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Metabolic homeostasis through physiological stimulation of beige fat development

English title Metabolic homeostasis through physiological stimulation of beige fat development
Applicant Trajkovski Mirko
Number 172906
Funding scheme SNSF Professorships
Research institution Département de physiologie cellulaire et métabolisme Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Physiology : other topics
Start/End 01.08.2017 - 31.07.2019
Approved amount 774'701.00
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All Disciplines (7)

Discipline
Physiology : other topics
Endocrinology
Medical Microbiology
Immunology, Immunopathology
Nutritional Research, Vitaminology
Pathophysiology
Metabolic Disorders

Keywords (9)

Lineage tracing; Caloric restriction; Beige fat; Metabolism; Adipocytes; Diabetes; Microbiota; Obesity; Brown and white adipose tissue

Lay Summary (French)

Lead
L’homéostasie métabolique à travers le développement du tissu adipeux beigeLe but principal de notre recherche est axé sur des approches rationnelles qui pourraient permettre le développement de stratégies dans le traitement de la dyslipidémie, le diabète et l’obésité.
Lay summary

L’obésité est une maladie métabolique qui atteint aujourd’hui des proportions épidémiques. Elle est associée avec une diminution de la sensibilité à l’insuline, au diabète, une dyslipidémie (déséquilibre de la quantité de lipides), de l’athérosclérose, etc. Le tissu adipeux blanc a pour rôle de stocker l’excès d’énergie sous la forme de graisse, c’est aussi un important régulateur de l’homéostasie énergétique globale. Le tissu adipeux brun, lui, a pour fonction principale de produire de la chaleur. Il est activé par l’exposition au froid, comme défense naturelle contre l’hypothermie. Des cellules de type brune peuvent aussi apparaître dans le tissu adipeux blanc (elles s’appellent alors les cellules beiges) dans un processus nommé brunissement. L’augmentation du tissu adipeux brun est accompagné d’une augmentation de la dépense énergétique. Ceci suggère que la manipulation des réserves de graisse pourrait être une cible thérapeutique importante dans le contexte de l’obésité.

Par ailleurs, nous vivons en symbiose avec un nombre important de bactéries. Elles peuplent notamment nos intestins et se définissent alors comme le microbiote intestinal. Des changements dans la composition de ce microbiote intestinal sont associés à de nombreux processus patho-physiologiques. Notre laboratoire a récemment décrit que le brunissement du tissu adipeux blanc est en partie lié à des changements dans la composition du microbiote intestinal. Nous avons découvert que la restriction calorique est également un important facteur physiologique stimulant le brunissement. Avec la thématique de recherche que nous proposons nous allons mettre en évidence l’importance du microbiote intestinal dans la régulation du brunissement après différentes stimulations et étudier l’implication du système immunitaire dans ce processus. Nous croyons que notre recherche pourrait mener au développement de nouvelles stratégies pour le traitement de la dyslipidémie, du diabète et de l’obésité.

Direct link to Lay Summary Last update: 24.02.2017

Responsible applicant and co-applicants

Employees

Publications

Publication
Microbiota guides insulin trafficking in beta cells.
Trajkovski Mirko, Stojanovic Ozren (2019), Microbiota guides insulin trafficking in beta cells., in Cell research, x.
Functional Gut Microbiota Remodeling Contributes to the Caloric Restriction-Induced Metabolic Improvements
Trajkovski Mirko (2018), Functional Gut Microbiota Remodeling Contributes to the Caloric Restriction-Induced Metabolic Improvements, in Cell Metabolism, 28(6), 907-921.
Common traits between the beige fat-inducing stimuli
Stojanović Ozren, Kieser Silas, Trajkovski Mirko (2018), Common traits between the beige fat-inducing stimuli, in Current Opinion in Cell Biology, 55, 67-73.
Hepatic protein tyrosine phosphatase receptor gamma links obesity-induced inflammation to insulin resistance
Brenachot Xavier, Ramadori Giorgio, Ioris Rafael M., Veyrat-Durebex Christelle, Altirriba Jordi, Aras Ebru, Ljubicic Sanda, Kohno Daisuke, Fabbiano Salvatore, Clement Sophie, Goossens Nicolas, Trajkovski Mirko, Harroch Sheila, Negro Francesco, Coppari Roberto (2017), Hepatic protein tyrosine phosphatase receptor gamma links obesity-induced inflammation to insulin resistance, in Nature Communications, 8(1), 1820-1820.
The Immune System Bridges the Gut Microbiota with Systemic Energy Homeostasis: Focus on TLRs, Mucosal Barrier, and SCFAs
Spiljar Martina, Merkler Doron, Trajkovski Mirko (2017), The Immune System Bridges the Gut Microbiota with Systemic Energy Homeostasis: Focus on TLRs, Mucosal Barrier, and SCFAs, in Frontiers in Immunology, 8, x-x.
Host–Microbiota Mutualism in Metabolic Diseases
Fabbiano Salvatore, Suárez-Zamorano Nicolas, Trajkovski Mirko (2017), Host–Microbiota Mutualism in Metabolic Diseases, in Frontiers in Endocrinology, 8, x-x.
Bone Regulates Browning and Energy Metabolism Through Mature Osteoblast/Osteocyte PPARγ Expression
Brun Julia, Berthou Flavien, Trajkovski Mirko, Maechler Pierre, Foti Michanlegelo, Bonnet Nicolas (2017), Bone Regulates Browning and Energy Metabolism Through Mature Osteoblast/Osteocyte PPARγ Expression, in Diabetes, 66(10), 2541-2554.
Regulation of body weight and energy homeostasis by neuronal cell adhesion molecule 1
Rathjen Thomas, Yan Xin, Kononenko Natalia L, Ku Min-Chi, Song Kun, Ferrarese Leiron, Tarallo Valentina, Puchkov Dmytro, Kochlamazashvili Gaga, Brachs Sebastian, Varela Luis, Szigeti-Buck Klara, Yi Chun-Xia, Schriever Sonja C, Tattikota Sudhir Gopal, Carlo Anne Sophie, Moroni Mirko, Siemens Jan, Heuser Arnd, van der Weyden Louise, Birkenfeld Andreas L, Niendorf Thoralf, Poulet James F A, Horvath Tamas L, Trajkovski Mirko, HauckeV, PoyMN (2017), Regulation of body weight and energy homeostasis by neuronal cell adhesion molecule 1, in Nature Neuroscience, 20(8), 1096-1103.

