Contribution of Adipose Tissue Oxidative Stress to Obesity-Associated Diabetes Risk and Ethnic Differences: Focus on Women of African Ancestry

Adipose tissue (AT) storage capacity is central in the maintenance of whole-body homeostasis, especially in obesity states. However, sustained nutrients overflow may dysregulate this function resulting in adipocytes hypertrophy, AT hypoxia, inflammation and oxidative stress. Systemic inflammation may also contribute to the disruption of AT redox equilibrium. AT and systemic oxidative stress have been involved in the development of obesity-associated insulin resistance (IR) and type 2 diabetes (T2D) through several mechanisms. Interestingly, fat accumulation, body fat distribution and the degree of how adiposity translates into cardio-metabolic diseases differ between ethnicities. Populations of African ancestry have a higher prevalence of obesity and higher T2D risk than populations of European ancestry, mainly driven by higher rates among African women. Considering the reported ethnic-specific differences in AT distribution and function and higher levels of systemic oxidative stress markers, oxidative stress is a potential contributor to the higher susceptibility for metabolic diseases in African women. This review summarizes existing evidence supporting this hypothesis while acknowledging a lack of data on AT oxidative stress in relation to IR in Africans, and the potential influence of other ethnicity-related modulators (e.g., genetic-environment interplay, socioeconomic factors) for consideration in future studies with different ethnicities.

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DsbA-L deficiency in T cells promotes diet-induced thermogenesis through suppressing IFN-γ production

Nature Communications ◽

10.1038/s41467-020-20665-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Haiyan Zhou ◽

Xinyi Peng ◽

Jie Hu ◽

Liwen Wang ◽

Hairong Luo ◽

...

Keyword(s):

T Cells ◽

Adipose Tissue ◽

T Cell ◽

Energy Homeostasis ◽

Metabolic Diseases ◽

Therapeutic Potential ◽

Whole Body ◽

Brown Adipose ◽

Ifn Γ ◽

Diet Induced Thermogenesis

AbstractAdipose tissue-resident T cells have been recognized as a critical regulator of thermogenesis and energy expenditure, yet the underlying mechanisms remain unclear. Here, we show that high-fat diet (HFD) feeding greatly suppresses the expression of disulfide-bond A oxidoreductase-like protein (DsbA-L), a mitochondria-localized chaperone protein, in adipose-resident T cells, which correlates with reduced T cell mitochondrial function. T cell-specific knockout of DsbA-L enhances diet-induced thermogenesis in brown adipose tissue (BAT) and protects mice from HFD-induced obesity, hepatosteatosis, and insulin resistance. Mechanistically, DsbA-L deficiency in T cells reduces IFN-γ production and activates protein kinase A by reducing phosphodiesterase-4D expression, leading to increased BAT thermogenesis. Taken together, our study uncovers a mechanism by which T cells communicate with brown adipocytes to regulate BAT thermogenesis and whole-body energy homeostasis. Our findings highlight a therapeutic potential of targeting T cells for the treatment of over nutrition-induced obesity and its associated metabolic diseases.

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Systemic oxidative stress is associated with lower aerobic capacity and impaired skeletal muscle energy metabolism in heart failure patients

Scientific Reports ◽

10.1038/s41598-021-81736-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Takashi Yokota ◽

Shintaro Kinugawa ◽

Kagami Hirabayashi ◽

Mayumi Yamato ◽

Shingo Takada ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Skeletal Muscle ◽

