Ghrelin, a circulating appetite-inducing hormone, is derived from a prohormone by posttranslational processing. On the basis of the bioinformatic prediction that another peptide also derived from proghrelin exists, we isolated a hormone from rat stomach and named it obestatin-a contraction of obese, from the Latin "obedere," meaning to devour, and "statin," denoting suppression. Contrary to the appetite-stimulating effects of ghrelin, treatment of rats with obestatin suppressed food intake, inhibited jejunal contraction, and decreased body-weight gain. Obestatin bound to the orphan G protein-coupled receptor GPR39. Thus, two peptide hormones with opposing action in weight regulation are derived from the same ghrelin gene. After differential modification, these hormones activate distinct receptors.

All arthropods periodically molt to replace their exoskeleton (cuticle). Immediately after shedding the old cuticle, the neurohormone bursicon causes the hardening and darkening of the new cuticle. Here we show that bursicon, to our knowledge the first heterodimeric cystine knot hormone found in insects, consists of two proteins encoded by the genes burs and pburs (partner of burs). The pburs͞burs heterodimer from Drosophila melanogaster binds with high affinity and specificity to activate the G proteincoupled receptor DLGR2, leading to the stimulation of cAMP signaling in vitro and tanning in neck-ligated blowflies. Native bursicon from Periplaneta americana is also a heterodimer. In D. melanogaster the levels of pburs, burs, and DLGR2 transcripts are increased before ecdysis, consistent with their role in postecdysial cuticle changes. Immunohistochemical analyses in diverse insect species revealed the colocalization of pburs-and burs-immunoreactivity in some of the neurosecretory neurons that also express crustacean cardioactive peptide. Forty-three years after its initial description, the elucidation of the molecular identity of bursicon and the verification of its receptor allow for studies of bursicon actions in regulating cuticle tanning, wing expansion, and as yet unknown functions. Because bursicon subunit genes are homologous to the vertebrate bone morphogenetic protein antagonists, our findings also facilitate investigation on the function of these proteins during vertebrate development.BMP antagonist ͉ heterodimeric polypeptide ligand ͉ LGR I nsects comprise Ͼ90% of all animal species and are of great economical and ecological importance. The evolutionary success of insects is due partially to their exoskeleton, which provides protection, mechanical support, and an effective barrier to desiccation and infections. During immature stages, continued growth requires that insects replace their exoskeleton. During this molting process, a new cuticle is synthesized and secreted by underlying epidermal cells and then is hardened after the remains of the old cuticle are shed at ecdysis. Molting and ecdysis are regulated by at least six different hormones (1). The steroid 20-hydroxyecdysone directs the synthesis of the new cuticle (2), and then a cascade of peptide hormones orchestrates the events surrounding ecdysis.According to current knowledge, the last uncharacterized hormone in this cascade, bursicon, is an Ϸ30-kDa neurohormone that is released after the completion of ecdysis (3, 4) and triggers the tanning (melanization and sclerotization) of the new cuticle as well as wing expansion (5). Bursicon of diverse insects, including blowf ly (Calliphora erythrocephala), cockroach (Periplaneta americana), cricket (Gryllus bimaculatus), locust (Locusta migratoria), and meal beetle (Tenebrio molitor) (4), initiates tanning in neck-ligated flies (6, 7), suggesting the conservation of this signaling system that is essential for insect survival.Recently, a subfamily of G protein-coupled receptors with a large ectodo...

The physiological role of an orphan G protein-coupled receptor, LGR5, was investigated by targeted deletion of this seven-transmembrane protein containing a large N-terminal extracellular domain with leucine-rich repeats.LGR5 null mice exhibited 100% neonatal lethality characterized by gastrointestinal tract dilation with air and an absence of milk in the stomach. Gross and histological examination revealed fusion of the tongue to the floor of oral cavity in the mutant newborns and immunostaining of LGR5 expression in the epithelium of the tongue and in the mandible of the wild-type embryos. The observed ankyloglossia phenotype provides a model for understanding the genetic basis of this craniofacial defect in humans and an opportunity to elucidate the physiological role of the LGR5 signaling system during embryonic development.The leucine-rich repeat-containing, G protein-coupled receptors (LGRs) designated LGR4 through LGR8 are structurally similar to receptors for gonadotropins and thyrotropin (11,12). These receptors are characterized by a large N-terminal extracellular domain containing leucine-rich repeats followed by a seven-transmembrane region. Phylogenetic analyses showed three LGR subgroups: the glycoprotein hormone receptors; the subgroup of LGR4, LGR5, and LGR6; and a third subgroup represented by LGR7 and LGR8 recently found to be receptors for the relaxin family ligands (13,15,23). Evolutionary analyses suggested that these three subgroups of LGRs existed before the divergence of vertebrates and invertebrates (10). LGR5, also known as GPR49, HG38, or FEX, is a large protein consisting of 18 extracellular leucine-rich repeats together with a seven-transmembrane region (8,12,17). UnlikeLGRs in the other two subgroups, the ligands and physiological functions for the LGR4, LGR5, and LGR6 genes are unclear.Ankyloglossia is a rare human craniofacial defect associated with difficulties in an infant's ability to breast-feed and defective speech articulation (6,16,18). In patients with this disorder, the lingual frenulum, which attaches the tongue to the floor of the oral cavity, extends to the tip of the tongue, thereby preventing optimal tongue movement. Limitation of tongue movement may vary from very mild to complete fusion of the tongue to the floor of the mouth. Ankyloglossia in breastfeeding infants can cause ineffective latch, inadequate milk transfer, and maternal nipple pain, resulting in slower weight gain and untimely weaning. Some cases of ankyloglossia are associated with cleft palate (CPX; MIM 303400; OMIM database, Johns Hopkins University, Baltimore, Md.) and are inherited as an X-linked disorder caused by mutations in TBX22, a T-box transcription factor gene located in Xq21 (3).In an attempt to elucidate the physiological roles of the subgroup of orphan LGRs consisting of LGR4, LGR5, and LGR6, we performed gene deletion experiments with LGR5 using a mouse model. Here, we report that the LGR5 null mice exhibit neonatal lethality associated with ankyloglossia characterized by fusion of the ...