Full text of DOI:10.1359/jbmr.2002.17.9.1563

JOURNAL OF BONE AND MINERAL RESEARCH
Volume 17, Number 9, 2002
© 2002 American Society for Bone and Mineral Research
Mini-Review
Is Leptin the Link Between Fat and Bone Mass?
THIERRY THOMAS1 and BARTOLOME BURGUERA2
ABSTRACT
Recently, leptin has emerged as a potential candidate responsible for protective effects of fat on bone tissue.
However, it remains difficult to draw a clear picture of leptin effects on bone metabolism because published
data are sometimes conflicting or apparently contradictory. Beyond differences in models or experimental
procedures, it is tempting to hypothesize that leptin exerts dual effects depending on bone tissue, skeletal
maturity, and/or signaling pathway. Early in life, leptin could stimulate bone growth and bone size through
direct angiogenic and osteogenic effects on stromal precursor cells. Later, it may decrease bone remodeling in
the mature skeleton, when trabecular bone turnover is high, by stimulating osteoprotegerin (OPG) expression.
Leptin negative effects on bone formation effected through central nervous system pathway could counter-
balance these peripheral and positive effects, the latter being predominant when the blood-brain barrier
permeability decreases or the serum leptin level rises above a certain threshold. Thus, the sex-dependent
specificity of the relationship between leptin and bone mineral density (BMD) in human studies could be, at
least in part, caused by serum leptin levels that are two- to threefold higher in women than in men,
independent of adiposity. Although these hypotheses remain highly speculative and require further investi-
gations, existing studies consistently support the role of leptin as a link between fat and bone. (J Bone Miner
Res 2002;17:1563–1569)
Key words: bone, fat, leptin, obesity, osteoporosis
The relationship between fat mass and bone mass also
appears to be gender specific. Reid et al.(10) found no
association in men, but they and others(9–11) did find a
significant relationship between BFM and BMD in women.
Early after menopause, a higher body mass index (BMI) is
related to a slower bone loss rate induced by estrogen
deficiency.(12,13) In a group of elderly female hip fracture
patients, BFM has been shown to be a better explanatory
factor for hip fracture than lean mass or body weight.(14)
Likewise, in the prospective cohort study EPIDOS, a de-
crease of 1 SD in BFM was associated with a 30% increase
in hip fracture risk, whereas lean mass was not significantly
associated with fracture risk.(15)
INTRODUCTION
LTHOUGH OBESITY is a major risk factor for many dis-
eases and has become a severe burden on healthcare
A
costs in Western societies, it may have at least one benefi-
cial effect, that of preventing osteoporosis, itself another
major health problem. Indeed, it is well established that
body weight is one of the strongest predictors of bone mass
in both sexes.(1–5) However, the mechanisms that explain
this relationship remain unclear and there is still ongoing
controversy as to whether body fat mass (BFM) or lean
mass is a better predictor of bone mineral density
(BMD).(5–9)
Obesity-induced mechanical loading certainly is a con-
tributing factor in the positive relationship between BFM
The authors have no conflict of interest.
1INSERM E9901, University Hospital of Saint-Etienne, Saint-Etienne, France.
2Division of Endocrinology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
1563

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THOMAS AND BURGUERA
and BMD. But this protective effect has been observed even and long forms of leptin receptors. This expression might be
at non–weight-bearing bone sites.(11) Thus, factors other dependent on the differentiation stage, because Ducy et
than skeletal loading are likely important in mediating the al.(61) found no expression of these receptors in mature
relationship between BFM and BMD. Indeed, several lines murine osteoblasts. Both leptin and its receptors also were
of evidence have suggested that the effects of BFM on found in murine fetal cartilage/bone template(62) as well as
BMD may be mediated by hormonal factors, including in the growth plate, especially in chondrocytes close to the
estrogens and insulin. Adipose tissue produces estrogens by vascular invasion of this tissue.(63) These data are of great
aromatization of androgens,(16) which represents the princi- interest regarding the recently shown angiogenic properties
pal source of estrogens after menopause.(17) This peripheral of leptin.(49)
estrogen production could affect bone turnover and BMD,
especially after menopause.(18,19) However, BFM and BMD
Do we have evidence that leptin affects bone
metabolism?
