p e d i a t r i c d e n t a l j o u r n a l x x x ( 2 0 1 7 ) 1 e6

Available online at www.sciencedirect.com

Pediatric Dental Journal

journal homepage: www.elsevier.com/locate/pdj

Review

Impact of a high-fat diet on bone health during

growth

Yuko Fujita*
Division of Developmental Stomatognathic Function Science, Department of Health Promotion, Kyushu Dental
University, Kitakyushu, Japan

article info abstract

Article history: Background: An inappropriate eating habit is a relatively easily modified risk factor for
Received 16 October 2017 obesity and osteoporosis in adults. The consumption of high-fat foods is known to induce
Accepted 1 November 2017 obesity. Although numerous studies have documented a relationship between high-fat diet
Available online xxx (HFD)-induced obesity and osteoporosis, no consensus has been reached. In addition, few
data on the relationships between mandibular properties and an HFD in the growth period
Keywords: are available.
High-fat diet Objective: This review aims to summarize current findings related to these issues, focusing
Obesity on the influence of an HFD on mandibular health, including mechanisms of periodontal
Jaw bone disease development.
Leptin Main results: Recent data suggest that HFD-induced obesity has a negative impact on the
mandible in mice. The loss of trabecular bone and reduction of cortical bone growth in mice
with HFD-induced obesity reflect a state of noninvasive and noninfective inflammation.
Authors' conclusions: These results are related to the potential association between meta-
bolic stress and systemic inflammatory changes occurring in bone and other tissues.
© 2017 Japanese Society of Pediatric Dentistry. Published by Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. High-fat dieteinduced obesity and bone mass . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. Relationships among a high-fat diet, leptin, and bone mineral density . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. High-fat diet and inflammation in bone tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5. High-fat dieteinduced obesity and periodontal disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

