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Myriam Aouadi group

Myriam Aouadi group
Myriam Aouadi group Photo: Emma Karlsson

Research focus

Since the discovery of macrophages in adipose tissue, many laboratories have focused their effort on understanding the contribution of these immune cells to metabolic diseases. Despite great progress in characterizing obesity as a state of low-grade inflammation, very little is known about the multiple phenotypes and functions of macrophages in metabolic tissues. The lack of methods to carefully investigate cell-to-cell variability in macrophage phenotype and to manipulate gene expression in a cell-specific manner has delayed answering these crucial questions. Our lab takes advantage of sophisticated methods to investigate macrophage subpopulations and their function in obesity-associated metabolic complications.

Projects

Study the mechanism whereby factors produced by liver macrophages regulate insulin sensitivity.

We have recently discovered that mice fed a high fat diet (HFD) become rapidly obese and insulin resistant independently of liver inflammation, which was thought to be an important driver in obesity-induced insulin resistance. On the other hand, depletion studies have shown that removing liver macrophages (LMs) prevents insulin resistance induced by obesity, suggesting an important role of LMs in the regulation of insulin sensitivity. Using RNAseq, we identified genes specifically expressed by liver macrophages, whose expression significantly increases with obesity and insulin resistance. We then took advantage of a powerful and unique tool, called glucan encapsulated RNAi particles (GeRP), that deliver siRNA and silence genes specifically in macrophages in vivo.

This technology is based on small interfering RNA (siRNA) encapsulated within glucan particles derived from baker’s yeast. By using intraperitoneal injections, we showed that GeRPs delivered siRNA and silenced genes specifically in macrophages in the adipose tissue of obese mice. However, by using intravenous administration, we showed that GeRPs delivered siRNA and silenced genes in LMs but not in hepatocytes or macrophages within other tissues.

Using this unique method, we found that silencing genes of interest specifically in LMs improves insulin sensitivity in obese mice. This project has so far confirmed that liver macrophages can play a role in the regulation of insulin sensitivity independantly of inflammation. This opened a new avenue towards the discovery of the multiple roles of immune cells other than only the inflammatory response.

Identify distinct phenotypes and functions of macrophages in liver and adipose tissue.

Macrophages are able to modulate their properties upon contact with different cell types as well as extracellular matrix. Their intrinsic heterogeneity during differentiation is compounded by reciprocal interactions with neighbouring cells, including other macrophages. In many different tissues, macrophages can occupy different anatomical niches and perform specialized functions even within the same organ. Emerging data suggest that macrophages acquire specialized functions, which are tailored for assisting local homeostasis, within each particular organ.

We use scRNAseq, metabolomics, flow cytometry, CytOF and in situ transcriptomic to study the heterogeneity of resident macrophage in liver and adipose tissue in health and metabolic disease.

Decoding the phenotype of macrophages through the study of non-coding RNA

We aim at identifying dysregulated genes but also non-coding RNAs such as microRNAs, enhancer RNAs, and long non-coding RNAs which have recently emerged as important regulators of gene expression, and which expression have been associated with several diseases.

Using the Global Run-On sequencing (GRO-seq) to directly measure rates of nascent transcription genome-wide, we propose to identify all transcript, genes and non-coding RNAs dysregulated in LMs in obesity that could be involved in the development of insulin resistance.

We are especially interested in enhancers, which are regions of DNA important for the regulation of genes transcription, and can be transcribed as non-coding RNAs called enhancer-derived RNAs (eRNAs).

The eRNAs can regulate the expression of the nearby gene, and have also been shown to be superior markers for active enhancers because of their small size and high dynamic ranges.

The mining of the GRO-seq data for eRNAs transcription to map functional enhancers, combined with genome-wide de novo motif analysis performed at sites of eRNAs dysregulation in LMs from obese and insulin resistant mice compared to lean mice, will allow us to identify the transcription factor(s) that could be involved in gene dysregulation in LMs in obesity.

