Ameliorating effects of lifelong physical activity on healthy aging and mitochondrial function in human white adipose tissue

2021 ◽  
Author(s):  
Anders Gudiksen ◽  
Albina Qoqaj ◽  
Stine Ringholm ◽  
Jørgen Wojtaszewski ◽  
Peter Plomgaard ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Exercise Training ◽  
White Adipose Tissue ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Healthy Aging ◽  
Venous Blood ◽  
Oxidative Capacity ◽  
Low Grade ◽  
Lifelong Exercise

Abstract Growing old is patently among the most prominent risk factors for lifestyle related diseases and deterioration in physical performance. Aging in particular affects mitochondrial homeostasis and maintaining a well-functioning mitochondrial pool is imperative in order to avoid age-associated metabolic decline. White adipose tissue (WAT) is a key organ in energy balance and impaired mitochondrial function in adipocytes has been associated with increased low-grade inflammation, altered metabolism, excessive ROS production and an accelerated aging phenotype. Exercise training improves mitochondrial health but whether lifelong exercise training can sufficiently maintain WAT mitochondrial function is currently unknown. Therefore, to dissect the role and dose-dependence of lifelong exercise training on aging WAT metabolic parameters and mitochondrial function, young and older untrained, as well as moderately and highly exercise trained older male subjects were recruited and abdominal subcutaneous (s)WAT biopsies and venous blood samples were obtained to measure mitochondrial function and key metabolic factors in WAT and plasma. Mitochondrial intrinsic respiratory capacity was lower in sWAT from older than in young subjects. In spite of this, maximal mitochondrial respiration per wet weight, markers of oxidative capacity, and mitophagic capacity were increased in sWAT from lifelong highly exercise trained than all other groups. Furthermore, ROS emission was generally lower in sWAT from lifelong highly exercise trained than older untrained subjects. Taken together, aging reduces intrinsic mitochondrial respiration in human sWAT, but lifelong high volume exercise training increases oxidative capacity by increasing mitochondrial volume likely contributing to healthy aging.

scholarly journals Poor Mitochondrial Health and Systemic Inflammation? Testing of a Classical Hypothesis

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 126-127
Author(s):  
Marta Zampino ◽  
Luigi Ferrucci ◽  
Richard Spencer ◽  
Kenneth Fishbein ◽  
Eleanor Simonsick ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Fat Body ◽  
Reference Group ◽  
Linear Regression Analysis ◽  
Oxidative Capacity ◽  
Conclusive Evidence ◽  
Resonance Spectroscopy ◽  
Low Grade ◽  
Severe Impairment

Abstract Chronic low-grade inflammation often occurs with aging and has been associated with negative health outcomes. Despite extensive research on the origins of “inflammaging”, the causative mechanisms remain unclear. However, a connection between poor mitochondrial health and chronic inflammation has been hypothesized, with decreasing mitochondrial function occurring with age and precipitating an increase in reactive oxygen species and other pro-inflammatory macromolecules such as mitochondrial DNA. We tested this hypothesis on a population of 619 subjects from the Baltimore Longitudinal Study of Aging, measuring muscle mitochondrial oxidative capacity in vivo by phosphorus magnetic resonance spectroscopy (P-MRS), and plasma interleukin (IL)-6, the most widely used biomarker of inflammaging. The P-MRS-derived post-exercise phosphocreatine recovery time constant tau-PCr, a measure of oxidative capacity, was expressed as a categorical variable through assignment to quintiles. Participants in the first quintile of tau-PCr (best mitochondrial function) were taken as reference and compared to the others using linear regression analysis adjusted for sex, age, lean and fat body mass, and physical activity. Those participants with the lowest oxidative capacity had significantly higher log(IL-6) levels as compared to the reference group. However, data from the other quintiles was not significantly different from the reference values. In conclusion, severe impairment of oxidative capacity is associated with increased inflammation. This study design does not provide conclusive evidence of whether increased inflammation and impaired bioenergetic recovery are both caused by underlying poor health status, or whether mitochondrial deficits lead directly to the observed inflammation; we anticipate addressing this important question with longitudinal studies.