* Division of Developmental Stomatognathic Function Science, Department of Health Promotion, Kyushu Dental University, 2-6-1
Manaduru, Kokurakita-ku, 803-8580 Kitakyushu, Japan.
E-mail address: y-fujita@kyu-dent.ac.jp.
https://doi.org/10.1016/j.pdj.2017.11.003
0917-2394/© 2017 Japanese Society of Pediatric Dentistry. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Fujita Y, Impact of a high-fat diet on bone health during growth, Pediatric Dental Journal (2017),
https://doi.org/10.1016/j.pdj.2017.11.003
2 p e d i a t r i c d e n t a l j o u r n a l x x x ( 2 0 1 7 ) 1 e6
1. Introduction
The prevalence of overweight and obesity is increasing
worldwide [1]. In 2015, 107.7 million children and 603.7 million
adults were obese. Since 1980, the prevalence of obesity has
doubled in more than 70 countries and has increased
continuously in most other countries. Although the preva-
lence of obesity is lower among children than among adults,
the rate of increase in childhood obesity has been greater than
the rate of increase in adult obesity in many countries [2]. In
recent decades, the eating habits of children and adolescents
have undergone many changes due to lifestyle diversification
in many countries. [3,4]. In Japan, the National Health and
Nutrition Survey showed that mean fat intake increased from
25.8 g/day in 1961 to 57.0 g/day in 2015 [5]. Overweight children
are at greater risk of developing type 2 diabetes, hypertension,
and hyperlipidemia, which in turn increase the risk of car-
diovascular disease later in life.[6]
The development of obesity and osteoporosis in adults can
be traced to dietary intake and physical activity during
childhood and adolescence. Inappropriate nutritional intake
is a relatively easily modified risk factor for obesity and oste-
oporosis. The relationship between the consumption of high-
fat foods and obesity is well established [7], but whether it
affects bone architecture in childhood and adolescence re-
mains controversial.
In this review, I summarize the effects of high-fat diet
(HFD)-induced obesity on bone health, including the health of
alveolar and periodontal bone, and examine the relationship
between leptin and bone mass using current findings from
human and animal studies. The mechanisms of bone loss due
to HFD-induced obesity are also discussed.
2. High-fat dieteinduced obesity and bone
mass
Although a relationship between obesity and osteoporosis has
been proposed in the clinical literature [8e10], no consensus
has been reached. Several researchers have observed an
increased fracture incidence in obese adolescents and chil-
dren compared with age-matched controls [8,9]. Additionally,
bone fragility may occur in obese children and adolescents
because of malnutrition [10].
In animal studies, a positive correlation between obesity
and long-bone density was found in 4-week-old male mice fed
an HFD for 19 weeks [11], whereas obesity was correlated
negatively with long-bone mass in 6-week-old male mice fed
an HFD for 14 weeks and 7-week-old male mice fed an HFD for
24 weeks [12,13]. Bartelt et al. showed that HFD-induced
obesity did not significantly affect long-bone mass in 4-
week-old male mice treated for 16 weeks [14]. They sug-
gested that conflicting results from previous studies regarding
the relationship between HFD-induced obesity and bone mass
were attributable to differences in the fatty acid profiles of the
diets. Several studies have shown associations between the
fatty acid compositions of diets and bone health. Weiss et al.
reported that a higher ratio of linoleic acid (n-6) to a-linolenic
acid (n-3) was associated with detrimental effects on bone
Please cite this article in press as: Fujita Y, Impact of a high-fat diet on bone health during growth, Pediatric Dental Journal (2017),
https://doi.org/10.1016/j.pdj.2017.11.003
health in humans [15], and Watkins et al. showed that a lower
ratio of dietary n-6/n-3 was associated with the promotion of
bone formation in rats [16]. Bartelt et al. proposed that more
precise data could be obtained by considering the fatty acid
ratio of dietary components when choosing standard diets
and HFDs [14]. However, regardless of the changes in bone
mass, many studies have shown significant increases in the
size and number of adipocytes in the long-bone marrow of
mice with HFD-induced obesity [13,14,17e19]. These findings
suggest that HFD-induced obesity causes significant bone loss
in mice, due mainly to resorptive changes in the trabecular
architecture caused by the increase in, and enlargement of,
adipocytes in bone marrow. However, the factors mediating
such environmental changes in bone marrow, and the ways in
which those mediators and bone-marrow adiposity affect
bone metabolism, remain unclear.
In microecomputed tomography analyses, 7-week-old male
mice fed an HFD for 4 weeks showed significantly reduced
trabecular bone volume, cortical bone thickness, and cortical
bone cross-sectional area in the mandible compared with
control mice fed a standard diet. In addition, significant de-
creases in cortical bone density in HFD-fed mice relative to age-
matched controls were observed after 12 weeks of HFD treat-
ment. Although cortical bone formation in the mandible was
slower in HFD-fed mice than in control mice, bone formation
on the periosteal surface increased with age in both groups for
12 weeks [20]. These data support the difference in responses of
trabecular and cortical bone to diet-induced obesity; bone loss
at these two sites is regulated differentially in mice.
3. Relationships among a high-fat diet,
leptin, and bone mineral density
A clinical investigation of the relationship between obesity
and osteoporosis suggested that adipose tissue influences
bone mineral density through the production of hormones and
adipokines, such as leptin [10]. Generally, leptin is known to be
an important circulating signal that inhibits food intake and
enhances energy expenditure through its actions in the brain
[21]. Therefore, several researchers have suggested that an
HFD plays a key role in the development of leptin resistance in
animals with HFD-induced obesity [22,23]. In confirmation of
this proposed role, Choi et al. showed that energy expenditure
was lower in mice fed an HFD than in those few a low-fat diet,
despite the similarity in intake between the two groups [24].
The relationship between leptin and bone is complex, with
diverging effects depending on whether central or peripheral
mechanisms are in operation [25,26]. Centrally, leptin has
been shown to inhibit bone formation through a hypotha-
lamic relay, and this effect is suppressed by b blockers [27,28].
Peripherally, leptin has a positive effect on bone in rats [29]; an
in vitro study also showed that leptin promotes increased
production of the potent antiresorptive factor osteoprotegerin
by osteoblasts [30].
Studies involving children have documented a direct rela-
tionship between the serum leptin concentration and bone
mass, but conflicting findings have been reported [31e33]; in
one study, the serum leptin concentration was not related to
bone mineral density in boys or girls [34].
 p e d i a t r i c d e n t a l j o u r n a l x x x ( 2 0 1 7 ) 1 e6
Seven-week-old male mice fed an HFD for 12 weeks
showed a significant increase in the serum leptin level
compared with age-matched controls, and the serum leptin
level was correlated negatively with trabecular bone mineral
density in the tibia [19]; these findings were consistent with
those of Patsch et al. [13]. In contrast, Iwaniec et al. demon-
strated that leptin was not required for increased femoral
cortical bone mass associated with increased body mass in
leptin-deficient ob/ob and diet-induced obese mouse models
[35]. These data support the correlation between trabecular,
but not cortical, bone mass and the serum leptin level in mice
with diet-induced obesity.
4. High-fat diet and inflammation in bone
tissue
Several in vitro and in vivo studies have shown that hyper-
nutrition leads to endoplasmic reticulum stress induced by free
fatty acidemediated reactive oxygen species (ROS), and thus
also to inflammation, in adipose tissue [36e38]. Another study
showed that oxidative stress causes alveolar bone resorption in
a mouse model of metabolic syndrome [39]. Oxidative stress is
characterized by an increased ROS level, which disrupts the
intracellular reductioneoxidation balance [40]. Recent animal
studies have also shown that an HFD contributes to obesity in
association with a state of chronic inflammation [41,42], and
elevates the production of pro-inflammatory cytokines,
including tumor necrosis factor-a, interleukin (IL)-1b, and IL-6,
which are released from adipocytes and macrophages via
activation of the c-Jun N-terminal kinase and nuclear factor-kB
pathways [37,43,44]. These data suggest that an increase in the
Fig. 1 e Proposed relationship among high-fat diet (HFD)-induced obesity, inflammation, and bone metabolism.
Please cite this article in press as: Fujita Y, Impact of a high-fat diet on bone health during growth, Pediatric Dental Journal (2017),
https://doi.org/10.1016/j.pdj.2017.11.003
3
ROS level induces inflammatory changes in adipocytes in bone
marrow. In addition, Dib et al. showed that leptin acts as a pro-
inflammatory adipocytokine in peripheral tissues of mice [45].
These cytokines have been shown to increase osteoclast dif-
ferentiation via the RANKL/RANK/OPG pathway [46]. Halade
et al. showed that significantly elevated levels of pro-
inflammatory cytokines, due to the accumulation of adipo-
cytes in bone marrow, result in an increase in bone resorption
in mice fed an HFD [47]. Kyung et al. showed that osteoclast
differentiation and bone resorption are stimulated in bone
marrowederived macrophages from obese mice [48]. Other
studies have suggested that obesity increases bone-marrow
adipogenesis, while inhibiting osteoblastogenesis, because ad-
ipocytes and osteoblasts are derived from a common multi-
potent mesenchymal stem cell [49,50]. Moreover, oxidative
stress has been shown to inhibit osteoblastogenesis in vitro
[51,52]. Thus, these data suggest that the deterioration of bone
structure in HFD-fed mice is due to an abnormal ROS level in
adipocytes, which increases inflammation in bone marrow and
other tissues, increases bone resorption, and decreases bone
formation. These findings are summarized in Fig. 1.
5. High-fat dieteinduced obesity and
periodontal disease
In a recent report, researchers suggested that systemic osteo-
porosis is linked to periodontal bone loss, based on significant
up-regulation of inflammatory cytokines in the bone and bone-
marrow cells of rats with osteoporosis [53]. Several animal
studies have also linked obesity to type 2 diabetes, and hyper-
caloric diet inducedeobesity to morbidity from periodontal
4 p e d i a t r i c d e n t a l j o u r n a l x x x ( 2 0 1 7 ) 1 e6

