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Fibroblast growth factor 1 (FGF1) is an autocrine/paracrine regulator whose binding to heparan sulphate proteoglycans effectively precludes its circulation. Although FGF1 is known as a mitogenic factor, FGF1 knockout mice develop insulin resistance when stressed by a high-fat diet, suggesting a potential role in nutrient homeostasis. Here we show that parenteral delivery of a single dose of recombinant FGF1 (rFGF1) results in potent, insulin-dependent lowering of glucose levels in diabetic mice that is dose-dependent but does not lead to hypoglycaemia. Chronic pharmacological treatment with rFGF1 increases insulin-dependent glucose uptake in skeletal muscle and suppresses the hepatic production of glucose to achieve whole-body insulin sensitization. The sustained glucose lowering and insulin sensitization attributed to rFGF1 are not accompanied by the side effects of weight gain, liver steatosis and bone loss associated with current insulin-sensitizing therapies. We also show that the glucose-lowering activity of FGF1 can be dissociated from its mitogenic activity and is mediated predominantly via FGF receptor 1 signalling. Thus we have uncovered an unexpected, neomorphic insulin-sensitizing action for exogenous non-mitogenic human FGF1 with therapeutic potential for the treatment of insulin resistance and type 2 diabetes.

The ageing suppressor -klotho binds to the fibroblast growth factor receptor (FGFR). This commits FGFR to respond to FGF23, a key hormone in the regulation of mineral ion and vitamin D homeostasis. The role and mechanism of this co-receptor are unknown. Here we present the atomic structure of a 1:1:1 ternary complex that consists of the shed extracellular domain of -klotho, the FGFR1c ligand-binding domain, and FGF23. In this complex, -klotho simultaneously tethers FGFR1c by its D3 domain and FGF23 by its C-terminal tail, thus implementing FGF23FGFR1c proximity and conferring stability. Dimerization of the stabilized ternary complexes and receptor activation remain dependent on the binding of heparan sulfate, a mandatory cofactor of paracrine FGF signalling. The structure of -klotho is incompatible with its purported glycosidase activity. Thus, shed -klotho functions as an on-demand non-enzymatic scaffold protein that promotes FGF23 signalling., Author(s): Gaozhi Chen [1, 2]; Yang Liu [2]; Regina Goetz [2]; Lili Fu [1, 2]; Seetharaman Jayaraman [3]; Ming-Chang Hu [4]; Orson W. Moe [4]; Guang Liang [1]; Xiaokun Li [...]

The nuclear receptor pregnane X receptor (PXR) is activated by a range of xenochemicals, including chemotherapeutic drugs, and has been suggested to play a role in the development of tumor cell resistance to anticancer drugs. PXR also has been implicated as a regulator of the growth and apoptosis of colon tumors. Here, we have used a xenograft model of colon cancer to define a molecular mechanism that might underlie PXR-driven colon tumor growth and malignancy. Activation of PXR was found to be sufficient to enhance the neoplastic characteristics, including cell growth, invasion, and metastasis, of both human colon tumor cell lines and primary human colon cancer tissue xenografted into immunodeficient mice. Furthermore, we were able to show that this PXR-mediated phenotype required FGF19 signaling. PXR bound to the FGF19 promoter in both human colon tumor cells and 'normal' intestinal crypt cells. However, while both cell types proliferated in response to PXR ligands, the FGF19 promoter was activated by PXR only in cancer cells. Taken together, these data indicate that colon cancer growth in the presence of a specific PXR ligand results from tumor-specific induction of FGF19. These observations may lead to improved therapeutic regimens for colon carcinomas, Introduction Decades of clinical research in patients with solid tumors have demonstrated that complete and durable tumor regressions are rare. Indeed the clinical experience with chemotherapy for most solid tumor [...]

