Y4 receptors and pancreatic polypeptide regulate food intake via hypothalamic orexin and brain-derived neurotropic factor dependent pathways

Sainsbury, Amanda; Shi, Yan-Chuan; Zhang, Lei; Aljanova, Aygul; Lin, Zhou; Nguyen, Amy D.; Herzog, Herbert; Lin, Shu

doi:10.1016/j.npep.2010.01.001

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Volume 44, Issue 3 , Pages 261-268, June 2010

Y4 receptors and pancreatic polypeptide regulate food intake via hypothalamic orexin and brain-derived neurotropic factor dependent pathways

Amanda Sainsbury
- Neuroscience Program, Garvan Institute of Medical Research, St. Vincent’s Hospital, 384 Victoria St., Darlinghurst, Sydney, NSW 2010, Australia
- School of Medical Sciences, University of NSW, Sydney, NSW, Australia
Yan-Chuan Shi
- Neuroscience Program, Garvan Institute of Medical Research, St. Vincent’s Hospital, 384 Victoria St., Darlinghurst, Sydney, NSW 2010, Australia
Lei Zhang
- Neuroscience Program, Garvan Institute of Medical Research, St. Vincent’s Hospital, 384 Victoria St., Darlinghurst, Sydney, NSW 2010, Australia
Aygul Aljanova
- Neuroscience Program, Garvan Institute of Medical Research, St. Vincent’s Hospital, 384 Victoria St., Darlinghurst, Sydney, NSW 2010, Australia
Zhou Lin
- Neuroscience Program, Garvan Institute of Medical Research, St. Vincent’s Hospital, 384 Victoria St., Darlinghurst, Sydney, NSW 2010, Australia
Amy D. Nguyen
- Neuroscience Program, Garvan Institute of Medical Research, St. Vincent’s Hospital, 384 Victoria St., Darlinghurst, Sydney, NSW 2010, Australia
Herbert Herzog
- Neuroscience Program, Garvan Institute of Medical Research, St. Vincent’s Hospital, 384 Victoria St., Darlinghurst, Sydney, NSW 2010, Australia
- Faculty of Medicine, University of NSW, Sydney, NSW, Australia
Shu Lin
- Neuroscience Program, Garvan Institute of Medical Research, St. Vincent’s Hospital, 384 Victoria St., Darlinghurst, Sydney, NSW 2010, Australia
- Corresponding author. Tel.: +61 2 9295 82 91; fax: +61 2 9295 82 81.

Received 27 October 2009; accepted 7 January 2010. published online 01 February 2010.

Abstract

Gut-derived peptides are known to regulate food intake by activating specific receptors in the brain, but the target nuclei and neurons influenced are largely unknown. Here we show that peripherally administered pancreatic polypeptide (PP) stimulates neurons in key nuclei of the hypothalamus critical for appetite and satiety regulation. In the lateral hypothalamic area (LHA), also known as the feeding center, neurons expressing the orexigenic neuropeptide orexin co-localize with the early neuronal activation marker c-Fos upon i.p. injection of PP into mice. In the ventromedial hypothalamus (VMH), also known as the satiety center, neurons activated by PP, as indicated by induction of c-Fos immunoreactivity, express the anorexigenic brain-derived neurotrophic factor (BDNF). Activation of neurons in the LHA and VMH in response to PP occurs via a Y4 receptor-dependent process as it is not seen in Y4 receptor knockout mice. We further demonstrate that in response to i.p. PP, orexin mRNA expression in the LHA is down-regulated, with Y4 receptors being critical for this effect as it is not seen in Y4 receptor knockout mice, whereas BDNF mRNA expression is up-regulated in the VMH in response to i.p. PP in the fasted, but not in the non-fasted state. Taken together these data suggest that PP can regulate food intake by suppressing orexigenic pathways by down-regulation of orexin and simultaneously increasing anorexigenic pathways by up-regulating BDNF.

Keywords: Pancreatic polypeptide, NPY receptors, c-Fos immunoreactivity, Orexin, Brain-derived neurotrophic factor, Lateral hypothalamic area, Ventromedial hypothalamus