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Study the functions of the hepatic sympathetic nerve and the receptor Adrb3 in liver-mediated adaptive thermogenesis.

Periodic Reporting for period 1 - Hepatic Thermogenesi (Study the functions of the hepatic sympathetic nerve and the receptor Adrb3 in liver-mediated adaptive thermogenesis.)

Reporting period: 2019-08-01 to 2021-07-31

The global epidemic of obesity is related to an unbalanced energy intake. Indeed, obesity results when the intake of energy exceeds that which is expended with the resultant storage of the excess energy as fat. Thermogenesis, the metabolic expenditure of energy as heat, is the primary way in which mammals lose dietarily-derived energy and some evidence suggests that certain obese humans may have defective thermogenesis. In small mammals, like rodents, the primary site of thermogenesis is thought to be in brown adipose tissue, a modified adipose tissue specialized in lipid burning as opposed to the lipid-storing function of white adipose tissue. Unfortunately, the activation of thermogenesis in human adipose tissues as a therapeutic approach to fight obesity proved to be largely disappointing. Among the probable causes of discrepancy with animal research, one should list the possible differences in mechanisms regulating thermogenesis in humans and rodents. With this in mind, this proposal intended to demonstrate the existence of a novel site of heat production and energy expenditure in the liver with the hope that this hepatic thermogenesis could be used in humans to treat various metabolic disorders.
The objectives of this Marie Skłodowska Curie Action (MSCA) were to (a) demonstrate the existence of a novel and liver-based form of thermogenesis; (b) determine the molecular mechanism underlying this hepatic heat production; (c) study the regulation of hepatic thermogenesis by the hepatic sympathetic nerve at the anatomical level and by the adrenergic receptor Adrb3 at the molecular level, and (d) translate these findings to humans by focusing on their relevance for the treatment of non-alcoholic fatty liver (NAFLD). With funding from the European Commission, the Fellow carrying this research was able not only to demonstrate the existence of heat production in the liver but also to study its mechanisms of regulation. In particular, the Fellow could demonstrate the importance of the sympathetic nervous system, the fight-or-flight response system of our bodies, to turn on hepatic thermogenesis. To disseminate these two results, the two following manuscripts have been drafted and are currently being reviewed and refined:

Demagny H., Bresciani N., Sun Y., Pontanari F., Schoonjans K., Infrared-based thermal evidence of hepatic thermogenesis (under development)

Demagny H., Sun Y., Pontanari F., Schoonjans K., Control of hepatic thermogenesis by the sympathetic nervous system – axis (under development)

For the exploitation of the results, the demonstration that the sympathetic nervous system controls hepatis thermogenesis opens the possibility to develop liver-specific sympathetic mimicking compounds to trigger heat production, and thus energy expenditure, in the liver. The fellow has secured a collaboration with a Californian biotech company to exploit these results. The proof-of-concept work is currently on-going.
Homeothermy has been studied for decades in different species but adaptive thermogenesis has regained new interest in the last 10 years because of the urge to find novel therapeutic approaches to increase energy expenditure and limit the worldwide epidemic of obesity. This project proposed to tackle an old scientific question with an innovative hypothesis and to study it by applying cutting-edge technologies developed from other scientific fields, namely physics and chemistry. Using both infrared-based thermography and miniaturized thermosensors, we demonstrated that the liver is a site of heat production in mice. We further established that the liver is required for adaptive thermogenesis. For this purpose, we insulted the integrity of the liver with three different approaches (surgical, chemical and nutritional) and showed that mice cannot keep their core body temperature without a functioning liver. Finally, we undertook a molecular dissection of the hepatic heat production using an unbiased OMICs approach and were able to demonstrate an involvement of the choline catabolic pathway in hepatic thermogenesis. The impacts of this project are numerous ranging from a paradigm shift in our fundamental conception of thermogenesis, which does not appear to be restricted to brown adipose tissue, to the development of novel molecules that could, one day, be used to treat metabolic disorders.
Pericentral veins in a mouse liver