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Abstract
Neuropeptide Y (NPY) is a powerful stimulant of appetite and an important regulator of energy homeostasis. Along with pancreatic polypeptide (PP) and peptide YY (PYY), NPY activates 5 G-protein coupled receptors: Y1, Y2, Y4, Y5 and Y6. As a processed pseudogene, the role of the human Y6 is of interest given emerging evidence of functional pseudogenes. In the mouse, where it is expressed as a fully functional protein, the role of Y6 is unknown.
In this study, we demonstrated that loss of Y6 in mice (Y6-/- mice) led to a marked elevation in metabolic rate without compensatory hyperphagia. As a result, Y6-/- mice showed significant reductions in body weight relative to wild type (WT) mice, which was accompanied by pronounced reductions in lean mass and an age-induced increase in adiposity at 20 and 24 weeks of age. Loss of Y6 receptors in mice led to significant enhancement of glucose tolerance. Secondary to the increase in adiposity, 24-week-old Y6-/- mice showed a significant elevation in non-fasted serum insulin level without any change in glucose tolerance. The effects of Y6 deletion were exacerbated by 16 weeks of high fat feeding, during which time Y6-/- mice showed increased body weight and fat gain, and pronounced deterioration of glucose homeostasis.
The metabolic deregulations in Y6-/- mice may arise from impaired central vasoactive intestinal peptide (VIP) signaling. Indeed, this work shows that Y6 are expressed in neurons expressing VIP in the hypothalamic suprachiasmatic nucleus (SCN). In line with the established role of VIP in regulating the growth hormone axis and circadian rhythm, we showed a significant reduction in serum IGF-1 level in Y6-/- relative to WT mice, along with aberrant corticosterone and feeding rhythms. Since low serum IGF-1 level and circadian arrhythmicity are associated with obesity, our results suggest that the reduction in lean mass and age-induced increase in adiposity in Y6-/- mice may be consequences of these factors. Additionally, peripheral administration of PP, but not PYY or PYY3-36, significantly increased c-fos expression in the SCN of WT but not Y6-/- mice relative to saline-treated animals, suggesting that PP is a physiological activator of Y6. Collectively, this data demonstrated that the mouse Y6 receptor plays an important role in the regulation of energy homeostasis, possibly via PP actions on VIP neurons, acting to influence the growth hormone axis and circadian rhythm.