NPY neuron-specific Y2 receptors regulate adipose tissue and trabecular bone but not cortical bone homeostasis in mice

Yan-Chuan Shi*, Shu Lin, Iris P. L. Wong, Paul A. Baldock, Aygul Aljanova, Ronaldo F. Enriquez, Lesley Castillo, Natalie F. Mitchell, Ji-Ming Ye, Lei Zhang, Laurence Macia, Ernie Yulyaningsih, Amy D. Nguyen, Sabrina J. Riepler, Herbert Herzog, Amanda Sainsbury

*Corresponding author for this work

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

Background: Y2 receptor signalling is known to be important in neuropeptide Y (NPY)-mediated effects on energy homeostasis and bone physiology. Y2 receptors are located post-synaptically as well as acting as auto receptors on NPY-expressing neurons, and the different roles of these two populations of Y2 receptors in the regulation of energy homeostasis and body composition are unclear.

Methodology/Principal Findings: We thus generated two conditional knockout mouse models, Y2(lox/lox) and NPYCre/+;Y2(lox/lox), in which Y2 receptors can be selectively ablated either in the hypothalamus or specifically in hypothalamic NPY-producing neurons of adult mice. Specific deletion of hypothalamic Y2 receptors increases food intake and body weight compared to controls. Importantly, specific ablation of hypothalamic Y2 receptors on NPY-containing neurons results in a significantly greater adiposity in female but not male mice, accompanied by increased hepatic triglyceride levels, decreased expression of liver cartinine palmitoyltransferase (CPT1) and increased expression of muscle phosphorylated acetyl-CoA carboxylase (ACC). While food intake, body weight, femur length, bone mineral content, density and cortical bone volume and thickness are not significantly altered, trabecular bone volume and number were significantly increased by hypothalamic Y2 deletion on NPY-expressing neurons. Interestingly, in situ hybridisation reveals increased NPY and decreased proopiomelanocortin ( POMC) mRNA expression in the arcuate nucleus of mice with hypothalamus-specific deletion of Y2 receptors in NPY neurons, consistent with a negative feedback mechanism between NPY expression and Y2 receptors on NPY-ergic neurons.

Conclusions/Significance: Taken together these data demonstrate the anti-obesogenic role of Y2 receptors in the brain, notably on NPY-ergic neurons, possibly via inhibition of NPY neurons and concomitant stimulation of POMC-expressing neurons in the arcuate nucleus of the hypothalamus, reducing lipogenic pathways in liver and/or skeletal muscle in females. These data also reveal as an anti-osteogenic effect of Y2 receptors on hypothalamic NPY-expressing neurons on trabecular but not on cortical bone.

Original languageEnglish
Article number11361
Pages (from-to)1-16
Number of pages16
JournalPLoS ONE
Volume5
Issue number6
DOIs
Publication statusPublished - 29 Jun 2010
Externally publishedYes

Keywords

  • NEUROPEPTIDE-Y
  • ARCUATE NUCLEUS
  • KNOCKOUT MICE
  • BODY-WEIGHT
  • PEPTIDE-YY
  • OB/OB MICE
  • ENERGY HOMEOSTASIS
  • OBESITY SYNDROME
  • ZUCKER RATS
  • PATHWAYS

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