Recent CIG publications Archive

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Mol Metab.: auth.: group Thorens

Mol Metab. 2021 Oct 8;101355. doi: 10.1016/j.molmet.2021.101355. Online ahead of print.

Plasma triacylglycerols are biomarkers of ß-cell function in mice and humans

Ana Rodríguez Sánchez-Archidona 1Céline Cruciani-Guglielmacci 2Clara Roujeau 3Leonore Wigger 4Justine Lallement 5Jessica Denom 6Marko Barovic 7Nadim Kassis 8Florence Mehl 9Jurgen Weitz 10Marius Distler 11Christian Klose 12Kai Simons 13Mark Ibberson 14Michele Solimena 15Christophe Magnan 16Bernard Thorens 17

Abstract

Objectives: To find plasma biomarkers prognostic of type 2 diabetes, which could also inform on pancreatic ß-cell deregulations or defects in the function of insulin target tissues. Such biomarkers could help stratify patients according to the underlying patho-mechanisms and lead to more precise therapeutic approaches.

Methods: We conducted a systems biology approach to characterize the plasma lipidomes of C57Bl/6J, DBA/2J, and BALB/cJ mice under different nutritional conditions as well as their pancreatic islet and liver transcriptomes. We searched for correlations between plasma lipids and tissue gene expression modules.

Results: We identified strong correlations between plasma triacylglycerols (TAGs) and islet gene modules that comprise key regulators of glucose- and lipid-regulated insulin secretion and of the insulin signaling pathway, the two top hits were Gck and Abhd6 for positive and negative correlations, respectively. Correlations were also found between sphingomyelins and islet gene modules that overlapped in part with the gene modules correlated with TAGs. In liver, the gene module most strongly correlated with plasma TAGs was enriched in mRNAs encoding fatty acid and carnitine transporters as well as multiple enzymes of the ß-oxidation pathway. In humans, plasma TAGs also correlated with the expression of several of the same key regulators of insulin secretion and of the insulin signaling pathway identified in mice. This cross-species comparative analysis further led to the identification PITPNC1 as a candidate regulator of glucose-stimulated insulin secretion.

Conclusion: TAGs emerge as biomarkers of a liver-to-ß-cell axis that links hepatic ß-oxidation to ß-cell functional mass and insulin secretion.

Keywords: PITPNC1; Triacylglycerols; plasma biomarkers; systems biology; type 2 diabetes; ß-cell function.

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iScience.: auth.: group Thorens

iScience. 2021 Sep 11;24(10):103122. doi: 10.1016/j.isci.2021.103122. eCollection 2021 Oct 22.

Glucokinase neurons of the paraventricular nucleus of the thalamus sense glucose and decrease food consumption

Sébastien Kessler 1Gwenaël Labouèbe 1Sophie Croizier 1Sevasti Gaspari 1David Tarussio 1Bernard Thorens 1

Abstract

The paraventricular nucleus of the thalamus (PVT) controls goal-oriented behavior through its connections to the nucleus accumbens (NAc). We previously characterized Glut2aPVT neurons that are activated by hypoglycemia, and which increase sucrose seeking behavior through their glutamatergic projections to the NAc. Here, we identified glucokinase (Gck)-expressing neurons of the PVT (GckaPVT) and generated a mouse line expressing the Cre recombinase from the glucokinase locus (Gck Cre/+ mice). Ex vivo calcium imaging and whole-cell patch clamp recordings revealed that GckaPVT neurons that project to the NAc were mostly activated by hyperglycemia. Their chemogenetic inhibition or optogenetic stimulation, respectively, enhanced food intake or decreased sucrose-seeking behavior. Collectively, our results describe a neuronal population of Gck-expressing neurons in the PVT, which has opposite glucose sensing properties and control over feeding behavior than the previously characterized Glut2aPVT neurons. This study allows a better understanding of the complex regulation of feeding behavior by the PVT.

Keywords: Behavioral neuroscience; Cellular neuroscience; Neuroscience.

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Front Neurosci.: auth.: group Benton

Front Neurosci. 2021 Sep 16;15:738088. doi:10.3389/fnins.2021.738088. eCollection 2021.

Olfactory Receptor Gene Regulation in Insects: Multiple Mechanisms for Singular Expression

Kaan Mika 1Richard Benton 1

Abstract

The singular expression of insect olfactory receptors in specific populations of olfactory sensory neurons is fundamental to the encoding of odors in patterns of neuronal activity in the brain. How a receptor gene is selected, from among a large repertoire in the genome, to be expressed in a particular neuron is an outstanding question. Focusing on Drosophila melanogaster, where most investigations have been performed, but incorporating recent insights from other insect species, we review the multilevel regulatory mechanisms of olfactory receptor expression. We discuss how cis-regulatory elements, trans-acting factors, chromatin modifications, and feedback pathways collaborate to activate and maintain expression of the chosen receptor (and to suppress others), highlighting similarities and differences with the mechanisms underlying singular receptor expression in mammals. We also consider the plasticity of receptor regulation in response to environmental cues and internal state during the lifetime of an individual, as well as the evolution of novel expression patterns over longer timescales. Finally, we describe the mechanisms and potential significance of examples of receptor co-expression.