remain positively and strongly correlated in women, even
after adjusting for serum estrogen levels.(20,21) It remains
controversial as to whether BFM is better associated with First, several in vitro studies suggest that stromal cells
BMD before(22,23) or after menopause.(6,24)
respond to leptin stimulation. Takahashi et al.(64) showed
Serum insulin levels also have been shown to be related that leptin induced MAPK-dependent cell proliferation in
to BMD,(25) and hyperinsulinemia has been proposed as a the mouse embryonic cell line C3H10T1/2, a multipotential
potential explanation for the association between obesity stromal cell line. These data recently were confirmed on a
and BMD in women, perhaps because of direct mitogenic different osteoblastic cell line.(58) These effects could be
effects of insulin on osteoblasts.(26,27) However, patients differentiation stage-dependent, because Thomas et al.(56)
with non–insulin-dependent diabetes mellitus have been observed no effect on proliferation in the human marrow
reported to have increased, decreased, or unchanged BMD stromal cell line hMS2–12, progenitor cells that probably
(reviewed by Thomas et al.(28)). Hence, other humoral or are more mature than the C3H10T1/2 cells. Conversely,
metabolic factors are almost certainly involved in the mech- leptin administration increased osteoblastic differentiation
anisms of fat-induced bone protection.
of these hMS2–12 cells, leading to an increase in the min-
Recently, leptin has emerged as a potential candidate eralization of the extracellular matrix.(56) Similar results
responsible for protective effects of fat on bone tissue. were observed in other cell models, with an increased num-
Leptin, the product of the ob gene, is secreted mainly by ber of mineralized nodules in rat cell culture treated with
white adipose tissue(29) and is correlated strongly with leptin(65) and in long-term human osteoblast cultures.(60)
BFM.(30–32) This 14-kDa protein is a representative marker
Leptin could be one of several factors that modulate the
of the body’s energetic status and raises considerable inter- reciprocal differentiation of stromal cells between osteo-
est. In fact, in addition to its effects on the central nervous blastic and adipocytic pathways, because it has the ability to
system,(33,34) recent studies provide new evidence of its role inhibit adipogenesis in a negative feedback loop.(50,56) The
in many different metabolic pathways. Besides insulin ac- cellular mechanisms, which mediate these effects, remain
tion, to which leptin is related strongly, leptin may alter unclear. The leptin-induced activation of the MAPK cas-
numerous endocrine functions, for example, hormonal se- cade may be critical because these biochemical events
cretion from the anterior pituitary,(35) ovaries,(36) testes,(37) stimulate both osteoblastic differentiation(66) and phos-
thyroid, and adrenal glands.(38) Experimental data suggest phorylation of peroxisome proliferator–activated receptor
that the central loop of leptin action regulating appetite and (PPAR␥), which has been shown to inhibit adipogenesis.(67)
these peripheral effects on endocrine glands are not related.(39)
In addition to direct positive effects on the osteoblastic
In addition to these effects, leptin may act as a growth differentiation of stromal cells, leptin also may modulate
factor, with the ability of directly enhancing development of bone remodeling. Indeed, it has been shown recently in
hemopoietic precursor cells,(40–44) myoblast-like cells,(45,46) human stromal cells that leptin inhibited the expression of
or lung cells.(47) Furthermore, it can modulate jejunum RANKL, the major downstream cytokine controlling oste-
epithelial cell activity,(48) and even more importantly, it oclastogenesis.(68) Furthermore, it stimulated the expression
exerts angiogenic effects on vascular endothelial cells.(49) of osteoprotegerin (OPG), its decoy receptor, by stromal
Conversely, leptin suppresses specific biochemical reac- cells(68) or mononuclear cells.(69) Leptin also was able to
tions that contribute to adipocyte differentiation and lipid induce the expression and secretion of the interleukin (IL)-1
accumulation.(50,51) Leptin acts through highly specific re- receptor antagonist by human monocytes,(70) which could
ceptors,(52) which have been described on hemopoietic pre- blunt an IL-1–related increase in bone turnover, another key
cursor cells,(40) in placenta and several fetal tissues,(53) event in estrogen deficiency–induced bone loss.
white and brown adipocytes,(54) in lung tissue,(49) and the
jejunum.(47)
Although leptin may exert direct effects on preosteoblas-
tic stromal cells, one has to keep in mind that its effects on
different endocrine systems could indirectly alter bone me-
tabolism as well. In fact, leptin has been shown to modulate
Are bone cells potential targets for leptin?
