12 research outputs found

    Plasma ferritin concentration is positively associated with in vivo fatty acid mobilization and insulin resistance in obese women

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    High rates of fatty acid (FA) mobilization from adipose tissue are associated with insulin resistance (IR) in obesity. In vitro evidence suggests that iron stimulates lipolysis in adipocytes, but whether iron is related to in vivo FA mobilization is unknown. We hypothesized that plasma ferritin concentration ([ferritin]), a marker of body iron stores, would be positively associated with FA mobilization. We measured [ferritin], the rate of appearance of FA in the systemic circulation (FA Ra; stable isotope dilution), key adipose tissue lipolytic proteins and IR (hyperinsulinaemicâ euglycaemic clamp) in 20 obese, premenopausal women. [Ferritin] was correlated with FA Ra (r = 0.65; P = 0.002) and IR (r = 0.57; P = 0.008); these relationships remained significant after controlling for body mass index and plasma [Câ reactive protein] (a marker of systemic inflammation) in multiple regression analyses. We then stratified subjects into tertiles based on [ferritin] to compare subjects with â Highâ ferritinâ versus â Lowâ ferritinâ . Plasma [hepcidin] was more than fivefold greater (P < 0.05) in the Highâ ferritin versus Lowâ ferritin group, but there was no difference in plasma [Câ reactive protein] between groups, indicating that the large difference in plasma [ferritin] reflects a difference in iron stores, not systemic inflammation. We found that FA Ra, adipose protein abundance of hormoneâ sensitive lipase and adipose triglyceride lipase, and IR were significantly greater in subjects with Highâ ferritin versus Lowâ ferritin (all P < 0.05). These data provide the first evidence linking iron and in vivo FA mobilization and suggest that elevated iron stores might contribute to IR in obesity by increasing systemic FA availability.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146491/1/eph12367_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146491/2/eph12367.pd

    Mitochondria-targeted antioxidant therapy with MitoQ ameliorates aortic stiffening in old mice.

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    Aortic stiffening is a major independent risk factor for cardiovascular diseases, cognitive dysfunction, and other chronic disorders of aging. Mitochondria-derived reactive oxygen species are a key source of arterial oxidative stress, which may contribute to arterial stiffening by promoting adverse structural changes-including collagen overabundance and elastin degradation-and enhancing inflammation, but the potential for mitochondria-targeted therapeutic strategies to ameliorate aortic stiffening with primary aging is unknown. We assessed aortic stiffness [pulse-wave velocity (aPWV)], ex vivo aortic intrinsic mechanical properties [elastic modulus (EM) of collagen and elastin regions], and aortic protein expression in young (~6 mo) and old (~27 mo) male C57BL/6 mice consuming normal drinking water (YC and OC) or water containing mitochondria-targeted antioxidant MitoQ (250 µM; YMQ and OMQ) for 4 wk. Both baseline and postintervention aPWV values were higher in OC vs. YC (post: 482 ± 21 vs. 420 ± 5 cm/s, P < 0.05). MitoQ had no effect in young mice but decreased aPWV in old mice (OMQ, 426 ± 20, P < 0.05 vs. OC). MitoQ did not affect age-associated increases in aortic collagen-region EM, collagen expression, or proinflammatory cytokine expression, but partially attenuated age-associated decreases in elastin region EM and elastin expression. Our results demonstrate that MitoQ reverses in vivo aortic stiffness in old mice and suggest that mitochondria-targeted antioxidants may represent a novel, promising therapeutic strategy for decreasing aortic stiffness with primary aging and, possibly, age-related clinical disorders in humans. The destiffening effects of MitoQ treatment may be at least partially mediated by attenuation/reversal of age-related aortic elastin degradation. NEW & NOTEWORTHY We show that 4 wk of treatment with the mitochondria-specific antioxidant MitoQ in mice completely reverses the age-associated elevation in aortic stiffness, assessed as aortic pulse-wave velocity. The destiffening effects of MitoQ treatment may be at least partially mediated by attenuation of age-related aortic elastin degradation. Our results suggest that mitochondria-targeted therapeutic strategies may hold promise for decreasing arterial stiffening with aging in humans, possibly decreasing the risk of many chronic age-related clinical disorders

    Skeletal muscle ferritin abundance is tightly related to plasma ferritin concentration in adults with obesity

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    Obesity is associated with complex perturbations to whole- body and tissue iron homeostasis. Recent evidence suggests a potentially important influence of iron storage in skeletal muscle on whole- body iron homeostasis, but this association is not clearly resolved. The primary aim of this study was to assess the relationship between whole- body and skeletal muscle iron stores by measuring the abundance of the key iron storage (ferritin) and import (transferrin receptor) proteins in skeletal muscle, as well as markers of whole- body iron homeostasis in men (n = 19) and women (n = 43) with obesity. Plasma ferritin concentration (a marker of whole- body iron stores) was highly correlated with muscle ferritin abundance (r = 0.77, P = 2 à  10- 13) and negatively associated with muscle transferrin receptor abundance (r = - 0.76, P = 1 à  10- 12). These relationships persisted when accounting for sex, age, BMI and plasma C- reactive protein concentration. In parallel with higher whole- body iron stores in our male versus female participants, men had 2.2- fold higher muscle ferritin abundance (P = 1 à  10- 4) compared with women. In accordance with lower muscle iron storage, women had 2.7- fold higher transferrin receptor abundance (P = 7 à  10- 10) compared with men. We conclude that muscle iron storage and import proteins are tightly and independently related to plasma ferritin concentration in adults with obesity, suggesting that skeletal muscle may be an underappreciated iron store.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163407/2/eph12853_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163407/1/eph12853.pd

    Chronic Supplementation With a Mitochondrial Antioxidant (MitoQ) Improves Vascular Function in Healthy Older Adults.

