Impact de la citrulline sur le métabolisme du tissu adipeux

Abstract : Obesity is frequently associated with type 2 diabetes and cardiovascular diseases, related to metabolic and endocrine dysregulation of white adipose tissue (WAT). During aging, the loss of muscle mass may be associated with obesity and defines the concept of sarcopenic obesity. Treatments implemented to counteract these conditions showed a very partial success. It is therefore appropriate to develop original alternative strategies that could lead to targeted therapies. Our team studies the metabolic regulation of WAT, the major source of energy storage in the body. Non-esterified fatty acids (NEFA) and glycerol are released in the blood from stored triglycerides through lipolysis and used as a source of energy for other tissues. In addition to their β-oxidation, NEFA are re-esterified in part, a process that limits their release in the blood. Glyceroneogenesis is the pathway necessary to NEFA re-esterification in the fasting state. Previous studies showed that administration of citrulline (CIT) for three months to aging rats induced a decrease of approximately 40% of the visceral WAT mass. This non-protein amino acid is given as a dietary supplement during aging or sports to increase muscle mass. We studied the effects of CIT on explant cultures of rat WAT. In the first part of this work, we show that CIT exerts a direct lipolytic and anti-glyceroneogenic effect on explants from rats whether young or old. However, the release of NEFA from the explants of young rats is limited by an increase in the oxidative capacity of the tissue. During aging, WAT mass augments in parallel to the increase in a pro-inflammatory state. To understand the influence of these two parameters regardless of age, we studied in the second part of this work, the effects of CIT on WAT explants from young rats fed a control (CD) or high fat (HFD) diet. We show an CIT-induced increase in lipolysis and beta-oxidative capacity of WAT from rats whatever the diet, while glyceroneogenesis is reduced. However, NEFA are selectively released from WAT of HFD rats, in connection with a drastic reduction of their re-esterification. NO is a mediator of these effects. In the third part of this work, we show that CIT acts directly on WAT from CD and HFD rats to induce the expression of uncoupling protein, UCP1, in line with the potential "browning" of WAT by this amino acid. These effects were not observed in explants from old rats. Altogether our results establish the basis for future investigations aimed at elucidating the mechanisms by which CIT reduces body fat and open new therapeutic perspectives to fight overweight and sarcopenic obesity.
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Nolwenn Joffin. Impact de la citrulline sur le métabolisme du tissu adipeux. Physiologie [q-bio.TO]. Université Sorbonne Paris Cité, 2015. Français. ⟨NNT : 2015USPCB036⟩. ⟨tel-01191472⟩

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