Energy Metabolism ◽

Aerobic Capacity ◽

Plantar Flexion ◽

Exercise Intolerance ◽

Whole Body ◽

Resonance Spectroscopy ◽

Systemic Oxidative Stress

AbstractOxidative stress plays a role in the progression of chronic heart failure (CHF). We investigated whether systemic oxidative stress is linked to exercise intolerance and skeletal muscle abnormalities in patients with CHF. We recruited 30 males: 17 CHF patients, 13 healthy controls. All participants underwent blood testing, cardiopulmonary exercise testing, and magnetic resonance spectroscopy (MRS). The serum thiobarbituric acid reactive substances (TBARS; lipid peroxides) were significantly higher (5.1 ± 1.1 vs. 3.4 ± 0.7 μmol/L, p < 0.01) and the serum activities of superoxide dismutase (SOD), an antioxidant, were significantly lower (9.2 ± 7.1 vs. 29.4 ± 9.7 units/L, p < 0.01) in the CHF cohort versus the controls. The oxygen uptake (VO2) at both peak exercise and anaerobic threshold was significantly depressed in the CHF patients; the parameters of aerobic capacity were inversely correlated with serum TBARS and positively correlated with serum SOD activity. The phosphocreatine loss during plantar-flexion exercise and intramyocellular lipid content in the participants' leg muscle measured by 31phosphorus- and 1proton-MRS, respectively, were significantly elevated in the CHF patients, indicating abnormal intramuscular energy metabolism. Notably, the skeletal muscle abnormalities were related to the enhanced systemic oxidative stress. Our analyses revealed that systemic oxidative stress is related to lowered whole-body aerobic capacity and skeletal muscle dysfunction in CHF patients.

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The Role of Adipose Tissue in Insulin Resistance in Women of African Ancestry

Journal of Obesity ◽

10.1155/2013/952916 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 16

Author(s):

Julia H. Goedecke ◽

Naomi S. Levitt ◽

Juliet Evans ◽

Nicole Ellman ◽

David John Hume ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

White Women ◽

African Ancestry ◽

Fat Distribution ◽

Future Research ◽

Industrialized Countries ◽

Tissue Biology ◽

Ectopic Fat Deposition

Women of African ancestry, particularly those living in industrialized countries, experience a disproportionately higher prevalence of type 2 diabetes (T2D) compared to their white counterparts. Similarly, obesity and insulin resistance, which are major risk factors for T2D, are greater in black compared to white women. The exact mechanisms underlying these phenomena are not known. This paper will focus on the role of adipose tissue biology. Firstly, the characteristic body fat distribution of women of African ancestry will be discussed, followed by the depot-specific associations with insulin resistance. Factors involved in adipose tissue biology and their relation to insulin sensitivity will then be explored, including the role of sex hormones, glucocorticoid metabolism, lipolysis and adipogenesis, and their consequent effects on adipose tissue hypoxia, oxidative stress, and inflammation. Finally the role of ectopic fat deposition will be discussed. The paper proposes directions for future research, in particular highlighting the need for longitudinal and/or intervention studies to better understand the mechanisms underlying the high prevalence of insulin resistance and T2D in women of African ancestry.

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Activated Ask1-MKK4-p38MAPK/JNK Stress Signaling Pathway in Human Omental Fat Tissue May Link Macrophage Infiltration to Whole-Body Insulin Sensitivity

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2009-0002 ◽

2009 ◽

Vol 94 (7) ◽

pp. 2507-2515 ◽

Cited By ~ 61

Author(s):

Matthias Blüher ◽

Nava Bashan ◽

Iris Shai ◽

Ilana Harman-Boehm ◽

Tanya Tarnovscki ◽

...

Keyword(s):

Adipose Tissue ◽

Insulin Sensitivity ◽

Fat Distribution ◽

Macrophage Infiltration ◽

Whole Body ◽

Strongly Correlated ◽

Jnk Pathway ◽

Paired Samples ◽

Adipocyte Cell ◽

Stress Sensing

Context: Adipose tissue in obesity is thought to be exposed to various stresses, predominantly in intraabdominal depots. We recently reported that p38MAPK and Jun N-terminal kinase (JNK), but not ERK and inhibitory-κB kinase β, are more highly expressed and activated in human omental (OM) adipose tissue in obesity. Objective: The aim was to investigate upstream components of the pathways that culminate in activation of p38MAPK and JNK. Setting and Patients: Phosphorylation and expression of kinases were studied in paired samples of OM and sc adipose tissue from lean and obese subjects of two different cohorts (n = 36 and n = 196) by Western and real-time PCR analyses. The association with fat distribution, macrophage infiltration, insulin sensitivity, and glucose metabolism was assessed by correlation analyses. Results: The amount of phosphorylated forms of the kinases provided evidence for an activated stress-sensing pathway consisting of the MAP3K Ask1 (but not MLK3 or Tak1), and the MAP2Ks MKK4, 3/6, (but not MKK7), specifically in OM. OM Ask1-mRNA was more highly expressed in predominantly intraabdominally obese persons and most strongly correlated with estimated visceral fat. Diabetes was associated with higher OM Ask1-mRNA only in the lean group. In OM, macrophage infiltration strongly correlated with Ask1-mRNA, but the obesity-associated increase in Ask1-mRNA could largely be attributed to the adipocyte cell fraction. Finally, multivariate regression analyses revealed OM-Ask1 as an independent predictor of whole-body glucose uptake in euglycemic-hyperinsulinemic clamps. Conclusions: An Ask1-MKK4-p38MAPK/JNK pathway reflects adipocyte stress associated with adipose tissue inflammation, linking visceral adiposity to whole-body insulin resistance in obesity.