Funding

  • Integrated Cardio Metabolic Center/Astrazeneca start-up fund (2015-2020).
  • Swedish Research Council project grant (2020-2025).
  • SRP Diabetes at Karolinska Institutet (2018-2020).
  • Novonordisk Foundation through the Tripartite Immuno-metabolism Consortium (2016-2020).
  • Novonordisk Foundation project grant and exploratory pre-seed grant (2019-2020)
  • Karolinska Institutet consolidator grant (2020-2025)
  • European Research Council consolidator grant (2020-2025)

Members

Myriam Aouadi

PhD, Group leader

I received my PhD in June 2006 from the University of Nice Sophia-Antipolis, France, in the laboratory of Yannick Le Marchand-Brustel. My worked focussed on the role of MAPK pathways in the commitment of embryonic stem cells in different lineages. I found that p38MAPK is an important player in the early steps of neurogenesis and myogenesis, while it is required for the late stages of adipogenesis. In 2006, I joined the laboratory of Michael Czech at the University of Massachusetts to work on the emerging field of immunometabolism, that investigates the interactions between immune and metabolic cells. During my postdoctoral studies, I developed a method to deliver siRNA specifically to macrophages in vivo. This unique technology allows the study of particular factors expressed by macrophages specifically. In 2009, I became assistant professor at the University of Massachusetts and used this novel technology to show that while macrophages in the adipose tissue could be detrimental to insulin sensitivity they could be beneficial as well.

I started my laboratory at the Integrated Cardio-Metabolic Center at the Karolinska institute in 2015. My lab investigates the multiple roles and heterogeneity of liver and adipose tissue macrophages in metabolic diseases.

Team work, curiosity, passion and enthusiasm are the important qualities that I am looking for and found in my lab members.

Emelie Barreby

PhD student

After obtaining my Master’s degree in Biomedicine at Karolinska Institutet I joined the lab of Myriam Aouadi in 2015, working as a research technician. My interest was to gain experience from working in a lab using state of the art techniques such as RNA-sequencing and targeted gene silencing. During this experience, inspired by Myriam and her research group, I decided to pursue a PhD and register for the doctoral program in 2017. Today, my work involves investigating the phenotype of liver macrophages to better understand their role during the pathogenesis of metabolic diseases by using techniques such as flow cytometry, CyTOF and single cell RNA sequencing.

As part of my doctoral training I also have the benefit of working side-by-side with bioinformaticians in the center to get trained in bioinformatics. In this way, I have had the opportunity to gain knowledge of the whole process from isolating cells and preparing RNA sequencing libraries to actually analyzing the sequencing data myself.

Cecilia Morgantini

MD, PhD, Postdoctoral fellow

Since the beginning of my medical training I had the desire to help people and the passion to understand the causes of their diseases. After a PhD in clinical physiology, driven by the idea to understand more about the molecular mechanism behind metabolic disorders, I joined the laboratory of Dr. Aouadi in 2015. In Aouadi’s lab using unique and sophisticated techniques allowing analysis and manipulation of gene expression at cellular level, I am studying the interaction between immune and metabolic cells. I strongly believe that combining basic research with clinical practice will improve the quality of patients’ care and will help to identify new customized treatments.

Laura Levi

Lab manager, PhD

I obtained my masters in industrial biotechnology at the University Federico II of Naples. For two years, I worked as a technician at the research center of Novartis Vaccines & Diagnostics in Siena. Next I enrolled in graduate school at Karolinska Institutet; my PhD focused on the connection between chronic infection and cancer development in vitro and in vivo. I joined Dr. Aouadi’s lab in January 2016 and since then I had the opportunity to work in a very dynamic and enthusiastic group. We are always developing unique and novel strategies to understand metabolic diseases. Our goal is to contribute to improving the patients’ quality of life.

As a lab manager, I provide technical and scientific support in all the different projects.

André Sulen

Postdoc, PhD

I graduated as a PhD from the University of Bergen in 2016. My project evaluated signal transduction in blood leukocytes as biomarkers for environmental stress exerted on the healthy population. It is well known that environmental cues regulate metabolism by modulating monocyte and macrophage transcriptional programs. In Myriam Aouadi´s group we use cutting-edge single-cell technologies, such as single-cell RNAseq and CyTOF, to better characterize the role of immune cells in metabolic tissues during obesity and development of type 2 diabetes. More specifically, my project aims to characterize macrophages in adipose tissue. Our objective is to increase our understanding of metabolic disease by using unbiased approaches that allow the discovery of new biological concepts and eventually novel therapeutic strategies to tackle diabetes.

