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
Abstract: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.
“…Combined, these data strongly indicate impaired mitochondrial bioenergetics after an HF diet due to impaired ADP sensitivity. Whereas genetic models and interventions that increase mitochondrial content typically have improved insulin sensitivity and glucose tolerance (1,2,6), consumption of the HF diet in the current study, and in others (10,11), paradoxically resulted in increased mitochondrial content despite the induction of glucose intolerance and insulin resistance. Therefore, the notion that mitochondrial dysfunction contributes to the development of insulin resistance has waned in recent years.…”
Although molecular approaches altering mitochondrial content have implied a direct relationship between mitochondrial bioenergetics and insulin sensitivity, paradoxically, consumption of a high-fat (HF) diet increases mitochondrial content while inducing insulin resistance. We hypothesized that despite the induction of mitochondrial biogenesis, consumption of an HF diet would impair mitochondrial ADP sensitivity in skeletal muscle of mice and therefore manifest in mitochondrial dysfunction in the presence of ADP concentrations indicative of skeletal muscle biology. We found that HF consumption increased mitochondrial protein expression; however, absolute mitochondrial respiration and ADP sensitivity were impaired across a range of biologically relevant ADP concentrations. In addition, HF consumption attenuated the ability of ADP to suppress mitochondrial HO emission, further suggesting impairments in ADP sensitivity. The abundance of ADP transport proteins were not altered, but the sensitivity to carboxyatractyloside-mediated inhibition was attenuated after HF consumption, implicating alterations in adenine nucleotide translocase (ANT) ADP sensitivity in these observations. Moreover, palmitoyl-CoA is known to inhibit ANT, and modeling intramuscular palmitoyl-CoA concentrations that occur after HF consumption exacerbated the deficiency in ADP sensitivity. Altogether, these data suggest that an HF diet induces mitochondrial dysfunction secondary to an intrinsic impairment in mitochondrial ADP sensitivity that is magnified by palmitoyl-CoA.
“…Combined, these data strongly indicate impaired mitochondrial bioenergetics after an HF diet due to impaired ADP sensitivity. Whereas genetic models and interventions that increase mitochondrial content typically have improved insulin sensitivity and glucose tolerance (1,2,6), consumption of the HF diet in the current study, and in others (10,11), paradoxically resulted in increased mitochondrial content despite the induction of glucose intolerance and insulin resistance. Therefore, the notion that mitochondrial dysfunction contributes to the development of insulin resistance has waned in recent years.…”
Although molecular approaches altering mitochondrial content have implied a direct relationship between mitochondrial bioenergetics and insulin sensitivity, paradoxically, consumption of a high-fat (HF) diet increases mitochondrial content while inducing insulin resistance. We hypothesized that despite the induction of mitochondrial biogenesis, consumption of an HF diet would impair mitochondrial ADP sensitivity in skeletal muscle of mice and therefore manifest in mitochondrial dysfunction in the presence of ADP concentrations indicative of skeletal muscle biology. We found that HF consumption increased mitochondrial protein expression; however, absolute mitochondrial respiration and ADP sensitivity were impaired across a range of biologically relevant ADP concentrations. In addition, HF consumption attenuated the ability of ADP to suppress mitochondrial HO emission, further suggesting impairments in ADP sensitivity. The abundance of ADP transport proteins were not altered, but the sensitivity to carboxyatractyloside-mediated inhibition was attenuated after HF consumption, implicating alterations in adenine nucleotide translocase (ANT) ADP sensitivity in these observations. Moreover, palmitoyl-CoA is known to inhibit ANT, and modeling intramuscular palmitoyl-CoA concentrations that occur after HF consumption exacerbated the deficiency in ADP sensitivity. Altogether, these data suggest that an HF diet induces mitochondrial dysfunction secondary to an intrinsic impairment in mitochondrial ADP sensitivity that is magnified by palmitoyl-CoA.
“…Many studies have found that high-fat diet (HFD)-induced obesity has a detrimental effect on bone mass and bone microstructure in tibiae, femurs, and vertebrae (Gerbaix et al, 2012;Jatkar et al, 2017;Miotto et al, 2016). A recent study on rats showed that HFD increased the number of osteoclasts and decreased the number of osteoblasts, and the disruption of alveolar bone microarchitecture and horizontal alveolar bone loss was greater in the obese rats than that in the normal rats (Montalvany-Antonucci et al, 2018).…”
Obesity has become increasingly prevalent. In the past 40 years, the prevalence of obesity has increased from less than 1% to 6%-8% in children, from 3% to 11% in men, and from 6% to 15% in women during the period of 1975(Jaacks et al., 2019. The rise in obesity poses a great threat to human health and has become a major healthcare challenge in all populations (
“…A previous report suggested that a correlation between estrogen signaling in mature osteoclasts may act through RIP140; however, this report provided no direct evidence of an estrogen receptor/RIP140 complex, focused on mature osteoclasts, and used a nonphysiologic model of estrogen withdrawal in both reproductive and skeletally immature animals (39). A recent report also showed cancellous changes in a global knockout model of RIP140; however, given RIP140's known systemic effects, a direct correlation to osteoclast activity is unclear (40). Given RIP140's wide-spectrum activities, such as in metabolism and inflammation, nondiscriminatingly targeting RIP140 might negate the beneficial impact of RIP140 ablation in osteoclast macrophage precursors (15)(16)(17).…”
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