Morozov, Pasko Rakic, Ingo Bechmann, Michael A Cowley, Klara Szigeti-Buck, Marcelo O Dietrich, Xiao-Bing Gao, Sabrina Diano1, and Tamas L Horvath

Journal:
Nature (2015) 519(7541):45 – 50.

PubMed Link:

http://www.ncbi.nlm.nih.gov/pubmed/?term=cannabinoid-induced+feeling+horvath

microRNA-379 couples glucocorticoid hormones to dysfunctional lipid homeostasis

microRNA-379 couples glucocorticoid hormones to dysfunctional lipid homeostasis

Summary:
In mammals, glucocorticoids (GCs) and their intracellular receptor, the glucocorticoid receptor (GR), represent critical checkpoints in the endocrine control of energy homeostasis. Indeed, aberrant GC action is linked to severe metabolic stress conditions as seen in Cushing’s syndrome, GC therapy and certain components of the Metabolic Syndrome, including obesity and insulin resistance. Here, we identify the hepatic induction of the mammalian conserved microRNA (miR)-379/410 genomic cluster as a key component of GC/GR-driven metabolic dysfunction. Particularly, miR-379 was up-regulated in mouse models of hyperglucocorticoidemia and obesity as well as human liver in a GC/GR-dependent manner. Hepatocyte-specific silencing of miR-379 substantially reduced circulating very-low-density lipoprotein (VLDL)-associated triglyceride (TG) levels in healthy mice and normalized aberrant lipid profiles in metabolically challenged animals, mediated through miR-379 effects on key receptors in hepatic TG re-uptake. As hepatic miR-379 levels were also correlated with GC and TG levels in human obese patients, the identification of a GC/GRcontrolled miRNA cluster not only defines a novel layer of hormone-dependent metabolic control but also paves the way to alternative miRNA-based therapeutic approaches in metabolic dysfunction.

Authors:
Roldan M de Guia, Adam J Rose, Anke Sommerfeld, Oksana Seibert, Daniela Strzoda, Annika Zota, Yvonne Feuchter, Anja Krones-Herzig, Tjeerd Sijmonsma, Milen Kirilov, Carsten Sticht, Norbert Gretz, Geesje Dallinga-Thie, Sven Diederichs, Nora Klöting, Matthias Blüher, Mauricio Berriel Diaz1 & Stephan Herzig

Journal:

The EMBO Journal (2015) 34(3): 344 360.

PubMed Link:

http://www.ncbi.nlm.nih.gov/pubmed/?term=herzig+microRNA-379

Adaptation of Hepatic Mitochondrial Function in Humans with Non-Alcoholic Fatty Liver Is Lost in Steatohepatitis

Adaptation of Hepatic Mitochondrial Function in Humans with Non-Alcoholic Fatty Liver Is Lost

Summary:
The association of hepatic mitochondrial function with insulin resistance and non-alcoholic fatty liver (NAFL) or steatohepatitis (NASH) remains unclear. This study applied high-resolution respirometry to directly quantify mitochondrial respiration in liver biopsies of obese insulin-resistant humans without (n = 18) or with (n = 16) histologically proven NAFL or with NASH (n = 7) compared to lean individuals (n = 12). Despite similar mitochondrial content, obese humans with or without NAFL had 4.3- to 5.0-fold higher maximal respiration rates in isolated mitochondria than lean persons. NASH patients featured higher mitochondrial mass, but 31%–40% lower maximal respiration, which associated with greater hepatic insulin resistance, mitochondrial uncoupling, and leaking activity. In NASH, augmented hepatic oxidative stress (H2O2, lipid peroxides) and oxidative DNA damage (8-OH-deoxyguanosine) was paralleled by reduced anti-oxidant defense capacity and increased inflammatory response. These data suggest adaptation of the liver (‘‘hepatic mitochondrial flexibility’’) at early stages of obesityrelated insulin resistance, which is subsequently
lost in NASH.

Authors:
Chrysi Koliaki, Julia Szendroedi, …, Marcelo O. Dietrich, Zhong-Wu Liu and Tamas L. Horvath

Journal:
Cell Metabolism (2015) 21(5): 739–746.

PubMed Link:

http://www.ncbi.nlm.nih.gov/pubmed/?term=koliakiadaptation+of+hepatic

Neonatal insulin action impairs hypothalamic neurocircuit formation in response to maternal high fat feeding

Neonatal insulin action impairs hypothalamic neurocircuit formation in response to maternal high fat feeding

Summary:

Maternal metabolic homeostasis exerts long-term effects on the offspring’s health outcomes. Here, we demonstrate that maternal high fat diet (HFD)-feeding during lactation predisposes the offspring for obesity and impaired glucose homeostasis in mice, which is associated with an impairment of the hypothalamic melanocortin circuitry. Whereas the number and neuropeptide expression of anorexigenic proopiomelanocortin-(POMC) and orexigenic agoui-related peptide (AgRP)-neurons, electrophysiological properties of POMC-neurons and posttranslational processing of POMC remain unaffected in response to maternal HFD-feeding during lactation, the formation of POMC- and AgRP-projections to hypothalamic target sites is severely impaired. Abrogating insulin action in POMC-neurons of the offspring prevents altered POMC-projections to the preautonomic paraventricular nucleus of the hypothalamus (PVH), pancreatic parasympathetic innervation and impaired glucose-stimulated insulin-secretion in response to maternal overnutrition. These experiments reveal a critical timing, when altered maternal metabolism disrupts metabolic homeostasis in the offspring via impairing neuronal projections and that abnormal insulin signaling contributes to this effect.