Keywords: Drosophila; evolution; feedback; gene expression; insects; neurodevelopment; olfactory receptor; sensory neuron.

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Nat Commun.: auth.: group Reymond

Nat Commun. 2021 Sep 24;12(1):5647. doi: 10.1038/s41467-021-25805-y.

Differentially expressed genes reflect disease-induced rather than disease-causing changes in the transcriptome

Eleonora Porcu 1 2 3Marie C Sadler 4 5Kaido Lepik 6 7Chiara Auwerx 8 4 5Andrew R Wood 9Antoine Weihs 10Maroun S Bou Sleiman 11Diogo M Ribeiro 4 12Stefania Bandinelli 13Toshiko Tanaka 14Matthias Nauck 15 16Uwe Völker 16 17Olivier Delaneau 4 12Andres Metspalu 18Alexander Teumer 16 19Timothy Frayling 20Federico A Santoni 21Alexandre Reymond 8Zoltán Kutalik 4 5 9 12

Abstract

Comparing transcript levels between healthy and diseased individuals allows the identification of differentially expressed genes, which may be causes, consequences or mere correlates of the disease under scrutiny. We propose a method to decompose the observational correlation between gene expression and phenotypes driven by confounders, forward- and reverse causal effects. The bi-directional causal effects between gene expression and complex traits are obtained by Mendelian Randomization integrating summary-level data from GWAS and whole-blood eQTLs. Applying this approach to complex traits reveals that forward effects have negligible contribution. For example, BMI- and triglycerides-gene expression correlation coefficients robustly correlate with trait-to-expression causal effects (rBMI = 0.11, PBMI = 2.0 × 10-51 and rTG = 0.13, PTG = 1.1 × 10-68), but not detectably with expression-to-trait effects. Our results demonstrate that studies comparing the transcriptome of diseased and healthy subjects are more prone to reveal disease-induced gene expression changes rather than disease causing ones.

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Elife.: auth.: group Gatfield

Elife. 2021 Sep 20;10:e67991. doi: 10.7554/eLife.67991. Online ahead of print.

Circular RNA repertoires are associated with evolutionarily young transposable elements

Franziska Gruhl 1Peggy Janich 1Henrik Kaessmann 2David Gatfield 1

Abstract

Circular RNAs (circRNAs) are found across eukaryotes and can function in post-transcriptional gene regulation. Their biogenesis through a circle-forming backsplicing reaction is facilitated by reverse-complementary repetitive sequences promoting pre-mRNA folding. Orthologous genes from which circRNAs arise, overall contain more strongly conserved splice sites and exons than other genes, yet it remains unclear to what extent this conservation reflects purifying selection acting on the circRNAs themselves. Our analyses of circRNA repertoires from five species representing three mammalian lineages (marsupials, eutherians: rodents, primates) reveal that surprisingly few circRNAs arise from orthologous exonic loci across all species. Even the circRNAs from orthologous loci are associated with young, recently active and species-specific transposable elements, rather than with common, ancient transposon integration events. These observations suggest that many circRNAs emerged convergently during evolution – as a byproduct of splicing in orthologs prone to transposon insertion. Overall, our findings argue against widespread functional circRNA conservation.

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Annu Rev Genet.: auth.: Groups Benton & Auer

Annu Rev Genet. 2021 Sep 16. doi: 10.1146/annurev-genet-071719-020719. Online ahead of print.

Drosophila sechellia: A Genetic Model for Behavioral Evolution and Neuroecology

Thomas O Auer 1Michael P Shahandeh 1Richard Benton 1

Abstract

Defining the mechanisms by which animals adapt to their ecological niche is an important problem bridging evolution, genetics, and neurobiology. We review the establishment of a powerful genetic model for comparative behavioral analysis and neuroecology, Drosophila sechellia. This island-endemic fly species is closely related to several cosmopolitan generalists, including Drosophila melanogaster, but has evolved extreme specialism, feeding and reproducing exclusively on the noni fruit of the tropical shrub Morinda citrifolia. We first describe the development and use of genetic approaches to facilitate genotype/phenotype associations in these drosophilids. Next, we survey the behavioral, physiological, and morphological adaptations of D. sechellia throughout its life cycle and outline our current understanding of the genetic and cellular basis of these traits. Finally, we discuss the principles this knowledge begins to establish in the context of host specialization, speciation, and the neurobiology of behavioral evolution and consider open questions and challenges in the field. Expected final online publication date for the Annual Review of Genetics, Volume 55 is November 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.