Oral Presentation Australian & New Zealand Obesity Society 2014 Annual Scientific Meeting

Hypothalamic pathways for energy intake and expenditure including recent insights into circadian cycles (#48)

Herbert Herzog 1
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia

Hypothalamic circuitries are important in receiving and integrating information from other brain areas as well as the periphery to control appetite and energy homeostasis. Among the many systems involved that influence orexigenic and anorexigenic processes in the hypothalamus, the neuropeptide Y (NPY) system is unique in that its major neuronal component, NPY, stimulates appetite and reduces energy expenditure, whereas its other family members, peptide YY (PYY) and pancreatic polypeptide (PP), which are mainly produced by endocrine cells in the periphery in response to food intake, act in an opposing fashion as satiety factors. NPY peptides are able to signal through a set of 5 known Y-receptors (Npy1r, Npy2r, Ppyr1, Npy5r and Npy6r) and despite the large amount of work being dedicated to unraveling functions of the NPY system, little information is available for the role of the Npy6r. Recent discoveries from our laboratory show that body weight, body composition, metabolic rate and activity of the hypothalamo-pituitary-somatotrophic axis are significantly influenced by Npy6r signaling in mice, since lack of Npy6r leads to reduced lean mass and increased energy expenditure that are accompanied by significant improvements in glucose homeostasis and reduced hypothalamic Ghrh mRNA expression and circulating IGF-1 levels. Interestingly, Npy6r deficient mice develop late onset obesity, and this is further exacerbated when mice are fed a high fat diet. We have also identified PP as the endogenous high affinity ligand for Npy6r in mice. The mechanism by which Npy6r mediates its effects on the growth hormone axis and energy homeostasis is most likely through alterations in VIP signaling in the hypothalamus. This is demonstrated by the strong overlap in expression of Vip and Npy6r within the SCN, the brain region to which the Npy6r is confined to, and the significant reduction in Vip expression in this nucleus in the absence of Npy6r signaling. Moreover, the fact that i.p. PP injection increases energy expenditure and decreases food intake, hypothalamic Ghrh mRNA expression and circulating IGF-1 levels in WT but not in Npy6r-/- mice, and that the effect on IGF-1 is blocked by prior administration of a VPAC2-specific antagonist, strongly supports this stand. Thus, PP-initiated signaling through Npy6r in VIP neurons regulates the growth hormone axis and body composition.