Bone marrow stromal cells have the ability of differenti- the growth hormone /insulin-like growth factor pathway,(71)
ating into osteoblasts as well as adipocytes, chondroblasts, the pituitary-thyroid axis,(72) as well as the pituitary-
and myoblasts.(55) Thomas et al.,(56) using a human stromal adrenal,(38) and gonadal axis.(36) The relative contribution of
cell line, and others(57–60) showed that these cells might these effects to the resultant action of leptin on bone re-
respond to leptin action because they expressed both short mains largely undetermined.

LEPTIN AND BONE
1565
Second, animal studies strongly suggest that leptin alters mice.(61) Actually, the most striking difference was the route
bone metabolism, but conclusions on the nature of these of leptin administration. Ducy et al. reported no change in
effects remain highly controversial so far. Logically, several serum leptin levels after icv leptin infusion,(61) strongly
studies have explored the putative effects of leptin on bone suggesting a central regulation of bone metabolism through
metabolism using animals either deficient in leptin, that is, a cascade of neuroendocrine events triggered by leptin.
the ob/ob mice, or with mutation in the leptin-receptor, that Paradoxically, these authors observed the same effects in
is, the fa/fa Zucker rats and the db/db mice. Foldes et al.(73) inhibiting bone formation with icv administration of the
showed that the obese fa/fa rats had a lower bone mass with neuropeptide Y,(61) an orexigenic peptide negatively regu-
shorter and lighter femurs, as compared with their normal lated by leptin at the hypothalamus level in the satiety
littermates (NLMs). The decrease in bone mass was asso- control loop.(84) Recently, Baldock et al.(85) reported inter-
ciated with an increase in bone resorption activity. Trabec- esting but puzzling data confirming, first, the existence of a
ular microarchitecture was also altered with an increase in central nervous regulation of bone formation and, second,
trabecular number but a decrease in trabecular thickness and the negative effects of NPY on osteoblast activity. Indeed,
no change in trabecular bone volume. A recent report on they showed that mice deficient in Y2 receptors (one of the
fa/fa rats presented different data with a significant increase five NPY receptor types) had a twofold increase in trabec-
in trabecular bone volume resulting in a significant increase ular bone volume. Furthermore, they showed that a selective
in biomechanical strength of long bones.(74) The reasons for deletion of hypothalamic Y2 receptors induced a similar
these discrepancies remain unclear but the association of increase in bone mass with a stimulated osteoblast activity
thicker cortices and shorter bones indeed may explain an and no change in osteoclast surfaces.
improved mechanical strength.
Next, recent studies, using normal rodent animals, indeed
Two studies evaluating the effects of peripheral leptin support the hypothesis that leptin effects on bone could
administration in ob/ob mice observed a stimulatory effect depend on the site of administration and, therefore, the
on bone growth(59) with a dramatic increase in cortical bone signaling pathway activated. Burguera et al.(68) showed that
formation(75) in treated animals as compared with their continuous subcutaneous administration of leptin to
controls. Indeed, intraperitoneal leptin administration to 6-month-old rats was able to prevent partially the rapid bone
4-week-old ob/ob male mice for 3 weeks reversed the defect loss induced by estrogen deficiency, in accordance with
in bone growth and osteopenia, as measured by DXA and leptin in vitro effects on OPG expression and osteoclasto-
peripheral quantitative computerized tomography (pQCT), genesis.(68,69) Using another model of rapid bone loss, the
despite a 40% decrease in food intake and a 14% decrease tail-suspended rat, characterized by a rapid increase in bone
in body weight.(59) No effect was observed in the lean resorption and a sustained decrease in bone formation,
littermates.
