Uncategorized Archive

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Int J Mol Sci.: co-auth.: W.Wahli

Int J Mol Sci. 2021 Aug 9;22(16):8555. doi: 10.3390/ijms22168555.

The PPARβ/δ-AMPK Connection in the Treatment of Insulin Resistance

David Aguilar-Recarte 1 2 3Xavier Palomer 1 2 3Walter Wahli 4 5 6Manuel Vázquez-Carrera 1 2 3

Abstract

The current treatment options for type 2 diabetes mellitus do not adequately control the disease in many patients. Consequently, there is a need for new drugs to prevent and treat type 2 diabetes mellitus. Among the new potential pharmacological strategies, activators of peroxisome proliferator-activated receptor (PPAR)β/δ show promise. Remarkably, most of the antidiabetic effects of PPARβ/δ agonists involve AMP-activated protein kinase (AMPK) activation. This review summarizes the recent mechanistic insights into the antidiabetic effects of the PPARβ/δ-AMPK pathway, including the upregulation of glucose uptake, muscle remodeling, enhanced fatty acid oxidation, and autophagy, as well as the inhibition of endoplasmic reticulum stress and inflammation. A better understanding of the mechanisms underlying the effects resulting from the PPARβ/δ-AMPK pathway may provide the basis for the development of new therapies in the prevention and treatment of insulin resistance and type 2 diabetes mellitus.

Keywords: AMPK; GDF15; PPARβ/δ; insulin resistance; type 2 diabetes mellitus.

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Metabolites.: auth.: W.Wahli

Metabolites. 2021 Jul 30;11(8):502. doi: 10.3390/metabo11080502.

Roles of Estrogens in the Healthy and Diseased Oviparous Vertebrate Liver

Blandine Tramunt 1 2Alexandra Montagner 1Nguan Soon Tan 3Pierre Gourdy 1 2Hervé Rémignon 4 5Walter Wahli 3 5 6

Abstract

The liver is a vital organ that sustains multiple functions beneficial for the whole organism. It is sexually dimorphic, presenting sex-biased gene expression with implications for the phenotypic differences between males and females. Estrogens are involved in this sex dimorphism and their actions in the liver of several reptiles, fishes, amphibians, and birds are discussed. The liver participates in reproduction by producing vitellogenins (yolk proteins) and eggshell proteins under the control of estrogens that act via two types of receptors active either mainly in the cell nucleus (ESR) or the cell membrane (GPER1). Estrogens also control hepatic lipid and lipoprotein metabolisms, with a triglyceride carrier role for VLDL from the liver to the ovaries during oogenesis. Moreover, the activation of the vitellogenin genes is used as a robust biomarker for exposure to xenoestrogens. In the context of liver diseases, high plasma estrogen levels are observed in fatty liver hemorrhagic syndrome (FLHS) in chicken implicating estrogens in the disease progression. Fishes are also used to investigate liver diseases, including models generated by mutation and transgenesis. In conclusion, studies on the roles of estrogens in the non-mammalian oviparous vertebrate liver have contributed enormously to unveil hormone-dependent physiological and physiopathological processes.

Keywords: G protein-coupled estrogen receptor; estrogen receptors; growth hormone; liver diseases; nuclear receptors; oogenesis; sexual dimorphism; vitellogenin; xenoestrogens; yolk

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Cell Rep.: co-auth.: W. Wahli

Cell Rep. 2021 Aug 10;36(6):109501. doi: 10.1016/j.celrep.2021.109501.

GDF15 mediates the metabolic effects of PPARβ/δ by activating AMPK

David Aguilar-Recarte 1Emma Barroso 1Anna Gumà 2Javier Pizarro-Delgado 1Lucía Peña 1Maria Ruart 1Xavier Palomer 1Walter Wahli 3Manuel Vázquez-Carrera 4

Abstract

Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) activates AMP-activated protein kinase (AMPK) and plays a crucial role in glucose and lipid metabolism. Here, we examine whether PPARβ/δ activation effects depend on growth differentiation factor 15 (GDF15), a stress response cytokine that regulates energy metabolism. Pharmacological PPARβ/δ activation increases GDF15 levels and ameliorates glucose intolerance, fatty acid oxidation, endoplasmic reticulum stress, and inflammation, and activates AMPK in HFD-fed mice, whereas these effects are abrogated by the injection of a GDF15 neutralizing antibody and in Gdf15-/- mice. The AMPK-p53 pathway is involved in the PPARβ/δ-mediated increase in GDF15, which in turn activates again AMPK. Consistently, Gdf15-/- mice show reduced AMPK activation in skeletal muscle, whereas GDF15 administration results in AMPK activation in this organ. Collectively, these data reveal a mechanism by which PPARβ/δ activation increases GDF15 levels via AMPK and p53, which in turn mediates the metabolic effects of PPARβ/δ by sustaining AMPK activation.

Keywords: AMPK; GDF15; PPARβ/δ; glucose tolerance; p53.

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Diabetes.: co-auth.: B. Thorens

Diabetes. 2021 Aug 10;db201281. doi: 10.2337/db20-1281. Online ahead of print.