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Dysregulation of Adipose Glutathione Peroxidase 3 in Obesity Contributes to Local and Systemic Oxidative Stress

Molecular Endocrinology ◽

10.1210/me.2008-0023 ◽

2008 ◽

Vol 22 (9) ◽

pp. 2176-2189 ◽

Cited By ~ 102

Author(s):

Yun Sok Lee ◽

A Young Kim ◽

Jin Woo Choi ◽

Min Kim ◽

Shintaro Yasue ◽

...

Keyword(s):

Oxidative Stress ◽

Adipose Tissue ◽

Glutathione Peroxidase ◽

Antidiabetic Drug ◽

Metabolic Complications ◽

Inflammatory Gene Expression ◽

Systemic Oxidative Stress ◽

Glutathione Peroxidase 3 ◽

Obese Subjects ◽

And Oxidative Stress

Abstract Glutathione peroxidase 3 (GPx3) accounts for the major antioxidant activity in the plasma. Here, we demonstrate that down-regulation of GPx3 in the plasma of obese subjects is associated with adipose GPx3 dysregulation, resulting from the increase of inflammatory signals and oxidative stress. Although GPx3 was abundantly expressed in kidney, lung, and adipose tissue, we observed that GPx3 expression was reduced selectively in the adipose tissue of several obese animal models as decreasing plasma GPx3 level. Adipose GPx3 expression was greatly suppressed by prooxidative conditions such as high levels of TNFα and hypoxia. In contrast, the antioxidant N-acetyl cysteine and the antidiabetic drug rosiglitazone increased adipose GPx3 expression in obese and diabetic db/db mice. Moreover, GPx3 overexpression in adipocytes improved high glucose-induced insulin resistance and attenuated inflammatory gene expression whereas GPx3 neutralization in adipocytes promoted expression of proinflammatory genes. Taken together, these data suggest that suppression of GPx3 expression in the adipose tissue of obese subjects might constitute a vicious cycle to expand local reactive oxygen species accumulation in adipose tissue potentially into systemic oxidative stress and obesity-related metabolic complications.

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Treatment of hyperthyroidism reduces systemic oxidative stress, as measured by markers of RNA and DNA damages

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab273 ◽

2021 ◽

Author(s):

Camilla B Larsen ◽

Kamilla Ryom Riis ◽

Kristian Hillert Winther ◽

Emil List Larsen ◽

Christina Ellervik ◽

...

Keyword(s):

