Regulation of retinoid homeostasis by the hormone FGF21

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Retinoids (Vitamin A (retinol) and its derivatives) are essential micronutrients and involved in a number of physiological processes by acting as ligands for nuclear receptors or as photon-acceptor in vision. More than 70% of all retinoids in the body are stored as retinyl esters in specialized liver cells. These stores are mobilized, involving the hydrolysis of retinyl esters and the secretion of the retinol binding protein 4 (RBP4):retinol complexes by hepatocytes. Especially during fasting, when the supply of lipoprotein-transported retinoids is negligible, circulating RBP4 is the principal source of retinol to meet cellular demands. The molecular signals that coordinate retinoid homeostasis between liver and extra-hepatic tissues are unknown. We made the surprising observation that fasting of mice reduced the amount of retinyl esters in white adipose tissue (WAT) but not liver. This suggests that retinol mobilization from the liver is replenished by reverse retinol transport from extrahepatic tissues back to the liver. Strikingly, when depleted of their hepatic retinyl ester stores, mice exhibited increased expression and secretion of the fasting-hormone fibroblast growth factor 21 (FGF21) from the liver. This was associated with increased lipolysis in WAT as well as hepatic ketogenesis, and led to improved glucose tolerance, suggesting a novel function of FGF21 in retinoid homeostasis and interorgan crosstalk. Thus, we hypothesize that FGF21 induces repartitioning of retinoids from WAT to the liver by activating retinyl ester hydrolases such as hormone-sensitive lipase. We propose that this pathway is relevant during physiological conditions (e.g. adaptation to feeding/fasting) and disturbed in metabolic diseases such as obesity and insulin resistance. In this project we propose to determine (i) the molecular events of fasting-induced retinol mobilization from adipose tissue and the requirement of FGF21, (ii) the molecular link between hepatic retinoid content and FGF21 expression, (iii) the role of FGF21-mediated interorgan crosstalk in metabolically-challenged mice (e.g. diet-induced obesity), and (iv) whether this interorgan crosstalk, involving reverse retinol transport to the liver, is required for the beneficial effects of FGF21 on insulin sensitivity. Addressing these aims will elucidate the relevance of the RBP4/FGF21/retinoid axis for novel therapeutic interventions that could target metabolic diseases.