LIVE VIRTUAL MEETING

Speakers

Pr. Myriam Aouadi
Stockholm,
Sweden
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Day 1 - 5.30PM to 6.00PM

Macrophages in liver metabolism

Despitegreat progress in characterizing obesity as a state of low-gradeinflammation, very little is known about the multiple phenotypes andfunctions of macrophages in metabolic tissues, such as liver.
Macrophagesare able to modulate their properties upon contact with differentcell types as well as extracellular matrix. Their intrinsicheterogeneity during differentiation is compounded by reciprocalinteractions with neighbouring cells, including other macrophages. Inmany different tissues, macrophages can occupy different anatomicalniches 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 eachparticular organ. Our lab uses a system biology approach toinvestigate macrophage subpopulations and their function inobesity-associated metabolic complications. We have recentlydiscovered that macrophages in the liver directly regulate metabolismindependently of their inflammatory status in obese animals andpatients. Our work shows that liver macrophages express factors thatcan affect the response of liver to stress, includinghyperinsulinemia, excessive lipid accumulation and oxidative stress.Therefore, macrophages represent a promising therapeutic target formetabolic and liver diseases.

Short biography

MyriamAouadi, Assistant Professor, Integrated Cardio Metabolic Center, Department of Medicine, Karolinska Institutet, Sweden.

Previous Positions
2012 – 2014 Assistant Professor, University of Massachusetts, Department of Molecular Medicine, USA
2009 – 2012 Research Assistant Professor, University of Massachusetts, Department of Molecular Medicine, USA

Education
2006 – 2009 Postdoctoral Fellow, University of Massachusetts, Department of Molecular Medicine, USA, Postdoctoral Mentor: Dr. Michael P. Czech
2006 PhD. Title: “Role of ERK and p38MAPK in neuron, cardiomyocyte and adipocyte differentiation”, University of Nice Sophia-Antipolis, Nice, France. Suma Cum Laude, PhD Supervisors: Frederic Bost and Yannick Le Marchand-Brustel
2002 Master of Science, University of Nice Sophia-Antipolis, Nice, France. Awarded with honors 

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.