Thomas et al.(86) recently showed that a similar administra-
In contrast, Ducy et al. reported that 3-month and tion of leptin prevented disuse-induced bone loss. In addi-
6-month old ob/ob mice and db/db mice had higher bone tion, systemic daily administration of leptin to sexually
mass associated with a higher mineral apposition rate as mature male mice significantly increased bone strength by
compared with their wild-type littermates, despite hypogonad- Ͼ20%.(58)
ism and hypercortisolism secondary to leptin deficiency.(61)
Third, human cross-sectional studies provide data, which,
Furthermore, they showed that intracerebroventricular however, are less conclusive. Although some authors(87–89)
(icv) administration of leptin to 4-month old ob/ob fe- reported a positive association between serum leptin levels
male mice for 4 weeks normalized their bone mass. and BMD, others(90–92) failed to find such a relationship. In
Therefore, these authors suggested that the increase in a large cohort of 692 subjects, Thomas et al.(87) observed a
BMD observed in obese humans might be secondary to positive association between leptin and BMD in women but
leptin resistance, a phenomenon believed to be critical in not in men, regardless of the bone site (weight-bearing or
human obesity development.(76) This leptin resistance has not) and menopausal status. Furthermore, adjusting for lep-
been related first to a defect of leptin transport across the tin significantly reduced the positive association between
blood-brain barrier(77) into the central nervous system, as BFM and BMD in women. However, because leptin is
suggested by a more efficient leptin uptake (measured as almost exclusively produced by fat with a very strong
the cerebro-spinal fluid [CSF]/plasma leptin ratio) up to association between serum leptin levels and fat mass,(30–32)
four to six times greater in lean compared with obese the relationship between leptin and BMD disappeared after
individuals.(78–80) Second, a true hypothalamic resistance adjusting for fat mass in most(87,88,91) but not all(89) studies.
to leptin might occur with the onset of obesity, because Interestingly, Pasco et al.(93) recently reported a direct rela-
there was no correlation between cerebrospinal fluid con- tionship between serum leptin level and bone mineral con-
centrations of leptin and its principal mediators neu- tent (BMC) at the femur and lateral spine and with BMD at
ropeptide Y (NPY) and melanocyte stimulating hormone the lateral spine, even after adjusting for fat mass in a
(␣-MSH) in obese women.(81) Furthermore, a progressive population of 214 healthy nonobese women aged 20–91
resistance to icv administration of leptin on food intake years old. These data, together with a previous study show-
accompanied the development of high fat diet–induced ing a positive association between serum leptin level and
obesity in C57Bl/6J mice.(82,83)
whole body bone area,(94) suggest that leptin might act on
The reasons for discrepancies between different studies the periosteal envelope of cortical bone, thereby increasing
using the ob/ob mice model remain unclear. Age or sex bone size. Moreover, in a group of 139 postmenopausal
might play a role but similar data were observed in male women aged 48–78 years old, leptin levels were signifi-

1566
THOMAS AND BURGUERA
cantly lower in postmenopausal women with vertebral frac- leptin level rises above a certain threshold. Therefore, the
tures than in those without fracture.(89) In this study, mul- sex-dependent specificity of the relationship between leptin
tiple regression analysis showed leptin but not fat mass, as and BMD in human studies could be at least in part due to
a significant contributing factor to fracture presence.(89)
serum leptin levels that are 2- to 3-fold higher in women
In addition, there is some evidence that leptin may act as than in men, independent of adiposity. While these hypoth-
a growth factor during fetal development. Leptin and its eses remain highly speculative and require further investi-
receptor are produced by human placenta(95) and umbilical gations, existing studies consistently support the role of
cord leptin levels are associated positively with height(96) leptin as a link between fat and bone.
and weight(97,98) at birth in humans. This association was
independent of insulin-like growth factor I cord levels.(98)
Furthermore, leptin levels in umbilical cord blood were
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