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Congenital lipodystrophy induces severe osteosclerosis
- Source :
- PLoS Genetics, PLoS Genetics, Vol 15, Iss 6, p e1008244 (2019)
- Publication Year :
- 2019
- Publisher :
- Public Library of Science, 2019.
-
Abstract
- Berardinelli-Seip congenital generalized lipodystrophy is associated with increased bone mass suggesting that fat tissue regulates the skeleton. Because there is little mechanistic information regarding this issue, we generated "fat-free" (FF) mice completely lacking visible visceral, subcutaneous and brown fat. Due to robust osteoblastic activity, trabecular and cortical bone volume is markedly enhanced in these animals. FF mice, like Berardinelli-Seip patients, are diabetic but normalization of glucose tolerance and significant reduction in circulating insulin fails to alter their skeletal phenotype. Importantly, the skeletal phenotype of FF mice is completely rescued by transplantation of adipocyte precursors or white or brown fat depots, indicating that adipocyte derived products regulate bone mass. Confirming such is the case, transplantation of fat derived from adiponectin and leptin double knockout mice, unlike that obtained from their WT counterparts, fails to normalize FF bone. These observations suggest a paucity of leptin and adiponectin may contribute to the increased bone mass of Berardinelli-Seip patients.<br />Author summary Berardinelli-Seip congenital generalized lipodystrophy is a human disorder associated with increased bone mass suggesting that fat, per se, regulates the skeleton. To test this hypothesis we generated a murine model of congenital generalized lipodystrophy in which both brown and white adipose tissue are entirely depleted during embryogenesis. These “fat-free” (FF) exhibit a marked increase in bone mass throughout their body. The increased bone mass represents stimulation of bone formation and not retarded bone breakdown. Additionally, the increased bone mass of FF mice markedly increases skeletal strength and resistance to fracture. Like patients with congenital lipodystrophy, FF mice are diabetic but their metabolic state does not contribute to their increased bone mass. To identify the fat-produced molecules regulating bone mass we transplanted genetically modified adipose tissue into FF mice which established that absence of the fat-produced molecules, adiponectin and leptin, significantly enhances bone formation. These observations suggest that reducing the combined effect of adiponectin and leptin, on bone, will increase its abundance and fracture resistance.
- Subjects :
- Leptin
Cancer Research
Physiology
Peptide Hormones
Organogenesis
Adipose tissue
Osteoclasts
QH426-470
Biochemistry
Congenital generalized lipodystrophy
Fats
chemistry.chemical_compound
Mice
0302 clinical medicine
Adipose Tissue, Brown
Animal Cells
Bone Density
Adipocyte
Immune Physiology
Medicine and Health Sciences
Adipocytes
Insulin
Femur
Musculoskeletal System
Genetics (clinical)
Connective Tissue Cells
Mice, Knockout
0303 health sciences
Innate Immune System
Animal Models
Lipids
Experimental Organism Systems
Connective Tissue
Cytokines
Female
Adiponectin
Lipodystrophy
Anatomy
Cellular Types
Osteosclerosis
Research Article
medicine.medical_specialty
Immunology
Subcutaneous Fat
Mouse Models
Biology
Intra-Abdominal Fat
Research and Analysis Methods
03 medical and health sciences
Model Organisms
Adipokines
Lipodystrophy, Congenital Generalized
Internal medicine
Genetics
medicine
Animals
Humans
Bone
Molecular Biology
Ecology, Evolution, Behavior and Systematics
Skeleton
030304 developmental biology
Bone Development
Biology and Life Sciences
Cell Biology
Molecular Development
medicine.disease
Hormones
Transplantation
Disease Models, Animal
Endocrinology
Biological Tissue
Glucose
chemistry
Immune System
Animal Studies
Organism Development
030217 neurology & neurosurgery
Developmental Biology
Subjects
Details
- Language :
- English
- ISSN :
- 15537404 and 15537390
- Volume :
- 15
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- PLoS Genetics
- Accession number :
- edsair.doi.dedup.....2bd3b94893584c713f5d1f18d34ffb66