Distinct Molecular Signatures of Clinical Clusters in People with Type 2 Diabetes: an IMIRHAPSODY Study

Roderick C Slieker 1 2Louise A Donnelly 3Hugo Fitipaldi 4Gerard A Bouland 1Giuseppe N Giordano 4Mikael Åkerlund 4Mathias J Gerl 5Emma Ahlqvist 4Ashfaq Ali 6Iulian Dragan 7Petra Elders 8Andreas Festa 9 10Michael K Hansen 11Amber A van der Heijden 8Dina Mansour Aly 4Min Kim 6 12Dmitry Kuznetsov 7Florence Mehl 7Christian Klose 5Kai Simons 5Imre Pavo 9Timothy J Pullen 13 14Tommi Suvitaival 6Asger Wretlind 6Peter Rossing 6 15Valeriya Lyssenko 16 17Cristina Legido Quigley 6 11Leif Groop 4 18Bernard Thorens 19Paul W Franks 4 20Mark Ibberson 7Guy A Rutter 13 21Joline Wj Beulens 2 22Leen M ‘t Hart 23 2 24Ewan R Pearson 25Affiliations expand

Abstract

Type 2 diabetes is a multifactorial disease with multiple underlying aetiologies. To address this heterogeneity a previous study clustered people with diabetes into five diabetes subtypes. The aim of the current study is to investigate the aetiology of these clusters by comparing their molecular signatures. In three independent cohorts, in total 15,940 individuals were clustered based on five clinical characteristics. In a subset, genetic- (N=12828), metabolomic- (N=2945), lipidomic- (N=2593) and proteomic (N=1170) data were obtained in plasma. In each datatype each cluster was compared with the other four clusters as the reference. The insulin resistant cluster showed the most distinct molecular signature, with higher BCAAs, DAG and TAG levels and aberrant protein levels in plasma enriched for proteins in the intracellular PI3K/Akt pathway. The obese cluster showed higher cytokines. A subset of the mild diabetes cluster with high HDL showed the most beneficial molecular profile with opposite effects to those seen in the insulin resistant cluster. This study showed that clustering people with type 2 diabetes can identify underlying molecular mechanisms related to pancreatic islets, liver, and adipose tissue metabolism. This provides novel biological insights into the diverse aetiological processes that would not be evident when type 2 diabetes is viewed as a homogeneous disease.

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Sci Adv.: auth. group Benton, co-auth.: T.Auer and GTF

Sci Adv. 2021 Aug 6;7(32):eabe3745. doi: 10.1126/sciadv.abe3745. Print 2021 Aug.

Olfactory receptor-dependent receptor repression in Drosophila

Kaan Mika 1Steeve Cruchet 1Phing Chian Chai 1Lucia L Prieto-Godino 1Thomas O Auer 1Sylvain Pradervand 1 2 3Richard Benton 4

Free article

Abstract

In olfactory systems across phyla, most sensory neurons express a single olfactory receptor gene selected from a large genomic repertoire. We describe previously unknown receptor gene-dependent mechanisms that ensure singular expression of receptors encoded by a tandem gene array [Ionotropic receptor 75c (Ir75c), Ir75b, and Ir75a, organized 5′ to 3′] in Drosophila melanogaster Transcription from upstream genes in the cluster runs through the coding region of downstream loci and inhibits their expression in cis, most likely via transcriptional interference. Moreover, Ir75c blocks accumulation of other receptor proteins in trans through a protein-dependent, posttranscriptional mechanism. These repression mechanisms operate in endogenous neurons, in conjunction with cell type-specific gene regulatory networks, to ensure unique receptor expression. Our data provide evidence for inter-olfactory receptor regulation in invertebrates and highlight unprecedented, but potentially widespread, mechanisms for ensuring exclusive expression of chemosensory receptors, and other protein families, encoded by tandemly arranged genes.

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Welcome Celso!

My name is Celso Martins, freshly arrived from Portugal.

I initiated my research career during my B.Sc. in Biology (University of Aveiro, Portugal), when I studied the effects of water hardness and alkalinity in a tiny freshwater cladoceran called Daphnia longispina.

However, I felt dragged to even smaller organisms, so I decided to take an M.Sc. in Microbiology ((University of Aveiro and ISCSEM, Portugal), in which I explored the effects that some antimicrobial polymers (won’t bother you with the names) exerted in the human oral microbiome. Then I spent a few months in a clinical diagnostic team performing molecular studies in cancer and prenatal disorders (Labco Porto, Portugal). After this short experience in a clinical environment, all I wanted was to go back to research! Therefore, I joined Professor Cristina Silva Pereira’s team (ITQB NOVA, Portugal), first as a Research Fellow and later as a PhD student.

My PhD focused on the (nasty) effects that pollutants exert in the soil mycobiota and ultimately revealed that the exposure to those pollutants (and their subsequent biodegradation) elicited molecular tradeoffs related to increased pathogenesis in fungi.

I am now delighted to join Vjestica Lab to explore an entirely new world related to the transcriptional events during and after fission yeast zygotic transition.