Conditional deletion of hypothalamic Y2 receptors reverts gonadectomy-induced bone loss in adult mice.
Reduction in levels of sex hormones at menopause in women is associated with two common, major outcomes, the accumulation of white adipose tissue, and the progressive loss of bone because of excess osteoclastic bone resorption exceeding osteoblastic bone formation. Current antiresorptive therapies can reduce osteoclastic activity but have only limited capacity to stimulate osteoblastic bone formation and restore lost skeletal mass. Likewise, the availability of effective pharmacological weight loss treatments is currently limited. Here we demonstrate that conditional deletion of hypothalamic neuropeptide Y2 receptors can prevent ongoing bone loss in sex hormone-deficient adult male and female mice. This benefit is attributable solely to activation of an anabolic osteoblastic bone formation response that counterbalances persistent elevation of bone resorption, suggesting the Y2-mediated anabolic pathway to be independent of sex hormones. Furthermore, the increase in fat mass that typically occurs after ovariectomy is prevented by germ line deletion of Y2 receptors, whereas in male mice body weight and fat mass were consistently lower than wild-type regardless of sex hormone status. Therefore, this study indicates a role for Y2 receptors in the accumulation of adipose tissue in the hypogonadal state and demonstrates that hypothalamic Y2 receptors constitutively restrain osteoblastic activity even in the absence of sex hormones. The increase in bone formation after release of this tonic inhibition suggests a promising new avenue for osteoporosis treatment.
Allison
Susan J
SJ
Bone and Mineral Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
Baldock
Paul
P
Sainsbury
Amanda
A
Enriquez
Ronaldo
R
Lee
Nicola J
NJ
Lin
En-Ju Deborah
EJ
Klugmann
Matthias
M
Klugman
Matthias
M
During
Matthew
M
Eisman
John A
JA
Li
Mei
M
Pan
Lydia C
LC
Herzog
Herbert
H
Gardiner
Edith M
EM
D000273:Adipose Tissue / Q000503:physiopathology; D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001835:Body Weight / Q000235:genetics; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control*; D005260:Female; D005269:Femur / Q000503:physiopathology; D017353:Gene Deletion; D007031:Hypothalamus / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009919:Orchiectomy / Q000009:adverse effects; D017476:Receptors, Neuropeptide Y / Q000172:deficiency* / Q000235:genetics*; D013131:Spine / Q000503:physiopathology
D017476:Receptors, Neuropeptide Y; C095889:neuropeptide Y2 receptor