Bone abnormalities in adolescent leptin-deficient mice

Ealey, Kafi N.; Fonseca, Debbie; Archer, Michael C.; Ward, Wendy E.

doi:10.1016/j.regpep.2006.04.013

Cited by 61 publications

(72 citation statements)

References 23 publications

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“…However, this conclusion is based on measurements limited to vertebrae. As shown in the current and earlier studies [27,30,32,33,36,44], leptin deficiency results in decreased femur length and mass. The results presented in this study indicate that increasing hypothalamic leptin in ob/ob mice via rAAVlep transfer does not result in osteopenia but leads to a normalization of cortical as well as cancellous bone volume to that of WT mice.…”

Section: Discussionsupporting

confidence: 78%

“…Leptin is produced predominantly by fat cells, functions as a sentinel of energy balance, and has been recently identified as an important bone regulatory factor [26]. The obese ob/ob mouse, which cannot produce leptin due to an inactivating mutation in the leptin gene has skeletal abnormalities; compared to wildtype (WT) mice, ob/ob mice have reduced bone length and reduced overall bone mass [27,32,33,36,44]. These findings suggest leptin is required for optimal peak bone growth and quality.…”

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confidence: 99%

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Central leptin gene therapy corrects skeletal abnormalities in leptin-deficient ob/ob mice

et al. 2007

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Skeletal growth is tightly coupled to energy balance via complex and incompletely understood mechanisms. Leptin-deficient ob/ob mice are obese and develop multiple pathologies associated with the metabolic syndrome. Additionally, ob/ob mice have skeletal abnormalities. The objective of this study was to evaluate the effects of leptin deficiency and long-duration selective central leptin repletion via recombinant adeno-associated virus-leptin (rAAV-lep) gene therapy on bone in growing ob/ob mice. The ob/ob mice were injected in the hypothalamus with either rAAV-lep or rAAV-GFP (control vector). Treated ob/ob and untreated wildtype (WT) mice were then maintained on a normal diet for 15 weeks. In a second experiment, similarly treated mice along with a group of pair-fed mice were maintained for 30 weeks. Leptin was not detected in blood of either rAAV-lep or rAAV-GFPtreated mice although rAAV-lep treated mice displayed leptin transgene expression in the hypothalamus. As expected, rAAV-lep normalized body weight and food intake. Compared to WT mice, rAAV-GFP-treated ob/ob mice had decreased femoral length (by 1.6 mm or 10 %, P<0.001), decreased total femur bone volume (by 3.3 mm 3 or 19%, P<0.001), but increased cancellous bone volume in the distal femur (by 0.04 mm 3 or 60%, P<0.09) and lumbar vertebrae (by 0.26 mm 3 or 118%, P<0.001). Treatment with rAAV-lep rescued the ob/ob skeletal phenotype by increasing femoral length and total bone volume, and decreasing femoral and vertebral cancellous bone volume, so that at 15 weeks post-rAAV-lep injection the ob/ob mice no longer differed from WT mice. No further skeletal changes in either the femur or lumbar vertebra were observed at 30 weeks post-rAAVlep administration. The results suggest that hypothalamic leptin functions as an essential permissive factor for normal bone growth.

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Section: Discussionsupporting

confidence: 78%

mentioning

confidence: 99%

Central leptin gene therapy corrects skeletal abnormalities in leptin-deficient ob/ob mice

et al. 2007

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“…Because leptin directly influences bone metabolism, the skeletal phenotype of the ob/ob mouse is not attributed solely to the observed metabolic changes. Moreover, many studies showed a complex skeletal phenotype with ob/ob having higher trabecular bone mass in the lumbar vertebrate, but lower trabecular and cortical bone mass in the long bones [42][43][44], as well as shorter femurs compared to control. Furthermore, ob/ob mice have decreased biomechanical properties (eg, maximum load) as determined by three-point bending of the femur [42][43][44].…”

Section: Bone Loss In Obese Type 2 Diabetesmentioning

confidence: 99%

“…Moreover, many studies showed a complex skeletal phenotype with ob/ob having higher trabecular bone mass in the lumbar vertebrate, but lower trabecular and cortical bone mass in the long bones [42][43][44], as well as shorter femurs compared to control. Furthermore, ob/ob mice have decreased biomechanical properties (eg, maximum load) as determined by three-point bending of the femur [42][43][44]. This mouse also have lower bone mass and markedly reduced bone formation in vertebrate and long bones compared to wild-type controls, and this deficiency can be corrected with leptin treatment [30,[42][43][44][45].…”