scholarly journals Exercise training enhances white adipose tissue metabolism in rats selectively bred for low- or high-endurance running capacity

2013 ◽  
Vol 305 (3) ◽  
pp. E429-E438 ◽  
Author(s):  
Erin J. Stephenson ◽  
Sarah J. Lessard ◽  
Donato A. Rivas ◽  
Matthew J. Watt ◽  
Ben B. Yaspelkis ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Exercise Training ◽  
White Adipose Tissue ◽  
Citrate Synthase ◽  
Mitochondrial Protein ◽  
Treadmill Running ◽  
Endurance Running ◽  
Insulin Resistant ◽  
Disease States ◽  
Hcr Model

Impaired visceral white adipose tissue (WAT) metabolism has been implicated in the pathogenesis of several lifestyle-related disease states, with diminished expression of several WAT mitochondrial genes reported in both insulin-resistant humans and rodents. We have used rat models selectively bred for low- (LCR) or high-intrinsic running capacity (HCR) that present simultaneously with divergent metabolic phenotypes to test the hypothesis that oxidative enzyme expression is reduced in epididymal WAT from LCR animals. Based on this assumption, we further hypothesized that short-term exercise training (6 wk of treadmill running) would ameliorate this deficit. Approximately 22-wk-old rats (generation 22) were studied. In untrained rats, the abundance of mitochondrial respiratory complexes I–V, citrate synthase (CS), and PGC-1 was similar for both phenotypes, although CS activity was greater than 50% in HCR ( P = 0.09). Exercise training increased CS activity in both phenotypes but did not alter mitochondrial protein content. Training increased the expression and phosphorylation of proteins with roles in β-adrenergic signaling, including β3-adrenergic receptor (16% increase in LCR; P < 0.05), NOR1 (24% decrease in LCR, 21% decrease in HCR; P < 0.05), phospho-ATGL (25% increase in HCR; P < 0.05), perilipin (25% increase in HCR; P < 0.05), CGI-58 (15% increase in LCR; P < 0.05), and GLUT4 (16% increase in HCR; P < 0.0001). A training effect was also observed for phospho-p38 MAPK (12% decrease in LCR, 20% decrease in HCR; P < 0.05) and phospho-JNK (29% increase in LCR, 20% increase in HCR; P < 0.05). We conclude that in the LCR-HCR model system, mitochondrial protein expression in WAT is not affected by intrinsic running capacity or exercise training. However, training does induce alterations in the activity and expression of several proteins that are essential to the intracellular regulation of WAT metabolism.

Tryptophan metabolism activation by indoleamine 2,3-dioxygenase in adipose tissue of obese women: an attempt to maintain immune homeostasis and vascular tone

2012 ◽  
Vol 303 (2) ◽  
pp. R135-R143 ◽  
Author(s):  
Isabelle Wolowczuk ◽  
Benjamin Hennart ◽  
Audrey Leloire ◽  
Alban Bessede ◽  
Marion Soichot ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
T Cell ◽  
White Adipose Tissue ◽  
Vascular Tone ◽  
T Cell Subsets ◽  
Low Grade ◽  
Adipose Tissues ◽  
Indoleamine 2,3 Dioxygenase ◽  
Arterial Blood ◽  
Ido1 Expression

