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Fibroblast Growth Factor 21 (FGF21) is an hepatokine, a liver-derived hormone produced by hepatocytes. FGF21 controls a broad range of endo-crine responses involved in the control of growth, fertility and longevity. The understanding of FGF21 biology is important for animal health. The host laboratory has provided recent evidence that hepatocyte FGF21 expression is strongly induced in response to fasting and in response to glu-cose overload, two contrasted metabolic signals. More specifically, the host lab has provided evidence that in both cases FGF21 expression is under the specific control of the Peroxisome-Proliferator Activated Receptor alpha (PPARalpha). This transcription factor of the nuclear receptor superfamily is very important for the adaptation to starvation. It is highly expressed in the hepatoyctes where it controls the expression of thousands of genes. These genes are mostly involved in the catabolism of fatty acids and the production of ketone bodies. Altogether, data from the host laboratory show that PPARalpha is a pioneering transcription factor required for the control of FGF21 and is critical for ketogenesis. Both caloric restriction and ketone bodies are well-known to promote animal health in vivo. Therefore, the aim of my project is to investigate whether the PPARalpha-FGF21 axis that determines the acute response to starvation is also involved in the response to caloric restriction (daily reduction in caloric intake) and to ketogenic diet (high fat, low carbohydrates). For this, the genetic mouse model that lacks PPARalpha in hepatocytes will be used to investigate whether hepatocyte PPARalpha and liver-derived FGF21 are required for the adaptation to caloric restriction and to ketogenic diet.
I have obtained a Ph.D. in physiology from the University of Toulouse (France) studying the signaling cascades underlying atherosclerosis in an INSERM laboratory. During this work I created and studied transgenic mouse models of atherosclerosis and PI3Kγ deficiency and investigated in vitro the specific role of the PI3Kγ in smooth muscle cells functions. After a one-year interruption of my career because of maternity leave, I decided to join the laboratory of Dr. Pshezhetsky in the Research Center of the CHU Sainte-Justine in Montreal as a postdoctoral fellow to perform research at the cutting edge of sialoglycobiology and metabolism. The aim of my project was to understand the role of sialylation and desialylation of insulin receptor in regulation of insulin signaling. In addition to my main research I was involved in several other projects, including a collaboration with my Ph. D. laboratory as well as a study of sialidases in the development of atherosclerosis. This international experience was a chance to work with new techniques and animal models as well as to have access to clinical data and samples from human patients. When back to France, I joined Dr Laffargue’s team in I2MC (Toulouse) work on molecular mechanisms involved in intraplaque angiogenesis. This year I got the opportunity to integrate INRA and the team of Dr Guillou as an AgreenSkills fellow to gain further experience in the field of metabolism and lipids. My project aims at questioning the role of hepatocyte PPARαFGF21 axis in the metabolic adaptation to caloric restriction and ketogenic diet, two nutritional sates having a positive impact on animal health and lifespan.
Guo, TL, Datwyler, P, Demina, E, Richards, MR, Ge, P, Zou, CX, Zheng, RX, Fougerat, A, Pshezhetsky, AV, Ernst, B; Cairo, CW, 2018. Selective Inhibitors of Human Neuraminidase 3. Journal of Medicinal Chemistry, 61(5): 1990-2008.
Gayral S, Garnotel R, Castaing-Berthou A, Blaise S, Fougerat, A, Berge E, Montheil A, Malet N, Wymann MP, Maurice P, Debelle L, Martiny L, Martinez LO, Pshezhetsky AV, Duca L, Laffargue M., 2014. Elastin-derived peptides potentiate atherosclerosis through the immune Neu1-PI3Kγ pathway. Cardiovascular Research, 102(1):118-27.
Dridi L, Seyrantepe V, Fougerat A, Pan X, Bonneil E, Thibault P, Moreau A, Mitchell GA, Heveker N, Cairo CW, Issad T, Hinek A, Pshezhetsky AV., 2013. Positive regulation of insulin signaling by neuraminidase 1. Diabetes 62(7): 2338-46.
Fougerat A, Smirnova N, Gayral S, Malet N, Hirsch E, Wymann MP, Perret B, Marinez LO, Douillon M, Laffargue M., 2012. Determinant role of phosphoinositide 3-kinase γ in MCP1-mediated amplification of PDGF-induced aortic smooth muscle cells migration. British Journal of Pharmacology, 166(5): 1643-53.
Fougerat A., Gayral S., et al., 2008. Genetic and pharmacological targeting of phosphoinositide 3-kinase γ reduces atherosclerosis and favors plaque stability by modulating inflammatory processes. Circulation, 117(10):1310 7.