The role of metalloproteinases and their tissue inhibitors in adipose tissue remodelling and whole-body lipid distribution: a cross-sectional clinical study

AbstractAerobic capacity is a strong predictor of longevity. With aging, aerobic capacity decreases concomitantly with changes in whole body metabolism leading to increased disease risk. To address the role of aerobic capacity, aging, and their interaction on metabolism, we utilized rat models selectively bred for low and high intrinsic aerobic capacity (LCRs/HCRs) and compared the metabolomics of serum, muscle, and white adipose tissue (WAT) at two time points: Young rats were sacrificed at 9 months of age, and old rats were sacrificed at 21 months of age. Targeted and semi-quantitative metabolomics analysis was performed on the ultra-pressure liquid chromatography tandem mass spectrometry (UPLC-MS) platform. The effects of aerobic capacity, aging, and their interaction were studied via regression analysis. Our results showed that high aerobic capacity is associated with an accumulation of isovalerylcarnitine in muscle and serum at rest, which is likely due to more efficient leucine catabolism in muscle. With aging, several amino acids were downregulated in muscle, indicating more efficient amino acid metabolism, whereas in WAT less efficient amino acid metabolism and decreased mitochondrial β-oxidation were observed. Our results further revealed that high aerobic capacity and aging interactively affect lipid metabolism in muscle and WAT, possibly combating unfavorable aging-related changes in whole body metabolism. Our results highlight the significant role of WAT metabolism for healthy aging.

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The Role of AMPK Signaling in Brown Adipose Tissue Activation

Cells ◽

10.3390/cells10051122 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1122

Author(s):

Jamie I. van der van der Vaart ◽

Mariëtte R. Boon ◽

Riekelt H. Houtkooper

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Whole Body ◽

Ampk Signaling ◽

Mitochondrial Homeostasis ◽

Brown Adipose ◽

Metabolic Stresses ◽

Amp Activated Protein Kinase ◽

Body Energy

Obesity is becoming a pandemic, and its prevalence is still increasing. Considering that obesity increases the risk of developing cardiometabolic diseases, research efforts are focusing on new ways to combat obesity. Brown adipose tissue (BAT) has emerged as a possible target to achieve this for its functional role in energy expenditure by means of increasing thermogenesis. An important metabolic sensor and regulator of whole-body energy balance is AMP-activated protein kinase (AMPK), and its role in energy metabolism is evident. This review highlights the mechanisms of BAT activation and investigates how AMPK can be used as a target for BAT activation. We review compounds and other factors that are able to activate AMPK and further discuss the therapeutic use of AMPK in BAT activation. Extensive research shows that AMPK can be activated by a number of different kinases, such as LKB1, CaMKK, but also small molecules, hormones, and metabolic stresses. AMPK is able to activate BAT by inducing adipogenesis, maintaining mitochondrial homeostasis and inducing browning in white adipose tissue. We conclude that, despite encouraging results, many uncertainties should be clarified before AMPK can be posed as a target for anti-obesity treatment via BAT activation.

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Total body skeletal muscle and adipose tissue volumes: estimation from a single abdominal cross-sectional image

Journal of Applied Physiology ◽

10.1152/japplphysiol.00744.2004 ◽

2004 ◽

Vol 97 (6) ◽

pp. 2333-2338 ◽

Cited By ~ 696

Author(s):

Wei Shen ◽

Mark Punyanitya ◽

ZiMian Wang ◽

Dympna Gallagher ◽

Marie-Pierre St.-Onge ◽

...

Keyword(s):

