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

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

Effects of Exercise on Adipose Tissue Remodeling

An excessive amount of fat in abdominal subcutaneous adipose tissue (aSAT) is a hallmark of obesity that often exhibits low capillary density, fibrotic extracellular matrix, immune cell infiltration, and dysregulated metabolic function. These abnormalities in aSAT are linked to excessive release of fat into the bloodstream, which can cause insulin resistance and systemic inflammation. Therefore, strategies to remodel aSAT structure and metabolic function for healthful fat storage hold high clinical interest. Regular exercise is recommended to treat obesity-induced health complications but the direct effects of exercise on aSAT are poorly understood. The aim of this dissertation were to assess the direct effects of exercise on aSAT morphology and factors regulating aSAT morphology, metabolic function, and inflammation. In Project 1, a total of 45 healthy adults who exercise regularly performed a single session of either low- (LOW), moderate- (MOD), or high- (HIGH) intensity exercise (n=15 in each group). aSAT samples were collected before and 1.5 hours after exercise. Transcriptomic analysis revealed a robust upregulation in the global “inflammatory response” pathway in all groups (adjusted p<1e-07), yet HIGH induced more extensive inflammatory responses than both LOW and MOD. Conversely, ribosomal and oxidative phosphorylation pathways were upregulated after MOD and LOW, but not HIGH. Of the few overlapping differentially expressed genes, we found the most robust changes in some core clock genes (adjusted p<0.0001). Findings from Project 1 suggest changes in the inflammatory, circadian clock, ribosomal, and oxidative phosphorylation gene sets shortly after acute exercise may be important contributors to exercise-induced aSAT adaptations. In Project 2, aSAT samples were collected from 36 adults with obesity before and after 12 weeks of moderate-intensity continuous training (MICT; 70%HRmax, 45 min; n=17) or high-intensity interval training (HIIT; 90%HRmax, 10×1min; n=19), maintaining their body weight throughout. MICT and HIIT induced similar modifications in aSAT structure (reduced adipocyte size, increased Col5a3, increased capillary density, all P≤0.05) and altered protein abundance of factors that regulate structural remodeling (reduced MMP9; increased ANGPTL2; both P≤0.02), lipid and oxidative metabolism (increased HSL, CD36, and COX4; P<0.03), and key proteins involved in the MAPK pathway when measured the day after the last exercise session. These findings from Project 2 indicate that exercise training may induce some early structural and metabolic adaptations in aSAT even without weight loss. In Project 3, aSAT was collected from 16 adults with overweight/obesity who exercise regularly for at least 2 years (EX) and 16 well-matched sedentary/non-exercisers (SED) who were tightly pair-matched for adiposity. Compared with SED, aSAT collected from EX had greater capillary density and a lower abundance of Col6a and macrophages (P<0.05). Global proteomics analysis revealed ribosomal, mitochondrial, and lipogenic proteins were upregulated, whereas complement and proteasomal proteins were downregulated in EX vs. SED (FDR<0.1). Phosphoproteomics indicated a greater abundance of phosphoproteins involved in protein translation, lipogenesis, and direct regulation of transcripts in EX vs. SED (P<0.01). Findings from Project 3 suggest that regular exercise in adults with overweight/obesity favorably remodels the aSAT structure and proteomic profile in ways that may lead to improved lipid storage capacity, which can contribute to preserved cardiometabolic health. Overall, the projects in this dissertation demonstrate regular exercise may induce robust structural and functional adaptations in aSAT that may contribute to improved/sustained cardiometabolic health. My dissertation projects also shed light on potential molecular mechanisms that may mediate the exercise effects on aSAT.PhDMovement Science PhDUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/192376/1/ahnchi_1.pd

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

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

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

Exercise training remodels subcutaneous adipose tissue in adults with obesity even without weight loss

Excessive adipose tissue mass underlies much of the metabolic health complications in obesity. Although exercise training is known to improve metabolic health in individuals with obesity, the effects of exercise training without weight loss on adipose tissue structure and metabolic function remain unclear. Thirty-six adults with obesity (body mass index = 33 ± 3 kg · m–2) were assigned to 12 weeks (4 days week–1) of either moderate-intensity continuous training (MICT; 70% maximal heart rate, 45 min; n = 17) or high-intensity interval training (HIIT; 90% maximal heart rate, 10 × 1 min; n = 19), maintaining their body weight throughout. Abdominal subcutaneous adipose tissue (aSAT) biopsy samples were collected once before and twice after training (1 day after last exercise and again 4 days later). Exercise training modified aSAT morphology (i.e. reduced fat cell size, increased collagen type 5a3, both P ≤ 0.05, increased capillary density, P = 0.05) and altered protein abundance of factors that regulate aSAT remodelling (i.e. reduced matrix metallopeptidase 9; P = 0.02; increased angiopoietin-2; P < 0.01). Exercise training also increased protein abundance of factors that regulate lipid metabolism (e.g. hormone sensitive lipase and fatty acid translocase; P ≤ 0.03) and key proteins involved in the mitogen-activated protein kinase pathway when measured the day after the last exercise session. However, most of these exercise-mediated changes were no longer significant 4 days after exercise. Importantly, MICT and HIIT induced remarkably similar adaptations in aSAT. Collectively, even in the absence of weight loss, 12 weeks of exercise training induced changes in aSAT structure, as well as factors that regulate metabolism and the inflammatory signal pathway in adults with obesity.Key pointsExercise training is well-known to improve metabolic health in obesity, although how exercise modifies the structure and metabolic function of adipose tissue, in the absence of weight loss, remains unclear.We report that both 12 weeks of moderate-intensity continuous training (MICT) and 12 weeks of high-intensity interval training (HIIT) induced modifications in adipose tissue structure and factors that regulate adipose tissue remodelling, metabolism and the inflammatory signal pathway in adults with obesity, even without weight loss (with no meaningful differences between MICT and HIIT).The modest modifications in adipose tissue structure in response to 12 weeks of MICT or HIIT did not lead to changes in the rate of fatty acid release from adipose tissue.These results expand our understanding about the effects of two commonly used exercise training prescriptions (MICT and HIIT) on adipose tissue remodelling that may lead to advanced strategies for improving metabolic health outcomes in adults with obesity.Abstract figure legend. Three months of moderate-intensity continuous training (MICT) or high-intensity interval training (HIIT) without weight loss induced similar structural and metabolic adaptations in subcutaneous adipose tissue in adults with obesity.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/172245/1/tjp15006_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/172245/2/tjp15006-sup-0002-PeerReview.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/172245/3/tjp15006.pd