Myriam Aouadi group
Our lab is interested in the immune system’s contribution to the development of insulin resistance and Type 2 Diabetes (T2D).
The rapidly rising prevalence of T2D over the past several decades has highlighted a pressing need to develop new therapeutics for this metabolic disease. Although obesity is considered a strong risk factor for T2D, several recent experimental and epidemiological studies suggest that some forms of obesity may be benign and not associated with a high risk for diabetes related disorders. This raises the crucial question we are interested in: what are the molecular and cellular mechanisms causing the development of T2D in obese patients?
Striking findings from recently published data have demonstrated that in obese subjects, with similar body mass index values, inflammation of the visceral adipose tissue is strongly associated with insulin resistance. This inflammation is caused by the accumulation of immune cells, including macrophages, in the adipose tissue. Therefore, we asked whether obesity-associated adipose tissue inflammation could contribute to the development of T2D.
To address this question, we used a technology that allows specific manipulation of gene expression in phagocytic cells, including macrophages. This technology is based on small interfering RNA (siRNA) encapsulated within glucan particles derived from baker’s yeast, denoted glucan-encapsulated siRNA particles (GeRPs).
By using intraperitoneal injections, we showed that GeRPs delivered siRNA and silenced genes specifically in macrophages in the adipose tissue of obese mice. Using this technology, we found that knockdown of inflammatory cytokines, such as TNF-α or osteopontin, improved glucose metabolism whereas knockdown of genes involved in lipid storage, such as lipoprotein lipase or CD36 exacerbated glucose intolerance. Therefore, macrophages have a detrimental effect on glucose homeostasis in obese animals but also play a beneficial role by increasing the lipid storage capacity of obese adipose tissue.
The latter finding is particularly relevant since in obese animals and humans the inability of adipose tissue to store excess fat results in ectopic deposition of lipids in non-adipose tissues, such as liver. Fatty liver or non-alcoholic fatty liver disease (NAFLD) is a high risk factor for T2D and often develops into steatohepatitis, which is characterized by inflammation with concurrent fat accumulation in liver. By using intravenous administration, we showed that GeRPs delivered siRNA and silenced genes in liver macrophages, denoted Kupffer cells (KCs) but not in hepatocytes or macrophages within other tissues. Interestingly, we have shown that silencing a master regulator of inflammation, NFκB, in KCs improves insulin sensitivity in obese mice.
In light of these pieces of evidence, we focus our research on unraveling the interactions between immune and metabolic cells to understand how inflammation regulate systemic metabolism and contributes to diseases.
|Myriam Aouadi, PhD, Group leader|
|Emelie Barreby, Research assistant|
Jennifer Jager, Postdoc
I obtained my doctoral degree from the University of Nice-Sophia Antipolis (Nice, France) in 2009. My research focused on the implication of the Tpl2/MAP kinase ERK pathway in adipose tissue inflammation and insulin resistance. In 2010, I pursued my postdoctoral training in Dr. Lazar’s team at the University of Pennsylvania (Philadelphia, USA). I was interested in the epigenomic regulation of gene expression and metabolism. In May 2015, I joined Dr. Aouadi’s group as a senior postdoc researcher to study the molecular regulators of liver function in the context of obesity and diabetes.
Cecilia Morgantini, PhD, Postdoctoral fellow
I trained as a physician in Internal Medicine and Metabolism at the University of Pisa (Italy) under the supervision of Prof. Ele Ferrannini. As a clinical fellow I interacted with patients with diabetes, and during this time I developed the desire to bring the bench to the bedside by working on the physiology of metabolic diseases. I therefore spent two years of my residency program in the Atherosclerosis Research Unit of UCLA, working on high-density-lipoprotein (HDL) functions and ApoA-I mimetic peptides in a mouse model of diabetes. In 2014 I obtained my phD from Scuola Superiore Sant’Anna in Pisa, where I carried on my studies on HDL functions and compositions in the pathogenesis of cardiovascular disease in type 2 diabetes focusing only on human. As part of my PhD program I also joined Lewis’ Lab at the Banting and Best Diabetes Center in Toronto, conducting integrative physiology studies attempting to determine the regulation of intestinal lipoprotein particle production. At the beginning of 2015 I joined, as a postdoc, the laboratory of Dr. Myriam Aouadi where I currently focus on molecular and cellular mechanisms involved in the development of insulin resistance and type 2 diabetes.
Francisco Verdeguer, PhD, Postdoctoral fellow
After graduating in Biology in my hometown at the University of Valencia, I moved to Paris where I obtained my PhD degree at the Pasteur Institute in 2010. Under the supervision of Dr. Marco Pontoglio I identified a new epigenetic role of the transcription factor HNF1b in the onset of Polycystic Kidney Disease. In early 2011, I moved to Pere Puigserver’s laboratory at Dana Farber Cancer Institute/Harvard Medical School in Boston, USA. I have been interested since then in the epigenetic and transcriptional regulation of nutrient sensing and energetic metabolism in the context of obesity and type 2 diabetes. I have finally joined Myriam Aoaudi’s group in early 2016 as a senior postdoc to pursue my interest in metabolic diseases.
Laura Levi, Laboratory technician
I took 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 step was to perform my PhD at Karolinska Institutet by focusing on the connection between chronic infection and cancer development in in vitro and in vivo models. I have been part of Dr. Aouadi’s lab since early 2016. As a research assistant, I provide technical support in the different projects.
Marcela Aparicio, PhD, Postdoctoral fellow
Liver innate immune cells and insulin resistance: the multiple facets of Kupffer cells.
J. Intern. Med. 2016 Aug;280(2):209-20
Lipid storage by adipose tissue macrophages regulates systemic glucose tolerance.
Am. J. Physiol. Endocrinol. Metab. 2014 Aug;307(4):E374-83
Local proliferation of macrophages contributes to obesity-associated adipose tissue inflammation.
Cell Metab. 2014 Jan;19(1):162-71
Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes.
Nat. Med. 2013 Sep;19(9):1132-40
Gene silencing in adipose tissue macrophages regulates whole-body metabolism in obese mice.
Proc. Natl. Acad. Sci. U.S.A. 2013 May;110(20):8278-83
Insulin signalling mechanisms for triacylglycerol storage.
Diabetologia 2013 May;56(5):949-64
Glucan particles for selective delivery of siRNA to phagocytic cells in mice.
Biochem. J. 2011 Jun;436(2):351-62
Coronin 2A mediates actin-dependent de-repression of inflammatory response genes.
Nature 2011 Feb;470(7334):414-8
RNAi-based therapeutic strategies for metabolic disease.
Nat Rev Endocrinol 2011 Apr;7(8):473-84
Orally delivered siRNA targeting macrophage Map4k4 suppresses systemic inflammation.
Nature 2009 Apr;458(7242):1180-4