Leptin, the protein product of the Ob gene, acts on multiple organs, including bone. Leptin deficient ob/ob mice and leptin receptor-deficient db/db mice exhibit a mosaic skeletal phenotype;compared to wild-type mice, mutant mice have reduced bone length and overall bone mass but exhibit site-specific increases in cancellous bone. These abnormalities suggest that leptin sufficiency is essential for normal bone growth, turnover and function. However, the precise mechanisms by which leptin regulates bone metabolism to produce these changes are only partially known, in part, because leptin has the potential to affect bone cells through multiple pathways;an indirect pathway involving a hypothalamic relay and a direct pathway involving the binding of leptin to its receptors on cartilage and bone cells. We hypothesize that the regulation of bone metabolism by leptin is even more complex than currently appreciated. We propose that the apparent skeletal resistance to the hypothalamic actions of leptin occurs as a result of a negative feedback loop involving afferent signaling via sensory neurons in bone and efferent signaling from the hypothalamus via sympathetic neurons. Furthermore, a second negative feedback loop involves regulation of adipocyte differentiation. Specifically, adipocytes produce leptin in proportion to their number and size but hypothalamic leptin antagonizes differentiation of bone marrow stromal cells to adipocytes while enhancing osteoblast differentiation. We will test these hypotheses in ob/ob and db/db mice by accomplishing the following specific aims;1) determine the respective roles of peripheral (serum leptin and leptin produced by the skeleton) and hypothalamic leptin on bone growth and turnover, and 2) determine if leptin regulates the differentiation of bone marrow-derived stromal cells to adipocytes and osteoblasts.
Aim 1 will test the hypothesis that leptin has peripheral-mediated as well as hypothalamic-mediated actions on bone. Additionally, it will test the hypothesis that the hypothalamic actions of the hormone are self limiting because of a negative feed back loop involving afferent signaling via sensory neurons and efferent signaling via sympathetic neurons. Importantly, the proposed studies will establish whether the transient compartment-specific effects of hypothalamic leptin on growth plate, cortical bone and cancellous bone can be explained by the hypothesized opposing peripheral- and hypothalamic-mediated actions of the hormone.
Aim 2 will test the hypothesis that hypothalamic and/or peripheral leptin regulates the differentiation of bone marrow stromal cells to form osteoblasts or adipocytes. These studies will establish whether the peripheral effects of leptin on stromal cell differentiation are opposed by hypothalamic-mediated actions of the hormone. The long-term goal of our research is to understand how lifestyle factors interact with genetics to determine peak bone mass. The proposed research will clarify the cellular mechanisms for leptin- induced regulation of bone growth and architecture. An understanding of the role of leptin and its complex mechanisms of action on bone growth is important because a low peak mass is a risk factor for osteoporosis.

Public Health Relevance

Leptin, a hormone produced predominantly by fat cells, is essential for normal bone to achieve an optimal peak bone mass. The proposed research will investigate the mechanisms by which leptin affects bone metabolism. This research is important because a low peak bone mass is a major risk factor for osteoporosis later in life.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Small Research Grants (R03)
Project #
5R03AR054609-02
Application #
7779414
Study Section
Special Emphasis Panel (ZAR1-EHB-H (M1))
Program Officer
Sharrock, William J
Project Start
2009-03-01
Project End
2012-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
2
Fiscal Year
2010
Total Cost
$72,369
Indirect Cost
Name
Oregon State University
Department
Nutrition
Type
Other Domestic Higher Education
DUNS #
053599908
City
Corvallis
State
OR
Country
United States
Zip Code
97339
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Iwaniec, Urszula T; Boghossian, Stephane; Trevisiol, Cynthia H et al. (2011) Hypothalamic leptin gene therapy prevents weight gain without long-term detrimental effects on bone in growing and skeletally mature female rats. J Bone Miner Res 26:1506-16
Jackson, M A; Iwaniec, U T; Turner, R T et al. (2011) Effects of increased hypothalamic leptin gene expression on ovariectomy-induced bone loss in rats. Peptides 32:1575-80
Turner, Russell T; Iwaniec, Urszula T (2011) Low dose parathyroid hormone maintains normal bone formation in adult male rats during rapid weight loss. Bone 48:726-32
Turner, R T; Iwaniec, U T (2010) Moderate weight gain does not influence bone metabolism in skeletally mature female rats. Bone 47:631-5
Menagh, Philip J; Turner, Russell T; Jump, Donald B et al. (2010) Growth hormone regulates the balance between bone formation and bone marrow adiposity. J Bone Miner Res 25:757-68