In this study, we defined the role of peroxisome proliferator-activated receptor ␤͞␦ (PPAR␦) in metabolic homeostasis by using subtype selective agonists. Analysis of rat L6 myotubes treated with the PPAR␦ subtype-selective agonist, GW501516, by the Affymetrix oligonucleotide microarrays revealed that PPAR␦ controls fatty acid oxidation by regulating genes involved in fatty acid transport, ␤-oxidation, and mitochondrial respiration. Similar PPAR␦-mediated gene activation was observed in the skeletal muscle of GW501516-treated mice. Accordingly, GW501516 treatment induced fatty acid ␤-oxidation in L6 myotubes as well as in mouse skeletal muscles. Administration of GW501516 to mice fed a high-fat diet ameliorated diet-induced obesity and insulin resistance, an effect accompanied by enhanced metabolic rate and fatty acid ␤-oxidation, proliferation of mitochondria, and a marked reduction of lipid droplets in skeletal muscles. Despite a modest body weight change relative to vehicle-treated mice, GW501516 treatment also markedly improved diabetes as revealed by the decrease in plasma glucose and blood insulin levels in genetically obese ob͞ob mice. These data suggest that PPAR␦ is pivotal to control the program for fatty acid oxidation in the skeletal muscle, thereby ameliorating obesity and insulin resistance through its activation in obese animals.obesity ͉ insulin resistance ͉ thermogenesis ͉ pancreatic ␤-cell ͉ PGC-1␣

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Here, we report the isolation and characterization of an endogenous peptide ligand of GPR103 from rat brains. The purified peptide was found to be the 43-residue RF-amide peptide QRFP. We also describe two mouse homologues of human GPR103, termed mouse GPR103A and GPR103B. QRFP binds and activates the human GPR103, as well as mouse GPR103A and GPR103B, with nanomolar affinities in transfected cells. Systematic in situ hybridization analysis in mouse brains showed that QRFP is expressed exclusively in the periventricular and lateral hypothalamus, whereas the two receptor mRNAs are distinctly localized in various brain areas without an overlap to each other. When administered centrally in mice, QRFP induced feeding behavior, accompanied by increased general locomotor activity and metabolic rate. QRFPinduced food intake was abolished by preadministration of BIBP3226, a specific antagonist for the Y1 neuropeptide Y receptor. Hypothalamic prepro-QRFP mRNA expression was up-regulated upon fasting and in genetically obese ob͞ob and db͞db mice. Central QRFP administration also evoked highly sustained elevation of blood pressure and heart rate. Our findings suggest that QRFP and GPR103A͞B may regulate diverse neuroendocrine and behavioral functions and implicate this neuropeptide system in metabolic syndrome.grooming ͉ hypothalamus ͉ QRFP ͉ wakefulness ͉ metabolic syndrome G protein-coupled receptors (GPCRs) are members of a large protein family that share common structural motifs, including seven transmembrane helices, and play pivotal roles in cell-to-cell communications and in the regulation of cell functions. A large number of GPCRs still remain as ''orphan receptors'' whose cognate ligands have yet to be identified. Identification of ligands for orphan GPCRs provides a basis for understanding the physiological roles of those GPCRs and their ligands, which can involve the central nervous, endocrine, reproductive, cardiovascular, immune, inflammatory, digestive, and metabolic systems.GPR103 (also referred to as SP9155 or AQ27) is an orphan GPCR that shows similarities with orexin, neuropeptide FF, and cholecystokinin receptors. Its mRNA has been detected predominantly in the brain including the cerebral cortex, pituitary, thalamus, hypothalamus, basal forebrain, midbrain, and pons in humans (1). Through bioinformatics approaches, two groups reported putative ligands for GPR103 as a part of a directed effort to identify the precursor genes for a novel RF-amide peptide and its receptor (2, 3). They identified a gene encoding a preproprotein that can be processed into several potential peptides, including a 26-aa (termed P518) and a 43-aa RF-amide peptide (termed QRFP) (2, 3). Both of these peptides activate GPR103, but the 43-aa QRFP exhibited more potent agonistic activity. When intravenously injected into rats, QRFP (43-aa) stimulates aldosterone release (3). The 26-aa RF-amide peptide (termed 26RFa) was independently purified from frog brain by monitoring NPFF-like immunoreactivity (4), and it exhibits orexigenic act...

A Wnt coreceptor low-density lipoprotein receptor-related protein 5 (LRP5) plays an essential role in bone accrual and eye development. Here, we show that LRP5 is also required for normal cholesterol and glucose metabolism. The production of mice lacking LRP5 revealed that LRP5 deficiency led to increased plasma cholesterol levels in mice fed a high-fat diet, because of the decreased hepatic clearance of chylomicron remnants. In addition, when fed a normal diet, LRP5-deficient mice showed a markedly impaired glucose tolerance. The LRP5-deficient islets had a marked reduction in the levels of intracellular ATP and Ca 2؉ in response to glucose, and thereby glucoseinduced insulin secretion was decreased. The intracellular inositol 1,4,5-trisphosphate (IP3) production in response to glucose was also reduced in LRP5؊͞؊ islets. Real-time PCR analysis revealed a marked reduction of various transcripts for genes involved in glucose sensing in LRP5؊͞؊ islets. Furthermore, exposure of LRP5؉͞؉ islets to Wnt-3a and Wnt-5a stimulates glucose-induced insulin secretion and this stimulation was blocked by the addition of a soluble form of Wnt receptor, secreted Frizzled-related protein-1. In contrast, LRP5-deficient islets lacked the Wnt-3a-stimulated insulin secretion. These data suggest that Wnt͞LRP5 signaling contributes to the glucose-induced insulin secretion in the islets.and LRP6 are coreceptors involved in the Wnt signaling pathway (1-6). The Wnt signaling pathway plays a pivotal role in embryonic development (7,8) and oncogenesis (9) through various signaling molecules including Frizzled receptors (10), recently characterized LRP5 and LRP6 (1-6), and Dickkopf proteins (4, 6). In addition, the Wnt signaling is also involved in adipogenesis by negatively regulating adipogenic transcription factors (Tcfs) (11). Although Wnt signaling has been characterized in both developmental and oncogenic processes, little is known about its function in the normal adult.Recent studies have revealed that loss of function mutations in the LRP5 gene cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (12). LRP5 is expressed in osteoblasts and transduces Wnt signaling via the canonical pathway, thereby modulating bone accrual development (12, 13). A point mutation in a ''propeller'' motif in LRP5 causes a dominant-positive high bone density by impairing the action of a normal antagonist of the Wnt pathway, Dickkopf, thereby increasing Wnt signaling (14,15). In addition, the human LRP5 gene is mapped within the region (IDDM4) linked to type 1 diabetes on chromosome 11q13 (16).In previous studies, we and others showed that LRP5 is highly expressed in many tissues, including hepatocytes and pancreatic beta cells (17,18). We also showed that LRP5 can bind apolipoprotein E (apoE) (18). This finding raises the possibility that LRP5 plays a role in the hepatic clearance of apoE-containing chylomicron remnants, a major plasma lipoprotein carrying diet-derived cholesterol.To evaluate the in vivo roles of LRP5, we generated LRP...