Skeletal Muscle ◽

Body Mass Index ◽

Adipose Tissue ◽

Magnetic Resonance ◽

Body Mass ◽

Whole Body ◽

Intervertebral Space ◽

Cross Sectional ◽

Abdominal Image ◽

Total Body

A single abdominal cross-sectional computerized axial tomography and magnetic resonance image is often obtained in studies examining adipose tissue (AT) distribution. An abdominal image might also provide additional useful information on total body skeletal muscle (SM) and AT volumes with related physiological insights. We therefore investigated the relationships between abdominal SM and AT areas from single images and total body component volumes in a large and diverse sample of healthy adult subjects. Total body SM and AT volumes were derived by whole body multislice magnetic resonance imaging in 123 men [age (mean ± SD) of 41.6 ± 15.8 yr; body mass index of 25.9 ± 3.4 kg/m2] and 205 women (age of 47.8 ± 18.7 yr; body mass index of 26.7 ± 5.6 kg/m2). Single abdominal SM and AT slice areas were highly correlated with total body SM ( r = 0.71–0.92; r = 0.90 at L4–L5 intervertebral space) and AT ( r = 0.84–0.96; r = 0.94 at L4–L5 intervertebral space) volumes, respectively. R2 increased by only 5.7–6.1% for SM and 2.7–4.4% for AT with the inclusion of subject sex, age, ethnicity, scanning position, body mass index, and waist circumference in the model. The developed SM and AT models were validated in an additional 49 subjects. To achieve equivalent power to a study measuring total body SM or AT volumes, a study using a single abdominal image would require 17–24% more subjects for SM and 6–12% more subjects for AT. Measurement of a single abdominal image can thus provide estimates of total body SM and AT for group studies of healthy adults.

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Cold tolerance, cold-induced hyperphagia, and nonshivering thermogenesis are normal in α1-AMPK−/− mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00444.2010 ◽

2011 ◽

Vol 301 (2) ◽

pp. R473-R483 ◽

Cited By ~ 20

Author(s):

Jake D. Bauwens ◽

Eric G. Schmuck ◽

Christopher R. Lindholm ◽

Rebecca L. Ertel ◽

Jacob D. Mulligan ◽

...

Keyword(s):

Adipose Tissue ◽

Cold Exposure ◽

Whole Body ◽

Nonshivering Thermogenesis ◽

Wild Type ◽

Brown Adipose ◽

Ampk Activity ◽

Amp Activated Protein Kinase ◽

Established Role

Recent studies indicate that a substantial amount of metabolically active brown adipose tissue (BAT) exists in adult humans. Given the unique ability of BAT to convert calories to heat, there is intense interest in understanding the regulation of BAT metabolism in hopes that its manipulation might be an effective way of expending excess calories. Because of the established role of AMP-activated protein kinase (AMPK) as a “metabolic master switch” and its extremely high levels of activity in BAT, it was hypothesized that AMPK might play a central role in regulating BAT metabolism. To test this hypothesis, whole body α1-AMPK−/− (knockout) and wild-type mice were studied 1) under control (room temperature) conditions, 2) during chronic cold exposure (14 days at 4°C), and 3) during acute nonshivering thermogenesis (injection of a β3-adrenergic agonist). Under control conditions, loss of α1-AMPK resulted in downregulation of two important prothermogenic genes in BAT, thyrotropin-releasing hormone (−9.2-fold) and ciliary neurotrophic factor (−8.7-fold). Additionally, it caused significant upregulation of α2-AMPK activity in BAT, white adipose tissue, and liver, but not cardiac or skeletal muscle. During acute nonshivering thermogenesis and chronic cold exposure, body temperature was indistinguishable in the α1-AMPK−/− and wild-type mice. Similarly, the degree of cold-induced hyperphagia was identical in the two groups. We conclude that α1-AMPK does not play an obligatory role in these processes and that adaptations to chronic loss of α1-AMPK are able to compensate for its loss via several mechanisms.

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Multiomics reveal unique signatures of human epiploic adipose tissue related to systemic insulin resistance

Gut ◽

10.1136/gutjnl-2021-324603 ◽

2021 ◽

pp. gutjnl-2021-324603

Author(s):

Laura Krieg ◽

Konrad Didt ◽

Isabel Karkossa ◽

Stephan H Bernhart ◽

Stephanie Kehr ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Gastric Bypass Surgery ◽