Collaboration

Group / person Country
Types of collaboration
University of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
- Exchange of personnel
ETH Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Max Delbruck Zentrum Berlin Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Academic Medical Center (AMC), Amsterdam Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
UT Sourthwestern United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
University of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
University of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
AstraZeneca Sweden (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Industry/business/other use-inspired collaboration
ETH Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
The Svedberg seminar 2019 Talk 06.05.2019 Uppsala, Sweden Trajkovski Mirko;
Johns Hopkins All Children's Hospital, Institute for Fundamental Biomedical Research (IFBR) Faculty Seminar Series Talk 05.04.2019 St. Petersburg, United States of America Trajkovski Mirko;
Type-2 Immunity Meeting Talk 12.06.2018 Bern, Switzerland Trajkovski Mirko;
European Calcified Society Conference Talk 26.05.2018 Valencia, Spain Trajkovski Mirko;
Chinese Society for Lipid Metabolism and Bioenergetics - Annual Conference Talk 20.04.2018 Shanghai, China Trajkovski Mirko;
Keystone Symposia Talk 04.03.2018 Banff, Canada Trajkovski Mirko;
Swiss Atherosclerosis Association (AGLA) Meeting Talk 09.01.2018 Bern, Switzerland Trajkovski Mirko;
Annual meeting of the Korean Society for the Study of Obesity Talk 18.08.2017 Seoul, Korean Republic (South Korea) Trajkovski Mirko;


Communication with the public

Communication Title Media Place Year
Media relations: print media, online media Tarmfloran viktig för att öka metabola hälsan Doktorn International 2019
Media relations: radio, television Des molécules qui imitent la restriction calorique RTS Rhaeto-Romanic Switzerland 2018
Media relations: print media, online media Eating less is healthy thanks to gut bacteria SNF press release Italian-speaking Switzerland Western Switzerland Rhaeto-Romanic Switzerland International German-speaking Switzerland 2018
Media relations: print media, online media Studie zeigt: Kalorienarme Ernährung ist gesund – dank Darmbakterien Gourmetnews International 2018

Awards

Title Year
Best doctoral thesis at the Faculty of Medicine 2019 2019

Associated projects

Number Title Start Funding scheme
144886 MicroRNAs role in brown and white adipose tissue differentiation and function 01.08.2013 SNSF Professorships

Abstract

Brown adipose tissue catabolizes lipids and sugars to produce heat. Brown fat cells also emerge in the subcutaneous white fat (known as “beige” cells) a process referred to as browning. Increased beige fat development promotes energy expenditure, improves insulin sensitivity and is associated with a lean and healthy phenotype. Browning appears consequent to physiological stimuli such as cold exposure or endurance exercise, and interventional stimuli such as microbiota depletion and Roux-en-Y Gastric Bypass Weight-Loss Surgery. It remains unknown what could be the common feature and possible common mechanism between the physiological and interventional conditions that promote browning, and what is the origin of the newly developed beige cells during these various stimuli. A characteristic of all these browning stimuli is the negative energy balance: the energy uptake is lower than the energy expenditure resulting in weight loss primarily due to the decreased fat mass.Caloric restriction (CR) is a classical example of energy scarcity. CR up to 40% of nutritious diet intake without malnutrition extends healthy lifespan from yeast to mammals, delays the onset of multiple age-associated diseases and improves metabolic health. The intestinal microbiota co-develops with the host and influences the whole-body metabolism by affecting energy balance. According to our recent data, CR stimulates development of functional beige fat within the subcutaneous and visceral adipose tissue, contributing to decreased white fat and adipocyte size. We also showed that cold-induced shift of the microbiota composition alone is sufficient to induce tolerance to cold, improved insulin sensitivity, increased energy expenditure as well as lower fat content, and this effect is at least in part mediated by browning of the white fat depots.With the proposed research we aim at identifying and characterizing the upstream mechanisms leading to browning following CR. The microbiota transplantation experiments would demonstrate whether the browning induced upon CR is mediated by the changes in the gut bacterial populations. We will uncover bacterial strains that are likely to play a role in the beige fat development. Thus characterizing them, and investigating their importance would suggest further means of promoting the beige fat development. Moreover, we will uncover the origin of the beige fat during caloric restriction and microbiota depletion, and we will provide new insights to the beige fat development during these browning stimuli. Finally, we believe that this project would provide at least one direct mechanistic link between the microbiota changes and the beige fat development and would also be an important resource for future studies on the metagenomic changes induced by caloric restriction and cold exposure. Together, we expect to establish and characterize a novel axis that leads to beige fat development, and provide mechanistic and metagenomic explanation for its appearance. We believe that manipulating the gut microbiota and exploiting the mechanistic link to the beige fat induction revealed by the proposed study would be of conceptual importance for our understanding of the beige fat development that could lead to development of novel therapeutic approaches for improving insulin sensitivity and reducing the obesity-induced diabetes onset.
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