Fibroblast growth factor-23 (FGF23) is a phosphaturic hormone that contributes to several hypophosphatemic disorders by reducing the expression of the type II sodium-phosphate cotransporters (NaPi-2a and NaPi-2c) in the kidney proximal tubule and by reducing serum 1,25-dihydroxyvitamin [D.sub.3] [1,25[(OH).sub.2][D.sub.3]] levels. The FGF receptor(s) mediating the hypophosphatemic action of FGF23 in vivo have remained elusive. In this study, we show that proximal tubules express FGFR1, -3, and -4 but not FGFR2 mRNA. To determine which of these three FGFRs mediates FGF23's hypophosphatemic actions, we characterized phosphate homeostasis in [FGFR3.sup.-/-] and [FGFR4.sup.-/-] null mice, and in conditional [FGFR1.sup.-/-] mice, with targeted deletion of FGFR1 expression in the metanephric mesenchyme. Basal serum phosphorus levels and renal cortical brush-border membrane (BBM) NaPi-2a and NaPi-2c expression were comparable between [FGFR1.sup.-/-], [FGFR3.sup.-/-], and [FGFR4.sup.-/-] mice and their wild-type counterparts. Administration of FGF23 to [FGFR3.sup.-/-] mice induced hypophosphatemia in these mice (8.0 [+ or -] 0.4 vs. 5.4 [+ or -] 0.3 mg/dl; p [less than or equal to] 0.001) and a decrease in renal BBM NaPi-2a and NaPi-2c protein expression. Similarly, in [FGFR4.sup.-/-] mice, administration of FGF23 caused a small but significant decrease in serum phosphorus levels (8.7 [+ or -] 0.3 vs. 7.6 [+ or -] 0.4 mg/dl; p [+ or -] 0.001) and in renal BBM NaPi-2a and NaPi-2c protein abundance. In contrast, injection of FGF23 into [FGFR1.sup.-/-] mice had no effects on serum phosphorus levels (5.6 [+ or -] 0.3 vs. 5.2 [+ or -] 4- 0.5 mg/dl) or BBM NaPi-2a and NaPi-2c expression. These data show that FGFR1 is the predominant receptor for the hypophosphatemic action of FGF23 in vivo, with FGFR4 likely playing a minor role. phosphaturia; phosphorus; proximal tubule

Phosphate homeostasis is maintained by a counterbalance between efflux from the kidney and influx from intestine and bone. FGF23 is a bone-derived phosphaturic hormone that acts on the kidney to increase phosphate excretion and suppress biosynthesis of vitamin D. FGF23 signals with highest efficacy through several FGF receptors (FGFRs) bound by the transmembrane protein Klotho as a coreceptor. Since most tissues express FGFR, expression of Klotho determines FGF23 target organs. Here we identify the parathyroid as a target organ for FGF23 in rats. We show that the parathyroid gland expressed Klotho and 2 FGFRs. The administration of recombinant FGF23 led to an increase in parathyroid Klotho levels. In addition, FGF23 activated the MAPK pathway in the parathyroid through ERK1/2 phosphorylation and increased early growth response 1 mRNA levels. Using both rats and in vitro rat parathyroid cultures, we show that FGF23 suppressed both parathyroid hormone (PTH) secretion and PTH gene expression. The FGF23-induced decrease in PTH secretion was prevented by a MAPK inhibitor. These data indicate that FGF23 acts directly on the parathyroid through the MAPK pathway to decrease serum PTH. This bone-parathyroid endocrine axis adds a new dimension to the understanding of mineral homeostasis., Introduction FGF23 is secreted by osteocytes (1) and osteoblasts (2) in response to high serum phosphate levels and after the administration of the vitamin D metabolite, 1,25[(OH).sub.2]-vitamin D (2-4). FGF23 [...]

Familial tumoral calcinosis is characterized by ectopic calcifications and hyperphosphatemia due to inactivatingmutations in FGF23 or UDP-N-acetyl-[alpha]-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3(GALNT3). Herein we report a homozygous missense mutation (H193R) in the KLOTHO [...]

Fibroblast growth factor 21 (FGF21) is a liver-derived endocrine factor that stimulates glucose uptake in adipocytes. Here, we show that FGF21 activity depends on [beta]Klotho, a single-pass transmembrane protein whose expression is induced during differentiation from preadipocytes to adipocytes. [beta]Klotho physically interacts with FGF receptors 1c and 4, thereby increasing the ability of these FGF receptors to bind FGF21 and activate the MAP kinase cascade. Knockdown of [beta]Klotho expression by siRNA in adipocytes diminishes glucose uptake induced by FGF21. Importantly, administration of FGF21 into mice induces MAP kinase phosphorylation in white adipose tissue and not in tissues without [beta]Klotho expression. Thus, [beta]Klotho functions as a cofactor essential for FGF21 activity. Klotho | glucose | adipocyte | siRNA | GLUT1