Combined deletion of Y1, Y2, and Y4 receptors prevents hypothalamic neuropeptide Y overexpression-induced hyperinsulinemia despite persistence of hyperphagia and obesity.
Neuropeptide Y (NPY) is a key regulator of energy homeostasis and is implicated in the development of obesity and type 2 diabetes. Whereas it is known that hypothalamic administration of exogenous NPY peptides leads to increased body weight gain, hyperphagia, and many hormonal and metabolic changes characteristic of an obesity syndrome, the Y receptor(s) mediating these effects is disputed and unclear. To investigate the role of different Y receptors in the NPY-induced obesity syndrome, we used recombinant adeno-associated viral vector to overexpress NPY in mice deficient of selective single or multiple Y receptors (including Y1, Y2, and Y4). Results from this study demonstrated that long-term hypothalamic overexpression of NPY lead to marked hyperphagia, hypogonadism, body weight gain, enhanced adipose tissue accumulation, hyperinsulinemia, and other hormonal changes characteristic of an obesity syndrome. NPY-induced hyperphagia, hypogonadism, and obesity syndrome persisted in all genotypes studied (Y1(-/-), Y2(-/-), Y2Y4(-/-), and Y1Y2Y4(-/-) mice). However, triple deletion of Y1, Y2, and Y4 receptors prevented NPY-induced hyperinsulinemia. These findings suggest that Y1, Y2, and Y4 receptors under this condition are not crucially involved in NPY's hyperphagic, hypogonadal, and obesogenic effects, but they are responsible for the central regulation of circulating insulin levels by NPY.
Lin
En-Ju D
EJ
Neuroscience Research Program, The Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia. d.lin@garvan.org.au
Sainsbury
Amanda
A
Lee
Nicola J
NJ
Boey
Dana
D
Couzens
Michelle
M
Enriquez
Ronaldo
R
Slack
Katy
K
Bland
Ross
R
During
Matthew J
MJ
Herzog
Herbert
H
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D005260:Female; D006801:Humans; D006946:Hyperinsulinism / Q000209:etiology / Q000517:prevention & control*; D006963:Hyperphagia / Q000097:blood / Q000209:etiology*; D007031:Hypothalamus / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009478:Neuropeptide Y / Q000502:physiology*; D009765:Obesity / Q000097:blood / Q000209:etiology*; D017476:Receptors, Neuropeptide Y / Q000502:physiology*
D001786:Blood Glucose; D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; C097212:neuropeptide Y-Y1 receptor; C095889:neuropeptide Y2 receptor; C109491:neuropeptide Y4 receptor