Human obesity is characterized by chronic low-grade inflammation in white adipose tissue and is often associated with hypertension. The potential induction of indoleamine 2,3-dioxygenase-1 (IDO1), the rate-limiting enzyme in tryptophan/kynurenine degradation pathway, by proinflammatory cytokines, could be associated with these disorders but has remained unexplored in obesity. Using immunohistochemistry, we detected IDO1 expression in white adipose tissue of obese patients, and we focused on its contribution in the regulation of vascular tone and on its immunoregulatory effects. Concentrations of tryptophan and kynurenine were measured in sera of 36 obese and 15 lean women. The expression of IDO1 in corresponding omental and subcutaneous adipose tissues and liver was evaluated. Proinflammatory markers and T-cell subsets were analyzed in adipose tissue via the expression of CD14, IL-18, CD68, TNFα, CD3ε, FOXP3 [a regulatory T-cell (Treg) marker] and RORC (a Th17 marker). In obese subjects, the ratio of kynurenine to tryptophan, which reflects IDO1 activation, is higher than in lean subjects. Furthermore, IDO1 expression in both adipose tissues and liver is increased and is inversely correlated with arterial blood pressure. Inflammation is associated with a T-cell infiltration in obese adipose tissue, with predominance of Th17 in the omental compartment and of Treg in the subcutaneous depot. The Th17/Treg balance is decreased in subcutaneous fat and correlates with IDO1 activation. In contrast, in the omental compartment, despite IDO1 activation, the Th17/Treg balance control is impaired. Taken together, our results suggest that IDO1 activation represents a local compensatory mechanism to limit obesity-induced inflammation and hypertension.

scholarly journals Plasticity of non-shivering thermogenesis and brown adipose tissue in high-altitude deer mice

2021 ◽  
Author(s):  
Soren Z. Coulson ◽  
Cayleih E. Robertson ◽  
Sajeni Mahalingam ◽  
Grant B. McClelland
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
High Altitude ◽  
Heat Production ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Deer Mice ◽  
Brown Adipose ◽  
Hypoxia Acclimation ◽  
Shivering Thermogenesis

High altitude environments challenge small mammals with persistent low ambient temperatures that require high rates of aerobic heat production in face of low O2 availability. An important component of thermogenic capacity in rodents is non-shivering thermogenesis (NST) mediated by uncoupled mitochondrial respiration in brown adipose tissue (BAT). NST is plastic, and capacity for heat production increases with cold acclimation. However, in lowland native rodents, hypoxia inhibits NST in BAT. We hypothesize that highland deer mice (Peromyscus maniculatus) overcome the hypoxic inhibition of NST through changes in BAT mitochondrial function. We tested this hypothesis using lab born and raised highland and lowland deer mice, and a lowland congeneric (P. leucopus), acclimated to either warm normoxia (25°C, 760 mmHg) or cold hypoxia (5°C, 430 mmHg). We determined the effects of acclimation and ancestry on whole-animal rates of NST, the mass of interscapular BAT (iBAT), and uncoupling protein (UCP)-1 protein expression. To identify changes in mitochondrial function, we conducted high-resolution respirometry on isolated iBAT mitochondria using substrates and inhibitors targeted to UCP-1. We found that rates of NST increased with cold hypoxia acclimation but only in highland deer mice. There was no effect of cold hypoxia acclimation on iBAT mass in any group, but highland deer mice showed increases in UCP-1 expression and UCP-1 stimulated mitochondrial respiration in response to these stressors. Our results suggest that highland deer mice have evolved to increase the capacity for NST in response to chronic cold hypoxia, driven in part by changes in iBAT mitochondrial function.

scholarly journals The vitamin D receptor regulates mitochondrial function in C2C12 myoblasts

2020 ◽  
Vol 318 (3) ◽  
pp. C536-C541 ◽  
Author(s):  
Stephen P. Ashcroft ◽  
Joseph J. Bass ◽  
Abid A. Kazi ◽  
Philip J. Atherton ◽  
Andrew Philp
Keyword(s):  
Skeletal Muscle ◽  
Vitamin D ◽  
Protein Content ◽  
Vitamin D Receptor ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Oxidative Capacity ◽  
C2c12 Myoblasts