Whole Body ◽

Expression Levels ◽

Entire Cohort ◽

Fat Depots ◽

Systemic Insulin Resistance ◽

Whole Body Metabolism

ObjectiveHuman white adipose tissue (AT) is a metabolically active organ with distinct depot-specific functions. Despite their locations close to the gastrointestinal tract, mesenteric AT and epiploic AT (epiAT) have only scarcely been investigated. Here, we aim to characterise these ATs in-depth and estimate their contribution to alterations in whole-body metabolism.DesignMesenteric, epiploic, omental and abdominal subcutaneous ATs were collected from 70 patients with obesity undergoing Roux-en-Y gastric bypass surgery. The metabolically well-characterised cohort included nine subjects with insulin sensitive (IS) obesity, whose AT samples were analysed in a multiomics approach, including methylome, transcriptome and proteome along with samples from subjects with insulin resistance (IR) matched for age, sex and body mass index (n=9). Findings implying differences between AT depots in these subgroups were validated in the entire cohort (n=70) by quantitative real-time PCR.ResultsWhile mesenteric AT exhibited signatures similar to those found in the omental depot, epiAT was distinct from all other studied fat depots. Multiomics allowed clear discrimination between the IS and IR states in all tissues. The highest discriminatory power between IS and IR was seen in epiAT, where profound differences in the regulation of developmental, metabolic and inflammatory pathways were observed. Gene expression levels of key molecules involved in AT function, metabolic homeostasis and inflammation revealed significant depot-specific differences with epiAT showing the highest expression levels.ConclusionMulti-omics epiAT signatures reflect systemic IR and obesity subphenotypes distinct from other fat depots. Our data suggest a previously unrecognised role of human epiploic fat in the context of obesity, impaired insulin sensitivity and related diseases.

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Cold exposure distinctively modulates parathyroid and thyroid hormones in cold-acclimatized and non-acclimatized humans

10.1101/2020.01.16.906081 ◽

2020 ◽

Author(s):

Zuzana Kovaničová ◽

Tímea Kurdiová ◽

Miroslav Baláž ◽

Patrik Štefanička ◽

Lukáš Varga ◽

...

Keyword(s):

Energy Metabolism ◽

Thyroid Hormones ◽

Cold Exposure ◽

Neck Surgery ◽

Cross Sectional Study ◽

Whole Body ◽

Cross Sectional ◽

Brown Adipose ◽

Ice Water

AbstractContextCold-induced activation of thermogenesis modulates energy metabolism, but the role of humoral mediators is not completely understood.ObjectiveTo investigate the role of parathyroid and thyroid hormones in acute and adaptive response to cold in humans.DesignCross-sectional study examining acute response to ice-water swimming and to experimental non-shivering thermogenesis (NST) induction in individuals acclimatized and non-acclimatized to cold. Seasonal variation in energy metabolism of ice-water swimmers and associations between circulating PTH and molecular components of thermogenic program in brown adipose tissue (BAT) of neck-surgery patients were evaluated.SettingClinical Research Center.Patients, ParticipantsIce-water swimmers (winter swim n=15, NST-induction n=6), non-acclimatized volunteers (NST-induction, n=11, elective neck surgery n = 36).Main Outcomes and ResultsIn ice-water swimmers, PTH and TSH increased in response to 15min winter swim, while activation of NST failed to regulate PTH and lowered TSH. In non-acclimatized men, NST-induction decreased PTH and TSH. Positive correlation between systemic levels of PTH and whole-body metabolic preference for lipids as well as BAT 18F-FDG uptake was found across the two populations. Moreover, NST-cooling protocol-induced changes in metabolic preference for lipids correlated positively with changes in PTH. Finally, variability in circulating PTH correlated positively with UCP1/UCP1, PPARGC1A and DIO2 in BAT from neck surgery patients.ConclusionsRegulation of PTH and thyroid hormones during cold exposure in humans depends on the cold acclimatization level and/or cold stimulus intensity. Role of PTH in NST is substantiated by its positive relationships with whole-body metabolic preference for lipids, BAT volume and UCP1 content.

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Specific adaptations in muscle and adipose tissue in response to chronic systemic glucose oversupply in rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1997.273.1.e1 ◽

1997 ◽

Vol 273 (1) ◽

pp. E1-E9 ◽

Cited By ~ 13

Author(s):

D. R. Laybutt ◽

D. J. Chisholm ◽

E. W. Kraegen

Keyword(s):