Fig. 2 e Inflammation and resorption of periodontal bone.

disease [54,55]. However, HFD-induced alveolar bone loss has
been taken to reflect a state of noninvasive and noninfective
inflammation in mice, such as that characteristic of autoim-
mune disorders [20]. Recently, Suganami et al. proposed the
concept of “homeostatic inflammation” in the pathogenesis of
noninfectious inflammatory diseases [56]. This state would
account for HFD-induced alveolar bone loss in mice, in which
systemic inflammatory changes in bone and other tissues may
have developed in association with metabolic stress [20].
In a previous study, rats fed a high-cholesterol diet showed
a modest increase in the distance between the cementoena-
mel junction and the alveolar bone crest [57]. Additionally,
mice fed an HFD for 8 weeks showed significant disruption of
the periodontal ligament fibers, which had lost their orienta-
tions with respect to the bone surface, and inhibition of the
constriction of the periodontal ligament space accompanied
by pronounced vasodilatation and inflammatory cell infiltra-
tion [20]. These data suggest that increased vascular perme-
ability due to inflammatory changes in the blood vessels of the
periodontium promotes monocyte adhesion to endothelial
cells and migration. In addition, osteoclasts differentiated
from those monocytes may have attached to the alveolar bone
surface, resulting in increased alveolar bone resorption, in
HFD-fed mice (Fig. 2).
Together, these findings demonstrate that spontaneous
deterioration of periodontal bone is a consequence of HFD-
induced obesity during growth.
6. Conclusion
Recent data suggest that HFD-induced obesity has a negative
impact on the mandible in mice. The loss of trabecular bone
and reduction of cortical bone growth in mice with HFD-
induced obesity reflect a state of noninvasive and noninfec-
tive inflammation. These results are related to the potential
association between metabolic stress and systemic inflam-
matory changes occurring in bone and other tissues. Another
possible explanation involves the direct or indirect effects of
increased serum leptin levels on trabecular bone in mice fed
an HFD.
Conflict of interest
I declare no conflict of interest.
Acknowledgements
I appreciate the help of Prof. Kenshi Maki in the editing of the
manuscript. This work was supported by Grants-in-Aid from
the Ministry of Education, Culture, Sports, Science and Tech-
nology, Japan (25713064 and 17K11967).
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