Section: Bone Loss In Obese Type 2 Diabetesmentioning

confidence: 99%

“…Furthermore, ob/ob mice have decreased biomechanical properties (eg, maximum load) as determined by three-point bending of the femur [42][43][44]. This mouse also have lower bone mass and markedly reduced bone formation in vertebrate and long bones compared to wild-type controls, and this deficiency can be corrected with leptin treatment [30,[42][43][44][45].…”

Section: Bone Loss In Obese Type 2 Diabetesmentioning

confidence: 99%

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Type 1 diabetic bone loss is prevented by novel osteogenic factors

Yamaguchi¹

2014

Integr. Diabetes Obesity,

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Obesity and diabetes are currently a major health problem worldwide with growing in prevalence. Obesity and diabetes induce secondary diseases with various pathophysiologic states including cardiovascular disease, neural disturbance, kidney disease, cancer and osteoporosis. Bone homeostasis is maintained through a delicate balance between osteoblastic bone formation and osteoclastic bone resorption. Aging and numerous pathological processes induce decrease in osteoblastic bone formation and increase in osteoclastic bone resorption, leading to osteoporosis with decrease in bone mass. Osteoblasts and adipocytes differentiate from a common precursor cell in the bone marrow mesenchymal stem cells. Type 1 and obese type 2 diabetes have been associated with increased fracture risk. Nutritional chemical factors are found to prevent diabetic osteoporosis. Zinc, Satsuma mandarin orange (Citrus unshiu MARC.) β-cryptoxanthin and plant component p-hydroxycinnamic acid was found to reveal stimulatory effects on osteoblastic bone formation and suppressive effects on osteoclastic bone resorption, thereby increasing bone mass. These factors were found to improve type 1 diabetic bone loss in vivo. Moreover, p-hydroxycinnamic acid suppressed adipogenesis in bone marrow cells in vitro. Such functional food factors may improve bone loss implicated with type 1diabetes and obese type 2 diabetes.

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Paradoxical Effects of Partial Leptin Deficiency on Bone in Growing Female Mice

Philbrick

Turner

Branscum

et al. 2015

The Anatomical Record

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Morbidly obese, leptin-deficient ob/ob mice display low bone mass, mild osteoclast-rich osteopetrosis, and increased bone marrow adiposity. While partial leptin deficiency results in increased weight, the skeletal manifestations of partial leptin deficiency are less well defined. We therefore analyzed femora and lumbar vertebrae in growing (7-week-old) female C57BL/6 wildtype (WT) mice, partial leptin-deficient ob/+ mice, and leptin-deficient ob/ob mice. The bones were evaluated by dual energy absorptiometry, microcomputed tomography and histomorphometry. As expected, ob/+ mice were heavier, had more white adipose tissue, and lower serum leptin than WT mice, but were lighter and had less white adipose tissue than ob/ob mice. With a few exceptions, cancellous bone architecture, cell (osteoblast, osteoclast, and adipocyte), and dynamic measurements did not differ between WT and ob/+ mice. In contrast, compared to WT and ob/+ mice, ob/ob mice had lower cancellous bone volume fraction and higher bone marrow adiposity in the femur metaphysis, and higher cancellous bone volume fraction in lumbar vertebra. Paradoxically, ob/+ mice had greater femoral bone volume than either WT or ob/ob mice. There was a positive correlation between body weight and femur volume in all three genotypes. However, the positive effect of weight on bone occurred with lower body weight in leptin-producing mice. The paradoxical differences in bone size among WT, ob/+, and ob/ob mice may be explained if leptin, in addition to stimulating bone growth and cancellous bone turnover, acts to lower the set-point at which increased body weight leads to a commensurate increase in bone size.

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Bone abnormalities in adolescent leptin-deficient mice

Cited by 61 publications

References 23 publications

Central leptin gene therapy corrects skeletal abnormalities in leptin-deficient ob/ob mice

Central leptin gene therapy corrects skeletal abnormalities in leptin-deficient ob/ob mice

Type 1 diabetic bone loss is prevented by novel osteogenic factors

Paradoxical Effects of Partial Leptin Deficiency on Bone in Growing Female Mice

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