Dual actions of fibroblast growth factor 19 on lipid metabolism

Abstract

hormone ( 3 ). In lieu of heparan sulfate binding, FGF19 requires a protein cofactor, ␤ Klotho, to effectively interact with and activate FGF receptors ( 4-6 ). The requirement for a co-receptor is a unique feature common to the FGF19 subfamily and is further exemplifi ed by another subfamily member, FGF21, which also lacks heparan sulfate affi nity and uses ␤ Klotho as its co-receptor ( 4 ). Consistent with their shared ability to use the same co-receptor for signaling, there is extensive overlap in the reported pharmacological effects of FGF19 and FGF21. FGF19 and FGF21 transgenic mice, as well as chronic administration of recombinant FGF19 or FGF21 proteins, similarly lowered serum glucose, triglyceride (TG), and cholesterol levels and improved insulin sensitivity and reduced body weight in high-fat diet-induced obesity models ( 7-9 ). Chronic treatment with FGF19 or FGF21 similarly reduced blood glucose levels and improved glucose disposal in ob/ob (B6.V-Lep ob /J) leptin-defi cient mice; however, plasma TG and cholesterol levels after treatment with FGF19 have not been reported in this model ( 8,9 ).The common co-receptor for FGF19 and FGF21, ␤ Klotho, is a single-pass transmembrane protein with two homologous extracellular domains that share sequence homology to ␤ -glucosidases in bacteria and plants ( 10 ). ␤ Klotho has a short intracellular domain and is unlikely to signal by itself. Its primary role is believed to mediate interactions between these two FGF molecules and FGF receptors (FGFR) to activate FGFR tyrosine kinase activity ( 11 ). ␤ Klotho interacts with only four of the seven major FGFRs, the "c" isoforms of FGFR1, -2, -3. and -4 ( 11 ). FGF19 and FGF21 can activate FGFR1c, -2c, and -3c complexed with ␤ Klotho in vitro ( 4, 6, 11-13 ). Recent results using an engineered FGF19 variant with altered receptor specifi city Abstract Elevated triglyceride (TG) and cholesterol levels are risk factors for cardiovascular disease and are often associated with diabetes and metabolic syndrome. Recent reports suggest that fi broblast growth factor (FGF)19 and FGF21 can dramatically improve metabolic dysfunction, including hyperglycemia, hypertriglyceridemia, and hypercholesterolemia. Due to their similar receptor specifi cities and co-receptor requirements, FGF19 and FGF21 share many common properties and have been thought to be interchangeable in metabolic regulation. Here we directly compared how pharmacological administration of recombinant FGF19 or FGF21 proteins affect metabolism in B6.VLep ob /J leptin-defi cient mice. FGF19 and FGF21 equally improved glucose parameters; however, we observed increased serum TG and cholesterol levels after treatment with FGF19 but not with FGF21. Increases in serum TGs were also observed after a 4-day treatment with FGF19 in C57BL6/J mice on a high-fat diet. This is in contrast to many literature reports that showed signifi cant improvements in hyperlipidemia after chronic treatment with FGF19 or FGF21 in high-fat diet models. We propose that FGF19 has lipid-raising an...

Fibroblast Growth Factor Receptor 4 (FGFR4) Deficiency Improves Insulin Resistance and Glucose Metabolism under Diet-induced Obesity Conditions

“…Here, we report that the FGFR4 deficiency prevents high fat diet induced insulin resistance and glucose intolerance. Using these KO mice, we also confirm that the previously reported effects of FGF19 to increase plasma TG is mediated through FGFR4 (9). Potential mechanisms leading to these metabolic changes are discussed.…”

“…The reported pharmacological effects of FGF19 and FGF21 can be separated into three general categories: 1) both FGF19 and FGF21 similarly improve glucose disposal and reduce body weight; 2) FGF21 reduces plasma triglycerides (TG) and cholesterol, whereas the effects of FGF19 depends on the model tested and the duration of treatment (9); and 3) although FGF19 inhibits bile acid synthesis and reduces the bile acid pool, there is no report that FGF21 regulates bile acid metabolism (10,2,5). Because both FGF19 and FGF21 similarly activate ␤Klotho complexed with FGFR1c, 2c, and 3c, it is reasonable to speculate that one of the receptors alone, or combination with one another, are responsible for the similar effects of FGF19 and FGF21 on glucose and body weight regulation.…”

Role of Lipocalin-type prostaglandin D2 synthase (L-PGDS) and its metabolite, prostaglandin D2, in preterm birth

“…L-PGDS also contributes to the production of PGD 2 in the central nervous system [15] ocular tissues [16], cardiovascular systems [17], and male genital organs [18] of various mammals and is also involved in the regulation of non-rapid eye movement sleep, sex determination [19] and protection of atherosclerosis [20]. Earlier studies have also reported the elevated levels of L-PGDS and PGD 2 in amniotic fluid during the later stages of pregnancy [12,21].…”

Mechanisms of enterohepatic fibroblast growth factor 15/19 signaling in health and disease

“…Although several studies have addressed this question, the validation of a comprehensive picture is still complicated by some important differences that may exist regarding acute, short-term (within minutes or hours) or chronic, long-term (within days or weeks) effects of FGF15/19 and corresponding receptor requirements in different organs (see also [45]). …”