Leptin is an adipose-derived hormone that regulates a wide variety of physiological processes, including feeding behavior, metabolic rate, sympathetic nerve activity, reproduction, and immune response. Circulating leptin levels are tightly regulated according to energy homeostasis in vivo. Although mechanisms for the regulation of leptin production in adipocytes are not well understood, G protein-coupled receptors may play an important role in this adipocyte function. Here we report that C2-C6 short-chain fatty acids, ligands of an orphan G protein-coupled receptor GPR41, stimulate leptin expression in both a mouse adipocyte cell line and mouse adipose tissue in primary culture. Acute oral administration of propionate increases circulating leptin levels in mice. The concentrations of short-chain fatty acids required to stimulate leptin production are within physiological ranges, suggesting the relevance of this pathway in vivo.

GPR7 and GPR8 are orphan G protein-coupled receptors that are highly similar to each other. These receptors are expressed predominantly in brain, suggesting roles in central nervous system function. We have purified an endogenous peptide ligand for GPR7 from bovine hypothalamus extracts. This peptide, termed neuropeptide B (NPB), has a C-6-brominated tryptophan residue at the N terminus. It binds and activates human GPR7 or GPR8 with median effective concentrations (EC50) of 0.23 nM and 15.8 nM, respectively. In situ hybridization shows distinct localizations of the prepro-NPB mRNA in mouse brain, i.e., in paraventricular hypothalamic nucleus, hippocampus, and several nuclei in midbrain and brainstem. Intracerebroventricular (i.c.v.) injection of NPB in mice induces hyperphagia during the first 2 h, followed by hypophagia. Intracerebroventricular injection of NPB produces analgesia to s.c. formalin injection in rats. Through EST database searches, we identified a putative paralogous peptide. This peptide, termed neuropeptide W (NPW), also has an N-terminal tryptophan residue. Synthetic human NPW binds and activates human GPR7 or GPR8 with EC 50 values of 0.56 nM and 0.51 nM, respectively. The expression of NPW mRNA in mouse brain is confined to specific nuclei in midbrain and brainstem. These findings suggest diverse physiological functions of NPB and NPW in the central nervous system, acting as endogenous ligands on GPR7 and͞or GPR8.T here are a large number of orphan G protein-coupled receptors (GPCR) whose cognate ligands have yet to be identified (1, 2). The search for endogenous ligands of orphan GPCRs is important because GPCRs are in general excellent drug targets (3). GPR7 and GPR8 are two orphan GPCRs (4). They were originally cloned from human genomic DNA by degenerative PCR using primers based on the sequences of the ␦-opioid receptor and somatostatin receptor. Indeed, GPR7 and GPR8 each share Ϸ40% overall amino acid identities with opioid and somatostatin receptors. Human GPR7 and GPR8 are 70% identical to each other at the nucleotide level and 64% identical at the amino acid level. Interestingly, no orthologue exists for the GPR8 gene in rodents, indicating that GPR8 may have originated as a replicate of GPR7 after divergence of the rodent from other species in mammalian evolution (5).The observation that GPR7 and GPR8 mRNAs are expressed in distinct areas in the central nervous system (CNS) (4, 5), together with the similarity of GPR7 and GPR8 with opioid and somatostatin receptors, strongly argue for the existence of endogenous peptide ligand(s) in CNS. In this study, we have purified a neuropeptide ligand for GPR7 from the bovine hypothalamus. This peptide, termed neuropeptide B (NPB), consists of 29 aa with a unique brominated N-terminal tryptophan. Through EST database searches, we also identified another isopeptide of the same family, termed neuropeptide W (NPW). While this manuscript was being prepared, three papers were published reporting two endogenous ligands for GPR7 and GPR8 (6-8). Sequ...