Authors:
Merly C. Vogt, Lars Paeger, Simon Hess, Sophie M. Steculorum, Motoharu Awazawa, Brigitte Hampel, Susanne Neupert, Hayley T. Nicholls, Jan Mauer, A. Christine Hausen1, Reinhard Predel, Peter Kloppenburg, Tamas L. Horvath, and Jens C. Brüning

Journal:
Cell (2014) 156(3): 495–509.

PubMed Link:

http://www.ncbi.nlm.nih.gov/pubmed/24462248

A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents

Summary: Mitochondria are key organelles in the maintenance
of cellular energy metabolism and integrity. Here,
we show that mitochondria number decrease but
their size increase in orexigenic agouti-related protein
(Agrp) neurons during the transition from fasted
to fed to overfed state. These fusion-like dynamic
changes were cell-type specific, as they occurred
in the opposite direction in anorexigenic pro-opiomelanocortin
(POMC) neurons. Interfering with mitochondrial
fusion mechanisms in Agrp neurons by
cell-selectively knocking down mitofusin 1 (Mfn1) or
mitofusin 2 (Mfn2) resulted in altered mitochondria
size and density in these cells. Deficiency in mitofusins
impaired the electric activity of Agrp neurons
during high-fat diet (HFD), an event reversed by
cell-selective administration of ATP. Agrp-specific
Mfn1 or Mfn2 knockout mice gained less weight
when fed a HFD due to decreased fat mass. Overall,
our data unmask an important role for mitochondrial
dynamics governed by Mfn1 and Mfn2 in Agrp neurons
in central regulation of whole-body energy
metabolism.

Authors:
Brian Finan, Bin Yang, Nickki Ottaway, David L Smiley, Tao Ma, Christoffer Clemmensen, Joe Chabenne, Lianshan Zhang, Kirk M Habegger, Katrin Fischer, Jonathan E Campbell, Darleen Sandoval, Randy J Seeley, Konrad Bleicher, Sabine Uhles, William Riboulet, Jürgen Funk, Cornelia Hertel, Sara Belli, Elena Sebokova, Karin Conde-Knape, Anish Konkar, Daniel J Drucker, Vasily Gelfanov, Paul T Pfluger, Timo D Müller, Diego Perez-Tilve, Richard D DiMarchi & Matthias H Tschöp

Journal:
Nature Medicine
(2015) 21(1): 27-36

PubMed Link:

http://www.ncbi.nlm.nih.gov/pubmed/?term=finan+a+rationally+designed

High-Density Lipoprotein Maintains Skeletal Muscle Function by Modulating Cellular Respiration in Mice

Background—Abnormal glucose metabolism is a central feature of disorders with increased rates of cardio-vascular disease (CVD). Low levels of high density lipoprotein (HDL) are a key predictor for CVD. We used genetic mouse models with increased HDL levels (apoA-I tg) and
reduced HDL levels (apoA-I ko) to investigate whether HDL modulates mitochondrial bioenergetics in skeletal muscle.
Methods and Results—ApoA-I ko mice exhibited fasting hyperglycemia and impaired glucose
tolerance test (GTT) compared to wild type (wt) mice. Mitochondria isolated from gastrocnemius muscle of apoA-I ko mice displayed markedly blunted ATP synthesis. Endurance capacity (EC) during exercise exhaustion test was impaired in apoA-I ko mice. HDL directly enhanced glucose oxidation by increasing glycolysis and mitochondrial respiration rate (OCR) in C2C12 muscle cells. ApoA-I tg mice exhibited lower fasting glucose levels, improved GTT, increased lactate levels, reduced fat mass, associated with protection against age-induced decline of EC compared
to wt mice. Circulating levels of fibroblast growth factor 21 (FGF21), a novel biomarker for mitochondrial respiratory chain deficiencies and inhibitor of white adipose lipolysis, were significantly reduced in apoA-I tg mice. Consistent with an increase in glucose utilization of skeletal muscle, genetically increased HDL and apoA-I levels in mice prevented high fat dietinduced impairment of glucose homeostasis.
Conclusions—In view of impaired mitochondrial function and decreased HDL levels in T2D, our findings indicate that HDL-raising therapies may preserve muscle mitochondrial function and address key aspects of T2D beyond CVD.