Adipose Tissue ◽

Insulin Sensitivity ◽

Glucose Uptake ◽

Glucose Infusion ◽

Whole Body ◽

Glucose Disposal ◽

Saline Control ◽

Slow Increase ◽

Glucose Clearance

Rats minimize hyperglycemia during chronic glucose infusion, but the metabolic processes are unclear. We investigated the tissues involved and the role of altered insulin sensitivity. Cannulated rats were infused with glucose (40 mg.kg-1.min-1) for 1 or 4 days or with saline (control). Hyperglycemia at 1 day (15.3 +/- 1.0 mM) was absent at 4 days (7.5 +/- 0.3 mM), but hyperinsulinemia persisted. Whole body glucose disposal was similarly elevated at 1 and 4 days, implying increased glucose clearance at 4 days (2-fold, P < 0.001). Muscle glucose uptake and glycogen content declined in glucose-infused rats from 1 to 4 days, whereas white adipose tissue (WAT) glucose uptake (6-fold, P < 0.001) and lipogenesis (3-fold, P < 0.001) increased. Muscle and liver triglyceride were doubled at both 1 and 4 days (P < 0.05 vs. control). Insulin sensitivity (assessed during euglycemic clamps) decreased in muscle to 34% of control at 1 and 4 days (P < 0.001 vs. control) and increased fivefold in WAT from 1 to 4 days (P < 0.05). Thus chronic glucose infusion results in a slow increase in efficiency of glucose clearance with enhanced WAT glucose uptake, lipogenesis, and insulin action. In contrast, the adaptation reduces glucose oversupply to muscle. Muscle shows sustained insulin resistance, with lipid accumulation a possible contributing factor.

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2006-P: The Role of Adipose Tissue-Resident Eosinophils in Adipocyte Metabolism and Whole-Body Energy Homeostasis

Diabetes ◽

10.2337/db19-2006-p ◽

2019 ◽

Vol 68 (Supplement 1) ◽

pp. 2006-P ◽

Cited By ~ 1

Author(s):

TING LI ◽

WILLIAM LESUER ◽

ABHILASHA SINGH ◽

JAMES D. HERNANDEZ ◽

XIAODONG ZHANG ◽

...

Keyword(s):

Adipose Tissue ◽

Energy Homeostasis ◽

Whole Body ◽

Body Energy

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Augmented expression and secretion of adipose-derived pigment epithelium-derived factor does not alter local angiogenesis or contribute to the development of systemic metabolic derangements

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00046.2014 ◽

2014 ◽

Vol 306 (12) ◽

pp. E1367-E1377 ◽

Cited By ~ 10

Author(s):

Thomas V. Lakeland ◽

Melissa L. Borg ◽

Maria Matzaris ◽

Amany Abdelkader ◽

Roger G. Evans ◽

...

Keyword(s):

Adipose Tissue ◽

Energy Expenditure ◽

Body Mass ◽

Pigment Epithelium ◽

In Vivo Studies ◽

Whole Body ◽

Pigment Epithelium Derived Factor ◽

Metabolic Role

Impaired coupling of adipose tissue expansion and vascularization is proposed to lead to adipocyte hypoxia and inflammation, which in turn contributes to systemic metabolic derangements. Pigment epithelium-derived factor (PEDF) is a powerful antiangiogenic factor that is secreted by adipocytes, elevated in obesity, and implicated in the development of insulin resistance. We explored the angiogenic and metabolic role of adipose-derived PEDF through in vivo studies of mice with overexpression of PEDF in adipocytes (PEDF-aP2). PEDF expression in white adipocytes and PEDF secretion from adipose tissue was increased in transgenic mice, but circulating levels of PEDF were not increased. Overexpression of PEDF did not alter vascularization, the partial pressure of O2, cellular hypoxia, or gene expression of inflammatory markers in adipose tissue. Energy expenditure and metabolic substrate utilization, body mass, and adiposity were not altered in PEDF-aP2 mice. Whole body glycemic control was normal as assessed by glucose and insulin tolerance tests, and adipocyte-specific glucose uptake was unaffected by PEDF overexpression. Adipocyte lipolysis was increased in PEDF-aP2 mice and associated with increased adipose triglyceride lipase and decreased perilipin 1 expression. Experiments conducted in mice rendered obese by high-fat feeding showed no differences between PEDF-aP2 and wild-type mice for body mass, adiposity, whole body energy expenditure, glucose tolerance, or adipose tissue oxygenation. Together, these data indicate that adipocyte-generated PEDF enhances lipolysis but question the role of PEDF as a major antiangiogenic or proinflammatory mediator in adipose tissue in vivo.

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