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    UNLABELLED: Excess reactive oxygen species production by mitochondria is a key mechanism of age-related vascular dysfunction. Our laboratory has shown that supplementation with the mitochondrial-targeted antioxidant MitoQ improves vascular endothelial function by reducing mitochondrial reactive oxygen species and ameliorates arterial stiffening in old mice, but the effects in humans are unknown. Here, we sought to translate our preclinical findings to humans and determine the safety and efficacy of MitoQ. Twenty healthy older adults (60-79 years) with impaired endothelial function (brachial artery flow-mediated dilation 7.60 m/s; n=11). Plasma oxidized LDL (low-density lipoprotein), a marker of oxidative stress, also was lower after MitoQ versus placebo (P0.1). These findings in humans extend earlier preclinical observations and suggest that MitoQ and other therapeutic strategies targeting mitochondrial reactive oxygen species may hold promise for treating age-related vascular dysfunction. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02597023.This work was supported by National Institutes of Health (NIH) awards AG049451, AG000279, AG053009, Colorado CTSA UL1 TR001082, and an industry contract with MitoQ Limited (MitoQ Limited provided MitoQ and some financial support). M.P. Murphy is supported by UK MRC MC_U105663142 and as a Wellcome Trust Investigator (110159/Z/15/Z)

    Skeletal muscle ferritin abundance is tightly related to plasma ferritin concentration in adults with obesity

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    Obesity is associated with complex perturbations to whole- body and tissue iron homeostasis. Recent evidence suggests a potentially important influence of iron storage in skeletal muscle on whole- body iron homeostasis, but this association is not clearly resolved. The primary aim of this study was to assess the relationship between whole- body and skeletal muscle iron stores by measuring the abundance of the key iron storage (ferritin) and import (transferrin receptor) proteins in skeletal muscle, as well as markers of whole- body iron homeostasis in men (n = 19) and women (n = 43) with obesity. Plasma ferritin concentration (a marker of whole- body iron stores) was highly correlated with muscle ferritin abundance (r = 0.77, P = 2 à  10- 13) and negatively associated with muscle transferrin receptor abundance (r = - 0.76, P = 1 à  10- 12). These relationships persisted when accounting for sex, age, BMI and plasma C- reactive protein concentration. In parallel with higher whole- body iron stores in our male versus female participants, men had 2.2- fold higher muscle ferritin abundance (P = 1 à  10- 4) compared with women. In accordance with lower muscle iron storage, women had 2.7- fold higher transferrin receptor abundance (P = 7 à  10- 10) compared with men. We conclude that muscle iron storage and import proteins are tightly and independently related to plasma ferritin concentration in adults with obesity, suggesting that skeletal muscle may be an underappreciated iron store.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163407/2/eph12853_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163407/1/eph12853.pd

    Exercise training decreases whole- body and tissue iron storage in adults with obesity

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    The regulation of iron storage is crucial to human health, because both excess and deficient iron storage have adverse consequences. Recent studies suggest altered iron storage in adults with obesity, with increased iron accumulation in their liver and skeletal muscle. Exercise training increases iron use for processes such as red blood cell production and can lower whole- body iron stores in humans. However, the effects of exercise training on liver and muscle iron stores in adults with obesity have not been assessed. The aim of this study was to determine the effects of 12 weeks of exercise training on whole- body iron stores, liver iron content and the abundance of ferritin (the key iron storage protein) in skeletal muscle in adults with obesity. Twenty- two inactive adults (11 women and 11 men; age, 31 ± 6 years; body mass index, 33 ± 3 kg/m2) completed 12 weeks (four sessions/week) of either moderate- intensity continuous training (MICT; 45 min at 70% of maximal heart rate; n = 11) or high- intensity interval training (HIIT; 10 à  1 min at 90% of maximal heart rate, interspersed with 1 min active recovery; n = 11). Whole- body iron stores were lower after training, as indicated by decreased plasma concentrations of ferritin (P = 3 à  10- 5) and hepcidin (P = 0.02), without any change in C- reactive protein. Hepatic R2*, an index of liver iron content, was 6% lower after training (P = 0.06). Training reduced the skeletal muscle abundance of ferritin by 10% (P = 0.03), suggesting lower muscle iron storage. Interestingly, these adaptations were similar in MICT and HIIT groups. Our findings indicate that exercise training decreased iron storage in adults with obesity, which might have important implications for obese individuals with dysregulated iron homeostasis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/167108/1/eph12950_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/167108/2/eph12950.pd
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