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Monomethylfumarate protects against ovariectomy-related changes in body composition.

ABSTRACT: Osteoporosis, low bone mass that increases fracture susceptibility, affects approximately 75 million individuals in the United States, Europe and Japan, with the number of osteoporotic fractures expected to increase by more than 3-fold over the next 50 years. Bone mass declines with age, although the mechanisms for this decrease are unclear. Aging enhances production of reactive oxygen species, which can affect bone formation and breakdown. The multiple sclerosis drug Tecfidera contains dimethylfumarate, which is rapidly metabolized to monomethylfumarate (MMF); MMF is thought to function through nuclear factor erythroid-derived-2-like-2 (Nrf2), a transcription factor activated by oxidative stress which induces the expression of endogenous anti-oxidant systems. We hypothesized that MMF-elicited increases in anti-oxidants would inhibit osteopenia induced by ovariectomy, as a model of aging-related osteoporosis and high oxidative stress. We demonstrated that MMF activated Nrf2 and induced anti-oxidant Nrf2 target gene expression in bone marrow-derived mesenchymal stem cells. Sham-operated or ovariectomized adult female mice were fed chow with or without MMF and various parameters monitored. Ovariectomy produced the expected effects, decreasing bone mineral density and increasing body weight, fat mass, bone marrow adiposity and serum receptor activator of nuclear factor-kappa-B ligand (RANKL) levels. MMF decreased fat but not lean mass. MMF improved trabecular bone microarchitecture after adjustment for body weight, although the unadjusted data showed few differences; MMF also tended to increase adjusted cortical bone and to reduce bone marrow adiposity and serum RANKL levels. Because these results suggest the possibility that MMF might be beneficial for bone, further investigation seems warranted.

SUBMITTER: Bollag AE

PROVIDER: S-EPMC6938560 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Monomethylfumarate protects against ovariectomy-related changes in body composition.

Bollag Anna E AE Guo Tianyang T Ding Ke-Hong KH Choudhary Vivek V Chen Xunsheng X Zhong QIng Q Xu Jianrui J Yu Kanglun K Awad Mohamed E ME Elsalanty Mohammed M Johnson Maribeth H MH McGee-Lawrence Meghan E ME Bollag Wendy B WB Isales Carlos M CM

The Journal of endocrinology 20190701

Osteoporosis, low bone mass that increases fracture susceptibility, affects approximately 75 million individuals in the United States, Europe and Japan, with the number of osteoporotic fractures expected to increase by more than 3-fold over the next 50 years. Bone mass declines with age, although the mechanisms for this decrease are unclear. Aging enhances production of reactive oxygen species, which can affect bone formation and breakdown. The multiple sclerosis drug Tecfidera contains dimethyl ...[more]