Valerio Azzimato

Postdoc

I obtained my PhD in Pharmacological Sciences from Università Statale di Milano in 2014. My research project focused on epigenetic mechanisms regulating intracellular communication in cardiovascular scenario. In 2015 I joined KI as a junior postdoc in order to investigate the interplay between DNA methylation, molecular pathways and metabolism in heart diseases. In February 2018, I joined Dr. Aouadi's group in order to study the role(s) of liver macrophages in the regulation of systemic metabolism. In this lab I have the opportunity to use state-of-the-art techniques to investigate the crosstalk between immune and metabolic cells. My aim is to better understand the molecular circuits responsible for the development of metabolic diseases.

Marcela Aparicio-Vergara, PhD, former postdoctoral fellow, now research manager of Nutrition & Health at NutriLeads, Netherlands.

Francisco Verdeguer, PhD, former postdoctoral fellow, now group leader at the University of Zurich.

Jennifer Jagger PhD, former postdoctoral fellow, now Principal investigator at the University of Nice, France.

Joost Willebrords PhD, former postdoctoral fellow, now R&D and Innovation Consultant at Leyton, Belgium.

Connie Xu, former research assistant, now molecular biologist at CareDx, Inc. Stockholm, Sweden

Aouadi Lab at Twitter

Selected publications

Liver macrophages regulate systemic metabolism through non-inflammatory factors
Nature Metabolism Published: 25 March 2019

Macrophage heterogeneity and energy metabolism.
Verdeguer F, Aouadi M
Exp. Cell Res. 2017 11;360(1):35-40

Liver innate immune cells and insulin resistance: the multiple facets of Kupffer cells.
Jager J, Aparicio-Vergara M, Aouadi M
J. Intern. Med. 2016 08;280(2):209-20

Lipid storage by adipose tissue macrophages regulates systemic glucose tolerance.
Aouadi M, Vangala P, Yawe JC, Tencerova M, Nicoloro SM, Cohen JL, et al
Am. J. Physiol. Endocrinol. Metab. 2014 Aug;307(4):E374-83

Local proliferation of macrophages contributes to obesity-associated adipose tissue inflammation.
Amano SU, Cohen JL, Vangala P, Tencerova M, Nicoloro SM, Yawe JC, et al
Cell Metab. 2014 Jan;19(1):162-171

Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes.
Jourdan T, Godlewski G, Cinar R, Bertola A, Szanda G, Liu J, et al
Nat. Med. 2013 Sep;19(9):1132-40

Gene silencing in adipose tissue macrophages regulates whole-body metabolism in obese mice.
Aouadi M, Tencerova M, Vangala P, Yawe JC, Nicoloro SM, Amano SU, et al
Proc. Natl. Acad. Sci. U.S.A. 2013 May;110(20):8278-83

Insulin signalling mechanisms for triacylglycerol storage.
Czech MP, Tencerova M, Pedersen DJ, Aouadi M
Diabetologia 2013 May;56(5):949-64

Glucan particles for selective delivery of siRNA to phagocytic cells in mice.
Tesz GJ, Aouadi M, Prot M, Nicoloro SM, Boutet E, Amano SU, et al
Biochem. J. 2011 Jun;436(2):351-62

Coronin 2A mediates actin-dependent de-repression of inflammatory response genes.
Huang W, Ghisletti S, Saijo K, Gandhi M, Aouadi M, Tesz GJ, et al
Nature 2011 Feb;470(7334):414-8

RNAi-based therapeutic strategies for metabolic disease.
Czech MP, Aouadi M, Tesz GJ
Nat Rev Endocrinol 2011 Apr;7(8):473-84

Orally delivered siRNA targeting macrophage Map4k4 suppresses systemic inflammation.
Aouadi M, Tesz GJ, Nicoloro SM, Wang M, Chouinard M, Soto E, et al
Nature 2009 Apr;458(7242):1180-4