FGF19: How gut talks to brain to keep your sugar down☆

The homeostatic systems regulating energy and glucose metabolism perform a complex balancing act of meeting short term requirements for increased energy whilst maintaining long term energy stores. Multiple signals are involved in this process, from the gastrointestinal tract, pancreas and adipose tissue, which in turn also modulate CNS pathways to control appetite and glucose metabolism. The effectiveness of bariatric surgery in treating both obesity and diabetes has highlighted the importance of gut hormones in metabolic control. A long list of signals released from enteroendocrine cells in the gastrointestinal tract act to regulate feeding, induce satiety and control blood glucose, among them cholecystokinin released from I cells, ghrelin from the gastric mucosa, peptide YY, oxyntomodulin and glucagon-like peptide 1 from the L cells. Recently, fibroblast growth factor 19 (FGF-19) and its rodent homolog, FGF-15, have been added to the catalog of gastrointestinal hormones regulating metabolism. FGF19 levels are reduced in individuals with metabolic syndrome, non-alcoholic fatty liver disease and FGF19 levels are restored to normal values in obese patients who undergo Roux-en-Y gastric bypass bariatric surgery [1,2]. FGF-15 is released from enteroendocrine cells of the ileum in response to post-prandial secretion of bile acids and reduces weight and improves glucose tolerance in obese mice, effects that were believed to be mediated through peripheral effects, mostly on the liver [1]. However, recent papers by Marcelin, in the current edition of Molecular Metabolism [3], Ryan et al. [4] and Morton et al. [5] have shown that the actions of FGF19 within the CNS play an important role in its ability to regulate appetite and glucose homeostasis. Marcelin et al. demonstrate that central FGF19 acts to decrease food intake and body weight and improve glucose tolerance in obese mouse models. In addition, all three groups show that the CNS mediated improvements in glucose homeostasis are independent of a reduction in body weight. Studies performed by Ryan et al. in chow fed rats demonstrate that administration of FGF-19 improved glucose tolerance with no change in insulin release. Morton et al. found similar results in ob/ob mice. A single ICV injection of FGF-19 improved glucose tolerance with no change in insulin secretion. Minimal model analysis of the data from the frequently sampled intravenous glucose tolerance testing suggested this improvement was the result of improved insulin-independent glucose