Y2Y4 receptor double knockout protects against obesity due to a high-fat diet or Y1 receptor deficiency in mice.
Neuropeptide Y receptors are critical regulators of energy homeostasis, but the functional interactions and relative contributions of Y receptors and the environment in this process are unknown. We measured the effects of an ad libitum diet of normal or high-fat food on energy balance in mice with single, double, or triple deficiencies of Y1, Y2, or Y4 receptors. Whereas wild-type mice developed diet-induced obesity, Y2Y4 double knockouts did not. In contrast, Y1 knockout or Y1Y2 or Y1Y4 receptor double knockout mice developed an exacerbated diet-induced obesity syndrome. Remarkably, the antiobesity effect of Y2Y4 deficiency was stronger than the obesogenic effect of Y1 deficiency, since Y1Y2Y4 triple knockouts did not develop obesity on the high-fat diet. Resistance to diet-induced obesity in Y2Y4 knockouts was associated with reduced food intake and improved glucose tolerance in the absence of changes in total physical activity. Fecal concentration of free fatty acids was significantly increased in Y2Y4 knockouts in association with a significantly reduced bile acid pool and marked alterations in intestinal morphology. In addition, hypothalamic proopiomelanocortin expression was decreased in diet-induced obesity (in both wild-type and Y1 receptor knockout mice) but not in obesity-resistant Y2Y4 receptor knockout mice fed a high-fat diet. Therefore, deletion of Y2 and Y4 receptors synergistically protects against diet-induced obesity, at least partially via changes in food intake and hypothalamic proopiomelanocortin expression.
Sainsbury
Amanda
A
Neurobiology Program, The Garvan Institute of Medical Research, St. Vincent's Hospital, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia. a.sainsbury-salis@garvan.org.au
Bergen
Hugo T
HT
Boey
Dana
D
Bamming
Darja
D
Cooney
Gregory J
GJ
Lin
Shu
S
Couzens
Michelle
M
Stroth
Nikolas
N
Lee
Nicola J
NJ
Lindner
Diana
D
Singewald
Nicolas
N
Karl
Tim
T
Duffy
Liesl
L
Enriquez
Ronaldo
R
Slack
Katy
K
Sperk
Günther
G
Herzog
Herbert
H
D000818:Animals; D004032:Diet; D004041:Dietary Fats / Q000494:pharmacology*; D005247:Feeding Behavior; D005786:Gene Expression Regulation; D018149:Glucose Intolerance; D007031:Hypothalamus / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000033:anatomy & histology; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity; D009765:Obesity / Q000235:genetics* / Q000517:prevention & control*; D017476:Receptors, Neuropeptide Y / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D022722:Thermogenesis
D004041:Dietary Fats; D017476:Receptors, Neuropeptide Y; C097212:neuropeptide Y-Y1 receptor; C095889:neuropeptide Y2 receptor; C109491:neuropeptide Y4 receptor