Oxidative Stress ◽

Urinary Excretion ◽

Geometric Mean ◽

Nodular Goiter ◽

Whole Body ◽

Oxidative Stress Markers ◽

Toxic Nodular Goiter ◽

Stress Markers ◽

Systemic Oxidative Stress ◽

Rna And Dna

Abstract Background Whole-body oxidative stress can be estimated by the urine excretion of oxidized guanosine species, 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), derived from RNA and DNA, respectively. These oxidative stress markers are not well explored in thyroid disorders. Methods Urinary excretion of 8-oxoGuo and 8-oxodG was measured in 51 hyperthyroid patients (toxic nodular goiter (TNG), n=30; Graves’ disease (GD), n=21) before or shortly after initiation of therapy and when stable euthyroidism had been achieved for at least 12 months. Results Adjusting for age, the baseline urinary excretion of oxidative stress markers correlated positively with plasma thyroxine (8-oxoGuo: p=0.002; 8-oxodG: p=0.021) and was significantly higher in GD than in TNG patients (p=0.001 for both oxidative stress markers). Restoration of euthyroidism significantly affected the excretion of the oxidative stress markers. In TNG, 8-oxoGuo decreased from geometric mean 2.11 nmol/mmol creatinine (95%CI:1.85-2.39) to 1.91 nmol/mmol (95%CI:1.67-2.19), p=0.001, while 8-oxodG decreased from 1.65 nmol/mmol (95%CI:1.41-1.93) to 1.48 nmol/mmol (95%CI:1.27-1.74), p=0.026. In GD, 8-oxoGuo decreased from 2.25 nmol/mmol (95%CI:1.95-2.59) to 1.79 nmol/mmol (95%CI:1.63-1.97), p=0.0003, while 8-oxodG decreased from 2.02 nmol/mmol (95%CI:1.73-2.38) to 1.54 nmol/mmol (95%CI:1.31-1.81), p=0.001. In the euthyroid state, there were no differences between groups. Conclusion Restoration of euthyroidism in patients with hyperthyroidism significantly decreased the systemic oxidative stress load by 10-25%. Our findings may help to explain the higher morbidity and mortality linked to hyperthyroid diseases, as shown in observational studies.

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Phenotypic Heterogeneity in Body Fat Distribution in Patients with Congenital Generalized Lipodystrophy Caused by Mutations in the AGPAT2 or Seipin Genes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2003-030835 ◽

2003 ◽

Vol 88 (11) ◽

pp. 5433-5437 ◽

Cited By ~ 118

Author(s):

Vinaya Simha ◽

Abhimanyu Garg

Keyword(s):

Adipose Tissue ◽

Body Fat ◽

Autosomal Recessive ◽

Acanthosis Nigricans ◽

Fat Distribution ◽

Body Fat Distribution ◽

Whole Body ◽

Severe Insulin Resistance ◽

Congenital Generalized Lipodystrophy ◽

Chromosome 9Q34

Abstract Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive syndrome characterized by extreme paucity of adipose tissue since birth, acanthosis nigricans, severe insulin resistance, marked hypertriglyceridemia, and early-onset diabetes mellitus. Recently, we reported mutations in the 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) gene in CGL pedigrees linked to chromosome 9q34 (CGL1 subtype), and mutations in the Seipin gene were reported in pedigrees linked to chromosome 11q13 (CGL2 subtype). Whether the two subtypes have differences in body fat distribution has not been investigated. We, therefore, compared whole-body adipose tissue distribution by magnetic resonance imaging in 10 CGL patients, of whom seven (six females, one male) had CGL1 and three (two males, one female) had CGL2. Both subtypes had marked lack of metabolically active adipose tissue located at most sc, intermuscular, bone marrow, intraabdominal, and intrathoracic regions. Paucity of mechanical adipose tissue in the palms, soles, orbits, scalp, and periarticular regions was noted in CGL2, whereas it was well preserved in CGL1 patients. We conclude that CGL patients with Seipin mutations have a more severe lack of body fat, which affects both metabolically active and mechanical adipose tissue, compared with patients with mutations in the AGPAT2 gene.

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Brown Adipose Tissue - role in metabolic disorders

IMC Journal of Medical Science ◽

10.3329/imcjms.v13i1.42049 ◽

2019 ◽

Vol 13 (1) ◽

pp. 002

Author(s):

Tahniyah Haq ◽

Frank Joseph Ong ◽

Sarah Kanji

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Metabolic Diseases ◽

Uncoupling Protein ◽

Whole Body ◽

Positron Emission ◽

Brown Adipose ◽

Magnetic Resonance Imaging Mri ◽

Fdg Pet Ct ◽

Body Energy

Brown adipose tissue, a thermogenic organ, previously thought to be present in only small mammals and children has recently been identified in adult humans. Located primarily in the supraclavicular and cervical area, it produces heat by uncoupling oxidative phosphorylation due to the unique presence of uncoupling protein 1 by a process called nonshivering thermogenesis. BAT activity depends on many factors including age, sex, adiposity and outdoor temperature. Positron-emission tomography using 18F-fluorodeoxyglucose and computed tomography (18F-FDG PET–CT), magnetic resonance imaging (MRI) and thermal imaging (IRT) are among several methods used to detect BAT in humans. The importance of BAT is due to its role in whole body energy expenditure and fuel metabolism. Thus it is postulated that it may be useful in the treatment of metabolic diseases. However, there are still many unanswered questions to the clinical usefulness of this novel tissue. IMC J Med Sci 2019; 13(1): 002

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Does Adipose Tissue Thermogenesis Play a Role in Metabolic Health?

