DS0403 - Exploration des systèmes et organes leur fonctionnement normal et pathologique : physiologie, physiopathologie, vieillissement

FGF21 links hepatic ChREBP and PPARa to systemic glucose control – Hepatokind

Submission summary

In the face of urbanization, surplus energy intake, sedentary habits and obesity, type 2 diabetes has developed into a major health concern worldwide. Non-alcoholic fatty liver disease (NAFLD), the hepatic hallmark of the metabolic syndrome, is also gaining increasing recognition as a component of the obesity epidemic worldwide. The spectrum of NAFLD ranges from simple fatty liver (hepatic steatosis), with benign prognosis, to a potentially progressive form, non-alcoholic steatohepatitis (NASH), which may lead to liver fibrosis, cirrhosis and hepatocellular carcinomas (HCC), resulting in increased mortality. No efficient therapies are currently available. In addition, the molecular mechanisms underlying fatty liver progression are still poorly understood. In this context, the search for novel therapeutic targets to prevent and/or treat metabolic-related disorders, such NAFLD/NASH, has become a priority. The liver is emerging as a central regulator of whole body energy homeostasis. Hepatokines are liver-derived proteins which have recently emerged as attractive targets for the development of novel type 2 diabetes treatments. FGF21 (Fibroblast growth factor 21), a metabolic hormone predominantly produced by the liver, represents an attractive therapeutic agent for obesity-related medical conditions. Several studies results recently revealed that FGF21 is bioactive in humans and suggest that FGF21-based therapies may be effective for the treatment of selected metabolic disorders. Therefore, it seems very important to better understand the regulation of this protein that shows such beneficial effects.

Classically observed to be up regulated during fasting by the nuclear receptor peroxisome proliferator-activated receptor (PPARa), new developments have demonstrated that FGF21 is also up regulated in hepatocytes stimulated by high glucose and suggesting an unexpected role for FGF21 in response to glucose overload and/or refeeding. In this context, a better understanding of FGF21 regulation and cellular actions is needed. The Hepato-Kind project includes two major aims involving efficient teamwork, sharing of unique tools, techniques and scientific expertise. The objectives are: i) to provide a better understanding of the molecular control of FGF21 by transcription factors ChREBP (Carbohydrate Responsive Element Binding Protein) and PPARa (independent and/or synergistic) in the liver under physiological and pathophysiological conditions; ii) to determine the cellular basis of FGF21 beneficial action in peripheral tissues (skeletal muscles, white and brown adipose tissue) and in pancreatic ß-cells using unique and novel combinational approaches (cell-specific knockouts, molecular and pharmacological approaches). In particular, we will fully characterize the phenotype of mice deficient for G6Pase (glucose 6-phosphatase), a key enzyme of glucose metabolism. Indeed, this model shows high level of circulating FGF21 and is protected from type 2 diabetes. In this model, we will determine the importance of FGF21 to the beneficial phenotype observed and the control of FGF21 by ChREBP and /or PPARa.
Lastly, our project relies on the use of highly novel and innovative pre-clinical models of all stages of NAFLDs. Therefore we will use these models in order to identify new hepatokines and/or possible biomarkers that may be relevant for the prevention of the most severe forms of NAFLDs.

Project coordination

Catherine POSTIC (Institut National de la Santé et de la Recherche Médicale)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


INSERM Institut National de la Santé et de la Recherche Médicale
U855 Nutrition et cerveau

Help of the ANR 480,757 euros
Beginning and duration of the scientific project: September 2015 - 48 Months

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