Authors:
Maarit Lehti, PhD., Elizabeth Donelan, M.S., William Abplanalp, M.S., Omar Al-Massadi, PhD., Kirk Habegger, PhD., Jon Weber, B.S., Chandler Ress, B.S., Johannes Mansfeld, M.S., Sonal Somvanshi, M.S., Chitrang Trivedi, PhD., Michaela Keuper, PhD., Teja Ograjsek, B.S., Cynthia Striese, Sebastian Cucuruz, Paul T. Pfluger, PhD., Radhakrishna Krishna, PhD., Scott M. Gordon, PhD., R. A. Gangani D. Silva, PhD., Serge Luquet, PhD., Julien Castel, PhD., Sarah Martinez, M.S., David D’Alessio, M.D., W. Sean Davidson, PhD., and Susanna M. Hofmann, M.D.

Journal:
Circulation. (2013) 128(22): 2364–2371

PubMed Link:

http://www.ncbi.nlm.nih.gov/pubmed/24170386

Efficient Generation of T*2-Weighted Contrast by Interslice Echo-Shifting for Human Functional and Anatomical Imaging at 9.4 Tesla

Purpose:
Standard gradient-echo sequences are often prohibitively slow for T!2-weighted imaging as long echo times prolong the repetition time of the sequence. Echo-shifting offers a way out of this dilemma by allowing an echo time that exceeds the repetition time. The purpose of this work is to present a gradient-echo sequence that is optimized for multislice T!2-weighted imaging applications by combining echoshifting with an interleaved slice excitation order.
Theory and Methods:
This combined approach offers two major advantages: First, it combines the advantages of both concepts, that is, echo time and pulse repetition time can be significantly increased without affecting scan time. Second, there is no echo-shifting related signal loss associated with this concept as only a single radiofrequency pulse is applied per pulse repetition time and slice.
Results:
A 9.4 Tesla high-resolution T!2-weighted anatomical brain scan of the proposed sequence is compared to a standard gradient-echo. Furthermore, results from 9.4 Tesla blood oxygen level dependent functional magnetic resonance imaging experiments with an in-plane resolution of 0.8 ” 0.8 mm2 are presented.
Conclusion:
The proposed sequence allows for efficient generation of T!2-weighted contrast by combining echo-shifting with an interleaved slice excitation order.

Authors:
Philipp Ehses, Jonas Bause, G. Shajan, and Klaus Scheffler

Journal:
Magn Reson Med. (2015) Aug 24

PubMed Link:

http://www.ncbi.nlm.nih.gov/pubmed/25597997

The orphan receptor Gpr83 regulates systemic energy metabolism via ghrelin-dependent and ghrelin-independent mechanisms

The G protein-coupled receptor 83 (Gpr83) is widely expressed in brain regions regulating energy metabolism. Here we report that hypothalamic expression of Gpr83 is regulated in response to nutrient availability and is decreased in obese mice compared with lean mice. In the arcuate nucleus, Gpr83 colocalizes with the ghrelin receptor (Ghsr1a) and the agoutirelated
protein. In vitro analyses show heterodimerization of Gpr83 with Ghsr1a diminishes activation of Ghsr1a by acyl-ghrelin. The orexigenic and adipogenic effect of ghrelin is accordingly potentiated in Gpr83-deficient mice. Interestingly, Gpr83 knock-out mice have normal body weight and glucose tolerance when fed a regular chow diet, but are protected from obesity and glucose intolerance when challenged with a high-fat diet, despite hyperphagia and increased hypothalamic expression of agouti-related protein, Npy, Hcrt and Ghsr1a. Together, our data suggest that Gpr83 modulates ghrelin action but also indicate that Gpr83 regulates systemic metabolism through other ghrelin-independent pathways.

Authors:
Timo D. Müller, Anne Müller, Chun-Xia Yi, Kirk M. Habegger, Carola W. Meyer, Bruce D. Gaylinn, Brian Finan, Kristy Heppner, Chitrang Trivedi, Maximilian Bielohuby, William Abplanalp, Franziska Meyer, Carolin L. Piechowski, Juliane Pratzka, Kerstin Stemmer1, Jenna Holland, Jazzmin Hembree, Nakul Bhardwaj, Christine Raver, Nickki Ottaway, Radha Krishna, Renu Sah6 Floyd R. Sallee, Stephen C. Woods, Diego Perez-Tilve, Martin Bidlingmaier, Michael O. Thorner, Heiko Krude, David Smiley, Richard DiMarchi, Susanna Hofmann, Paul T. Pfluger, Gunnar Kleinau, Heike Biebermann & Matthias H. Tschöp

Journal:
Nature Communications (2013) 4: 1968.

PubMed Link:

http://www.ncbi.nlm.nih.gov/pubmed/23744028