PMID: 31362266

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Project description:ObjectivesAging, body composition, and body mass index (BMI) are important factors in bone mineral density (BMD). Although several studies have investigated the various parameters and factors that differentially influence BMD, the results have been inconsistent. Thus, the primary goal of the present study was to further characterize the relationships of aging, body composition parameters, and BMI with BMD in Chinese Han males older than 50 years.MethodsThe present study was a retrospective analysis of the body composition, BMI, and BMD of 358 Chinese male outpatients between 50 and 89 years of age that were recruited from our hospital between 2009 and 2011. Qualified subjects were stratified according to age and BMI as follows: 50-59 (n = 35), 60-69 (n = 123), 70-79 (n = 93), and 80-89 (n = 107) years of age and low weight (BMI: < 20 kg/m2; n = 21), medium weight (20 ? BMI < 24 kg/m2; n = 118), overweight (24 ? BMI < 28 kg/m2; n = 178), and obese (BMI ? 28 kg/m2; n = 41). Dual-energy X-ray absorptiometry (DEXA) was used to assess bone mineral content (BMC), lean mass (LM), fat mass (FM), fat-free mass (FFM), lumbar spine (L1-L4) BMD, femoral neck BMD, and total hip BMD. Additionally, the FM index (FMI; FM/height2), LM index (LMI; LM/height2), FFM index (FFMI; [BMC+LM]/height2), percentage of BMC (%BMC; BMC/[BMC+FM+LM] × 100%), percentage of FM (%FM; FM/[BMC+FM+LM] × 100%), and percentage of LM (%LM; LM/(BMC+FM+LM) × 100%) were calculated. Osteopenia or osteoporosis was identified using the criteria and T-score of the World Health Organization.ResultsAlthough there were no significant differences in BMI among the age groups, there was a significant decline in height and weight according to age (p < 0.0001 and p = 0.0002, respectively). The LMI and FFMI also declined with age (both p < 0.0001) whereas the FMI exhibited a significant increase that peaked in the 80-89-years group (p = 0.0145). Although the absolute values of BMC and LM declined with age (p = 0.0031 and p < 0.0001, respectively), there was no significant difference in FM. In terms of body composition, there were no significant differences in %BMC but there was an increase in %FM (p < 0.0001) and a decrease in %LM (p < 0.0001) with age. The femoral neck and total hip BMD significantly declined with age (p < 0.0001 and p = 0.0027, respectively) but there were no differences in L1-L4. BMD increased at all sites (all p < 0.01) as BMI increased but there were declines in the detection rates of osteoporosis and osteopenia (both p < 0.001). A logistic regression revealed that when the medium weight group was given a BMI value of 1, a decline in BMI was an independent risk factor of osteoporosis or osteopenia, while an increase in BMI was a protective factor for BMD. At the same time, BMD in L1-L4 exhibited a significant positive association with FMI (p = 0.0003) and the femoral neck and total hip BMDs had significant positive associations with FFMI and LMI, respectively (both p < 0.0001).ConclusionsThese data indicate that LMI and FFMI exhibited significant negative associations with aging in Chinese Han males older than 50 years, whereas FMI had a positive association. BMD in the femoral neck and total hip declined with age but an increased BMI was protective for BMD. LMI and FFMI were protective for BMD in the femoral neck and total hip.

Project description:ObjectiveWe have previously shown that 24 young lean men (12 pairs of identical twins) subjected to a standardized 353 MJ (84 000 kcal) overfeeding protocol over 100 days exhibited individual differences in body weight and composition gains. The mean (+s.d.) gains in fat mass (FM) and fat-free mass (FFM) were 5.4+1.9 kg and 2.7+1.5 kg for a total body energy (BE) gain of 221+75 MJ, representing 63% of the energy surplus consumed. We report here on the most important baseline correlates of these overfeeding-induced changes with the aim of identifying biomarkers of the response.ResultsBaseline maximal oxygen uptake per kg body mass was negatively correlated with gains in weight, FM and BE (all P<0.05). Enzyme activities indicative of skeletal muscle oxidative potential correlated with gains in FM and BE (all P<0.05). Baseline thyroid-stimulating hormone levels in response to thyrotropin-releasing hormone stimulation correlated positively with changes in FM-to-FFM ratio (P<0.05). Plasma concentrations of androstenediol sulfate, dehydroepiandrosterone and 17-hydroxy pregnenolone were negatively correlated with gains in FM and BE (0.01<P<0.05), whereas the level of estrone was negatively correlated and androsterone glucoronide was positively correlated with FFM gains (P<0.05). Baseline leptin and abdominal fat cell size correlated positively with gains in weight, FM and BE (P<0.05). When compared with the six highest BE gainers, the six lowest gainers exhibited higher thermic effect of a meal (TEM) and plasma levels of total testosterone, cortisol, estradiol, androstenedione and androstenediol sulfate (all P<0.05). High baseline levels of total TEM, testosterone and androstenediol sulfate were associated with lower FM gains, whereas high baseline levels of FT4 and estrone were found in low-FFM gainers.ConclusionAlthough none of the variables exerted individually an overwhelmingly strong influence on overfeeding-induced changes, baseline FFM, maximal oxygen uptake, muscle oxidative capacity, androgens and leptin levels were the most consistent significant biomarkers of the responsiveness to chronic overfeeding.

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Monomethylfumarate protects against ovariectomy-related changes in body composition.

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Monomethylfumarate protects against ovariectomy-related changes in body composition.

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