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The hypothalamus plays a key role in the regulation of energy homeostasis and endocrine function. Relaxin-3 is a hypothalamic neuropeptide that belongs to the insulin superfamily of peptides. It is expressed in the nucleus incertus of the brainstem, which has projections to the hypothalamus and is thought to act in the brain via the RXFP3 receptor, although the RXFP1 receptor may also play a role. RXFP3 and RXFP1 are present in the hypothalamic paraventricular nucleus, an area with a well-characterized role in the regulation of energy balance. The paraventricular nucleus also modulates reproductive function by providing inputs to hypothalamic gonadotropin-releasing hormone neurons. The physiological roles for relaxin-3 remain to be established. Evidence for a role of relaxin-3 as a hypothalamic orexigenic peptide will be reviewed, including its effects on the hypothalamo-pituitary-thyroid axis and energy expenditure. Studies pointing towards a putative role of relaxin-3 in the hypothalamic-pituitary-gonadal axis will be discussed. Central endocrine effects of relaxin-3 will be compared to relaxin. We conclude that relaxin-3 may act as a hypothalamic signal to coordinate appetite, thyroid function, and reproductive status. Further studies will be required to determine whether these are physiological roles for relaxin-3 and to determine the receptors involved.

The gut hormone peptide YY (PYY) belongs to the pancreatic polypeptide (PP) family along with PP and neuropeptide Y (NPY). These peptides mediate their effects through the NPY receptors of which there are several subtypes (Y1, Y2, Y4, and Y5). The L cells of the gastrointestinal tract are the major source of PYY, which exists in two endogenous forms: PYY(1-36) and PYY(3-36). The latter is produced by the action of the enzyme dipeptidyl peptidase-IV (DPP-IV). PYY(1-36) binds to and activates at least three Y receptor subtypes (Y1, Y2, and Y5), whereas PYY(3-36) is more selective for Y2 receptor (Y2R). The hypothalamic arcuate nucleus, a key brain area regulating appetite, has access to nutrients and hormones within the peripheral circulation. NPY neurons within the arcuate nucleus express the Y2R. In response to food ingestion plasma PYY(3-36) concentrations rise within 15 min and plateau by approximately 90 min. The peak PYY(3-36) level achieved is proportional to the calories ingested, suggesting that PYY(3-36) may signal food ingestion from the gut to appetite-regulating circuits within the brain. We found that peripheral administration of PYY(3-36) inhibited food intake in rodents and increased C-Fos immunoreactivity in the arcuate nucleus. Moreover, direct intra-arcuate administration of PYY(3-36) inhibited food intake. We have shown that Y2R null mice are resistant to the anorectic effects of peripherally administered PYY(3-36), suggesting that PYY(3-36) inhibits food intake through the Y2R. In humans, peripheral infusion of PYY(3-36), at a dose which produced normal postprandial concentrations, significantly decreased appetite and reduced food intake by 33% over 24 h. These findings suggest that PYY(3-36) released in response to a meal acts via the Y2R in the arcuate nucleus to physiologically regulate food intake.