Vitamin D deficiency has been linked to a reduction in skeletal muscle function and oxidative capacity; however, the mechanistic bases of these impairments are poorly understood. The biological actions of vitamin D are carried out via the binding of 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) to the vitamin D receptor (VDR). Recent evidence has linked 1α,25(OH)2D3 to the regulation of skeletal muscle mitochondrial function in vitro; however, little is known with regard to the role of the VDR in this process. To examine the regulatory role of the VDR in skeletal muscle mitochondrial function, we used lentivirus-mediated shRNA silencing of the VDR in C2C12 myoblasts (VDR-KD) and examined mitochondrial respiration and protein content compared with an shRNA scrambled control. VDR protein content was reduced by ~95% in myoblasts and myotubes ( P < 0.001). VDR-KD myoblasts displayed a 30%, 30%, and 36% reduction in basal, coupled, and maximal respiration, respectively ( P < 0.05). This phenotype was maintained in VDR-KD myotubes, displaying a 34%, 33%, and 48% reduction in basal, coupled, and maximal respiration ( P < 0.05). Furthermore, ATP production derived from oxidative phosphorylation (ATPOx) was reduced by 20%, suggesting intrinsic impairments within the mitochondria following VDR-KD. However, despite the observed functional decrements, mitochondrial protein content, as well as markers of mitochondrial fission were unchanged. In summary, we highlight a direct role for the VDR in regulating skeletal muscle mitochondrial respiration in vitro, providing a potential mechanism as to how vitamin D deficiency might impact upon skeletal muscle oxidative capacity.

scholarly journals Adipokines: inflammation and the pleiotropic role of white adipose tissue

2004 ◽  
Vol 92 (3) ◽  
pp. 347-355 ◽  
Author(s):  
Paul Trayhurn ◽  
I. Stuart Wood
Keyword(s):  
Adipose Tissue ◽  
Growth Factor ◽  
Inflammatory Cytokines ◽  
Acute Phase ◽  
White Adipose Tissue ◽  
Acute Phase Proteins ◽  
Endocrine Function ◽  
Low Grade ◽  
Circulating Levels

White adipose tissue is now recognised to be a multifunctional organ; in addition to the central role of lipid storage, it has a major endocrine function secreting several hormones, notably leptin and adiponectin, and a diverse range of other protein factors. These various protein signals have been given the collective name ‘adipocytokines’ or ‘adipokines’. However, since most are neither ‘cytokines’ nor ‘cytokine-like’, it is recommended that the term ‘adipokine’ be universally adopted to describe a protein that is secreted from (and synthesised by) adipocytes. It is suggested that the term is restricted to proteins secreted from adipocytes, excluding signals released only by the other cell types (such as macrophages) in adipose tissue. Theadipokinome(which together with lipid moieties released, such as fatty acids and prostaglandins, constitute thesecretomeof fat cells) includes proteins involved in lipid metabolism, insulin sensitivity, the alternative complement system, vascular haemostasis, blood pressure regulation and angiogenesis, as well as the regulation of energy balance. In addition, there is a growing list of adipokines involved in inflammation (TNFα, IL-1β, IL-6, IL-8, IL-10, transforming growth factor-β, nerve growth factor) and the acute-phase response (plasminogen activator inhibitor-1, haptoglobin, serum amyloid A). Production of these proteins by adipose tissue is increased in obesity, and raised circulating levels of several acute-phase proteins and inflammatory cytokines has led to the view that the obese are characterised by a state of chronic low-grade inflammation, and that this links causally to insulin resistance and the metabolic syndrome. It is, however, unclear as to the extent to which adipose tissue contributes quantitatively to the elevated circulating levels of these factors in obesity and whether there is a generalised or local state of inflammation. The parsimonious view is that the increased production of inflammatory cytokines and acute-phase proteins by adipose tissue in obesity relates primarily to localised events within the expanding fat depots. It is suggested that these events reflect hypoxia in parts of the growing adipose tissue mass in advance of angiogenesis, and involve the key controller of the cellular response to hypoxia, the transcription factor hypoxia inducible factor-1.

scholarly journals PGC-1α Is Required for Exercise- and Exercise Training-Induced UCP1 Up-Regulation in Mouse White Adipose Tissue

PLoS ONE ◽  
2013 ◽  
Vol 8 (5) ◽  
pp. e64123 ◽  
Author(s):  
Stine Ringholm ◽  
Jakob Grunnet Knudsen ◽  
Lotte Leick ◽  
Anders Lundgaard ◽  
Maja Munk Nielsen ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Exercise Training ◽  
White Adipose Tissue
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