Combined high-fat-resveratrol diet and RIP140 knockout mice reveal a novel relationship between elevated bone mitochondrial content and compromised bone microarchitecture, bone mineral mass, and bone strength in the tibia

Scope While resveratrol (RSV) is associated with the prevention of high‐fat (HF) diet‐induced insulin resistance, the effects on bone health combined with an HF‐diet is unknown. Therefore, we determined the effect of RSV on bone microarchitecture in the presence of an HF‐diet, while also elucidating...

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Bibliographic Details
Published in:Molecular nutrition & food research 2016-09, Vol.60 (9), p.1994-2007
Main Authors: Miotto, Paula M., Frendo-Cumbo, Scott, Sacco, Sandra M., Wright, David C., Ward, Wendy E., Holloway, Graham P.
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - genetics
Animals
Body Weight - drug effects
Bone Density - drug effects
Bone health
Bone Resorption - drug therapy
Bone turnover
Diet, High-Fat - adverse effects
Male
Mice, Inbred C57BL
Mice, Knockout
Mitochondria
Mitochondria - drug effects
Mitochondria - metabolism
Nuclear Proteins - genetics
Osteoclasts - drug effects
Osteoclasts - metabolism
RANK Ligand - metabolism
Resveratrol
Stilbenes - pharmacology
Tibia - drug effects
Tibia - physiology
Tibia - ultrastructure
Type 2 diabetes
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Summary:Scope While resveratrol (RSV) is associated with the prevention of high‐fat (HF) diet‐induced insulin resistance, the effects on bone health combined with an HF‐diet is unknown. Therefore, we determined the effect of RSV on bone microarchitecture in the presence of an HF‐diet, while also elucidating molecular adaptations within bone that could contribute to bone health status. Methods and results Male C57BL6 mice were provided control (10% fat) or HF‐diet (60% fat) in the presence or absence of RSV for 12 weeks. While RSV prevented HF diet‐induced glucose intolerance, HF‐RSV compromised tibial microarchitecture, mineral mass, and strength. The compromised outcomes following HF‐RSV corresponded with higher markers of osteoclast‐activation and bone‐resorption (decreased OPG/RANKL ratio; increased cathepsin K), as well as higher markers of tibial mitochondrial content. A molecular model of elevated mitochondrial content (RIP140 knock out (KO) mice) was utilized to determine proof‐of‐principle that increasing mitochondrial content coincides with decrements in bone health. RIP140 KO mice displayed higher markers of mitochondrial content, and similar to HF‐RSV, had compromised bone microarchitecture, lower BMD/strength, and higher markers of osteoclast‐activation/bone‐resorption. Conclusion These data show that in the presence of an HF‐diet, RSV negatively alters bone health, a process associated with increased mitochondrial content and markers of bone resorption. We evaluate the effects of a combined high fat‐resveratrol (HF‐RSV) diet on bone mitochondrial content and bone health. Our results demonstrate that HF‐RSV results in increased bone mitochondrial content, which is associated with greater markers of bone resorption and weaker bone. We further establish a relationship between elevated mitochondrial content and impaired bone health by using RIP140 knockout mice. Similar to HF‐RSV mice, RIP140 KO mice have increased bone resorption and impaired bone health – establishing a negative association between excess bone mitochondrial content and bone health.
ISSN:1613-4125
1613-4133
DOI:10.1002/mnfr.201500870