Our westernized societies are witnessing a frightening increase in metabolic disorders, linked namely to inappropriate nutritional and lifestyle habits, and favored by genetic predisposition. One of these major chronic diseases is the metabolic syndrome, which reciprocally links alteration of glucose and lipid metabolisms to obesity, diabetes and cardiovascular diseases.

A strict energy balance is required for the harmonious growth and health of multicellular organisms. This balance depends on a very well tuned machinery involving input of the circadian rhythm process, identification and absorption of nutrients, energy storage and expenditure, as well as the control of appetite. Altered regulation of the processes involved in energy balance contributes to the development of metabolic diseases. This work package focuses on the involvement of a family of transcription factors named PPAR, which are key actors in organism development and energy homeostasis. These proteins act as “molecular switches” by activating or inhibiting gene expression.

One of the objectives is to investigate the role of PPARs in circadian regulation of metabolism in the liver, as well as the circadian signals that transmit the information from the “main clock”, situated in the brain, to the liver. Another project aims at identifying the endogenous chemicals that activate hepatic PPARs and whether the latter mediate the beneficial effects of dietary phytoestrogens (derived from plants) on obesity. We will also determine how these transcription factors regulate cholesterol metabolism, which is linked to sex hormone production by the liver, in a gender specific manner.

Besides their role in liver function, PPARs are also expressed in the hypothalamus. This specific region of the brain is one of the main actors of energy homeostasis, as it controls feeding and hepatic glucose production. Whether PPAR-regulated lipid metabolism is critical in the control of lipid sensing by the hypothalamic neurons is a key question of this program. The role of these “molecular switches” in pancreas development and functions is studied as well, because of the importance of this organ in glucose metabolism.

Diabetes results from the inappropriate death of insulin-producing cells in the pancreas, and their regeneration constitutes a major challenge. We are currently using a transgenic mouse model of inducible diabetes to study such a possibility. The role of gluco-incretins, hormones secreted by the gut and that have trophic effects on insulin-producing cells, is closely examined in this context.

This work package has contributed to the creation of the Metabolic Evaluation Facility, which is used to analyze the metabolic status of mice models of complex human disorders.