Regulation of retinoid-homöostasis by the hormone FGF21

Vitamin A (retinol and its derivatives) is an essential micronutrient, which is known to be required for growth, development and the maintenance of human health. The vast amounts of the vitamin A reserves are stored in the liver, which ensure a constant supply of the body. Upon fasting, the liver mobilizes its vitamin A store and secrets retinol into circulation to maintain vitamin A supply. The molecular signals that facilitate retinoid homeostasis between liver and peripheral tissues are unknown. Unexpectedly, in preliminary studies we observed that after fasting, mice exhibited reduced vitamin A content in their fat depots but not in the liver. This suggests that under fasting vitamin A stores of the liver are replenished by a reverse transport of retinol from extrahepatic tissues to the liver. Notably, when experimentally depleting mice of their hepatic vitamin A stores, we observed increased hepatic secretion of the fasting-hormone fibroblast growth factor 21 (FGF21). Furthermore, this was associated with metabolic changes usually associated with fasting. Together, this suggests that upon fasting liver secretes FGF21, which acts as hormone to facilitate interorgan crosstalk between extra-hepatic tissues and the liver, to maintain vitamin A homeostasis. In this project, we anticipate to unravel the functional role of FGF21 in the maintenance of vitamin A homeostasis. Furthermore, we will extend our investigations to known physiological processes (e.g. adaptation to feeding/fasting) and patho-physiological mouse models (e.g. obesity and insulin resistance). This will allow us to elucidate the relevance of the FGF21/vitamin A axis for novel therapeutic interventions that could target metabolic diseases.

Retinoids (vitamin A/retinol and derivatives) are essential micronutrients, inevitable for life. The major storage sites of vitamin A are the liver and the adipose tissue. The mobilization of vitamin A stores requires binding of retinol to retinol-binding protein 4 (RBP4) and secretion of the retinol:RBP4 complex from hepatocytes into the bloodstream. This project investigated the cross-talk between adipose tissue and the liver as well as the interrelation of RBP4-dependent retinol mobilization with the fasting induced, insulin-sensitizing protein fibroblast growth factor 21 (FGF21). Acute but not chronic retinol mobilization via hepatic RBP4 overexpression in mice resulted in the induction of fgf-21 expression in the liver and in increased FGF-21 levels in the circulation. Conversely, hepatic overexpression of fgf-21 resulted in the know positive effects of FGF-21 such as insulin sensitization and weight loss, but without affecting circulating retinol:RBP4 levels. Furthermore, adipose tissue specific deletion of the major fat and vitamin A mobilizing lipases adipose triglyceride lipase or hormone-sensitive lipase in mice led to compromised hepatic expression of peroxisomal proliferator-activated receptor (PPAR)-alpha or circulating retinol:RBP4 levels, respectively. These defects where observed under fasting, where these lipases of the adipose tissue are active and energy is known to largely derive from adipose tissue lipolysis. Apparently, fasting induces PPAR-alpha activation in liver that expresses and secretes FGF-21 as a back-talk to the adipose tissue. Apparently, if lipolysis of the adipose tissue is compromised this leads to disruption of this back-talk and consequently, in addition to impaired lipid and energy homeostasis, also to failures in maintaining constant circulating vitamin A concentrations. Since fgf21 is known to be a direct target of PPAR-alpha, it suggests that vitamin A homeostasis is directly or indirectly co-regulated. Furthermore, under fasting the adipose tissue is an essential source for vitamin A. However, the detailed molecular mechanisms how the constant supply of circulating retinol:RPB4 levels are maintained and how liver and the adipose tissue contribute to this process are unclear and require further investigations.