Synergistic attenuation of obesity by Y2- and Y4-receptor double knockout in ob/ob mice.
OBJECTIVE
Neuropeptide Y regulates numerous processes including food intake, body composition, and reproduction by at least five different Y receptors. We previously demonstrated a synergistic interaction between Y2 and Y4 receptors in reducing adiposity in chow- or fat-fed Y2Y4-receptor double-knockout mice. In the present study, we investigated whether this synergy could reduce the massive obesity of leptin-deficient ob/ob mice.


METHODS
Mice with germline deletions of Y2 and Y4 receptors were crossed onto the ob/ob strain. Body weight was measured weekly until 15-18 wk of age before decapitation for collection of trunk blood and tissues.


RESULTS
Male and female Y24ob triple mutants showed highly significant reductions in body weight and white adipose tissue mass compared with ob/ob mice. This reduction in body weight was not evident in Y2ob or Y4ob double mutants, and the effect on adiposity was significantly greater than that seen in Y2ob or Y4ob mice. These changes were associated with significant attenuation of the increased brown adipose tissue mass and small intestinal hypertrophy seen in ob/ob mice and with normalization of the low circulating free thyroxine concentrations seen in female ob/ob mice and the high circulating corticosterone concentrations seen in male ob/ob mice.


CONCLUSIONS
These data reveal a synergistic interaction between Y2 and Y4 receptors in attenuating the massive obesity of ob/ob mice, possibly mediated by stimulation of thyroid function and inhibition of intestinal nutrient absorption. Dual pharmacologic antagonism of Y2 and Y4 receptors could help people to attain and maintain a healthy weight.
Lee
Nicola J
NJ
Neuroscience Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, New South Wales, Australia.
Enriquez
Ronaldo F
RF
Boey
Dana
D
Lin
Shu
S
Slack
Katy
K
Baldock
Paul A
PA
Herzog
Herbert
H
Sainsbury
Amanda
A
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D015519:Bone Density; D004195:Disease Models, Animal; D005260:Female; D005269:Femur; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism* / Q000517:prevention & control*; D017476:Receptors, Neuropeptide Y / Q000378:metabolism*
D017476:Receptors, Neuropeptide Y; C095889:neuropeptide Y2 receptor; C109491:neuropeptide Y4 receptor