Journal of Obesity ◽

10.1155/2013/204094 ◽

2013 ◽

Vol 2013 ◽

pp. 1-4

Author(s):

Craig Porter ◽

Elisabet Børsheim ◽

Labros S. Sidossis

Keyword(s):

Adipose Tissue ◽

Energy Metabolism ◽

Brown Adipose Tissue ◽

Metabolic Diseases ◽

Oxidative Capacity ◽

Whole Body ◽

Research Strategies ◽

Brown Adipocytes ◽

Brown Adipose

The function ascribed to brown adipose tissue in humans has long been confined to thermoregulation in neonates, where this thermogenic capacity was thought lost with maturation. Recently, brown adipose tissue depots have been identified in adult humans. The significant oxidative capacity of brown adipocytes and the ability of their mitochondria to respire independently of ATP production, has led to renewed interest in the role that these adipocytes play in human energy metabolism. In our view, there is a need for robust physiological studies determining the relationship between molecular signatures of brown adipose tissue, adipose tissue mitochondrial function, and whole body energy metabolism, in order to elucidate the significance of thermogenic adipose tissue in humans. Until such information is available, the role of thermogenic adipose tissue in human metabolism and the potential that these adipocytes may prevent or treat obesity and metabolic diseases in humans will remain unknown. In this article, we summarize the recent literature pertaining to brown adipose tissue function with the aims of drawing the readers’ attention to the lack of data concerning the role of brown adipocytes in human physiology, and to the potential limitations of current research strategies.

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DNA Methylation as a Marker of Body Shape in Premenopausal Women

Frontiers in Genetics ◽

10.3389/fgene.2021.709342 ◽

2021 ◽

Vol 12 ◽

Author(s):

Adeline Divoux ◽

Alexey Eroshkin ◽

Edina Erdos ◽

Katalin Sandor ◽

Timothy F. Osborne ◽

...

Keyword(s):

Dna Methylation ◽

Adipose Tissue ◽

Body Fat ◽

Body Shape ◽

Metabolic Diseases ◽

Premenopausal Women ◽

Fat Distribution ◽

The Body ◽

Fat Depots ◽

Increased Risk

Preferential accumulation of fat in the gluteo-femoral (GF) depot (pear shape) rather than in the abdominal (A) depot (apple shape), protects against the development of metabolic diseases but the underlying molecular mechanism is still unknown. Recent data, including our work, suggest that differential epigenetic marking is associated with regulation of genes attributed to distinct fat distribution. Here, we aimed to compare the genomic DNA methylation signatures between apple and pear-shaped premenopausal women. To investigate the contribution of upper and lower body fat, we used paired samples of A-FAT and GF-FAT, analyzed on the BeadChip Methylation Array and quantified the differentially methylated sites between the 2 groups of women. We found unique DNA methylation patterns within both fat depots that are significantly different depending on the body fat distribution. Around 60% of the body shape specific DNA methylation sites identified in adipose tissue are maintained ex vivo in cultured preadipocytes. As it has been reported before in other cell types, we found only a hand full of genes showing coordinated differential methylation and expression levels. Finally, we determined that more than 50% of the body shape specific DNA methylation sites could also be detected in whole blood derived DNA. These data reveal a strong DNA methylation program associated with adipose tissue distribution with the possibility that a simple blood test could be used as a predictive diagnostic indicator of young women who are at increased risk for progressing to the apple body shape with a higher risk of developing obesity related complications.Clinical Trial Registration:https://clinicaltrials.gov/ct2/show/NCT02728635 and https://clinicaltrials.gov/ct2/show/NCT02226640, identifiers NCT02728635 and NCT02226640.

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