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Hypothalamic control of bone formation: distinct actions of leptin and y2 receptor pathways

Paul A Baldock1, Amanda Sainsbury, Susan Allison

  • 1Bone and Mineral Program, Garvan Institute of Medical Research, St Vincent's Hospital, Darlinghurst, Sydney, Australia. p.baldock@garvan.org.au

Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research
|September 15, 2005
PubMed
Abstract

Insights

Leptin and Y2 receptors influence bone formation through distinct pathways. While Y2 receptor deficiency stimulates bone growth, leptin inhibits it, with these effects opposing each other as obesity increases.

Area of Science:

  • Neuroendocrinology
  • Bone Physiology
  • Metabolic Regulation

Background:

  • Hypothalamic neurons, specifically leptin and Y2 receptors, are known to regulate energy homeostasis.
  • Previous studies show central bone formation enhancement in leptin-deficient (ob/ob) and Y2 receptor null (Y2-/-) mice, suggesting a shared pathway.
  • Neuropeptide Y (NPY) expression is elevated in these models, hinting at its role in central control of bone physiology.

Purpose of the Study:

  • To investigate the interaction between leptin and Y2 receptors in modulating osteoblast activity and bone formation.
  • To determine if leptin and Y2 receptor pathways regulate bone through the same or distinct mechanisms.

Main Methods:

  • Examined double mutant Y2-/- ob/ob mice to assess additive effects of concomitant leptin and Y2 receptor deficiency on bone.
  • Utilized recombinant adeno-associated viral vector overproduction of NPY (AAV-NPY) in Y2-/- mice to induce leptin excess and weight gain.
  • Assessed cancellous bone volume and bone cell function in experimental models.

Main Results:

  • Osteoblast activity was elevated in ob/ob, Y2-/-, and Y2-/- ob/ob mice, but cancellous bone volume was reduced in ob/ob and Y2-/- ob/ob mice due to increased bone resorption.
  • AAV-NPY administration in both wildtype and Y2-/- mice led to increased adipose tissue and leptin expression, reducing osteoblast activity.
  • Despite leptin's anti-osteogenic effect in obese mice, osteoblast activity remained significantly higher in Y2-/- AAV-NPY mice compared to wildtype AAV-NPY mice.

Conclusions:

  • Neuropeptide Y (NPY) is not a primary regulator of leptin-dependent osteoblast activity, as bone formation stimulation (leptin-deficient) and inhibition (excess leptin) occur with high NPY.
  • The Y2-/- pathway consistently stimulates bone formation, while leptin suppresses it as circulating levels rise, leading to opposing actions during obesity.
  • Distinct signaling pathways for leptin and Y2 receptors are revealed at physiological leptin levels, despite indistinguishable cancellous bone responses in the absence of leptin.

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