Changes in systemic and subcutaneous adipose tissue inflammation and oxidative stress in response to exercise training in obese black African women.

KEY POINTS: Inflammation and oxidative stress are interrelated during obesity and contribute to the development of insulin resistance; and exercise training represents a key component in the management of these conditions. Black African women, despite high gluteal subcutaneous adipose tissue (SAT) and less visceral fat, are less insulin sensitive than their white counterparts. Exercise training improved systemic oxidative stress in obese black women, which was related to gynoid fat reduction and not insulin sensitivity. Inflammatory markers changed depot-specifically in response to exercise training, increasing in gluteal SAT without changing in abdominal SAT. The increase of inflammatory state in gluteal SAT after exercise training is suggested to result from tissue remodelling consecutive to the reduction of gynoid fat but does not contribute to the improvement of whole-body insulin sensitivity in obese black South African women. ABSTRACT: Inflammation and oxidative stress are interrelated during obesity and contribute to the development of insulin resistance. Exercise training represents a key component in the management of obesity. We evaluated the effects of 12 weeks' combined resistance and aerobic exercise training on systemic and abdominal vs. gluteal subcutaneous adipose tissue (SAT) inflammatory and oxidative status in obese black South African women. Before and after the intervention, body composition (dual energy X-ray absorptiometry), cardio-respiratory fitness ( VO2peak ), serum and SAT inflammatory and oxidative stress markers were measured from 15 (control group) and 20 (exercise group) women and insulin sensitivity (SI ; frequently sampled intravenous glucose tolerance test) was estimated. Following the intervention, VO2peak (9.8%), body fat composition (1-3%) and SI (9%) improved, serum thiobarbituric acid reactive substances (TBARS) decreased (6.5%), and catalase activity increased (23%) in the exercise compared to the control group (P < 0.05), without changes in circulating inflammatory markers. The mRNA content of interleukin-10, tumour necrosis factor α, nuclear factor κB and macrophage migration inhibitory factor increased in the gluteal SAT exercise compared to the control group P < 0.05), with no changes in abdominal SAT. These changes of inflammatory profile in gluteal SAT, in addition to the reduction of circulating TBARS, correlated with the reduction of gynoid fat, but not with the improvement of SI . The changes in systemic oxidative stress markers and gluteal SAT inflammatory genes correlated with the reduction in gynoid fat but were not directly associated with the exercise-induced improvements in SI .

Ethnic differences in hepatic and systemic insulin sensitivity and their associated determinants in obese black and white South African women.

AIMS/HYPOTHESIS: There is evidence to suggest that ectopic fat deposition in liver and skeletal muscle may differ between black and white women resulting in organ-specific differences in insulin sensitivity. Accordingly, the aim of the study was to examine ethnic differences in hepatic and peripheral insulin sensitivity, and the association with hepatic and skeletal muscle lipid content, and skeletal muscle gene expression. METHODS: In a cross-sectional study including 30 obese premenopausal black and white women, body composition (dual energy x-ray absorptiometry), liver fat and skeletal muscle (soleus and tibialis anterior) fat accumulation (proton-magnetic resonance spectroscopy), skeletal muscle gene expression, insulin sensitivity (two-step isotope labelled, hyperinsulinaemic-euglycaemic clamp with 10 mU m(-2) min(-1) and 40 mU m(-2) min(-1) insulin infusions), and serum adipokines were measured. RESULTS: We found that, although whole-body insulin sensitivity was not different, obese white women presented with lower hepatic insulin sensitivity than black women (% suppression of endogenous glucose production [% supp EGP], median [interquartile range (IQR)]: 17 [5-51] vs 56 [29-100] %, p = 0.002). While liver fat tended to be lower (p = 0.065) and skeletal muscle fat deposition tended to be higher (p = 0.074) in black compared with white women, associations with insulin sensitivity were only observed in black women (% supp EGP vs liver fat: r = -0.57, p < 0.05 and % supp EGP vs soleus fat: r = -0.56, p < 0.05). CONCLUSIONS/INTERPRETATION: These findings may suggest that black women are more sensitive to the effects of ectopic lipid deposition than white women.

Melanocyte migration is influenced by E-cadherin-dependent adhesion of keratinocytes in both two- and three-dimensional in vitro wound models.

During wound healing, melanocytes are required to migrate into the wounded area that is still in the process of re-construction. The role and behaviour of melanocytes during this process is poorly understood, that is, whether melanocyte migration into the wound is keratinocyte-dependent or not. This paper attempts, through the use of both two- and three-dimensional in vitro models, to understand the role and behaviour of melanocytes during the process of wound healing. In addition, it sheds light on whether keratinocytes influence/contribute toward melanocyte migration and ultimately wound healing. Scratch assays were performed to analyse migration and Western blot analyses measured cellular E-cadherin expression. Immunohistochemistry was used to analyse the in vivo 3D wound healing effect. Scratch assays performed on co-cultures of melanocytes and keratinocytes demonstrated that melanocytes actively migrated, with the use of their dendrites, into the scratch ahead of the proliferating keratinocyte sheet. Migration of the melanocyte into the wound bed was accompanied by loss of attachment to keratinocytes at the wound front with concomitant downregulation of E-cadherin expression as observed through immunocytochemistry. This result suggests that, in vitro, melanocyte migration occurs independently of keratinocytes but that the migration is influenced by keratinocyte E-cadherin expression. We now demonstrate that melanocyte migration during re-pigmentation is an active process, and suggest that targeting of mechanisms involved in active melanocyte migration (e.g. the melanocyte dendrite) may enhance the re-pigmentation process.

Ethnic differences in regional adipose tissue oestrogen receptor gene expression.

Studies have shown ethnic differences in body fat distribution, characterised by greater peripheral and less central fat accumulation in black compared to white South African (SA) women. As sex hormones play an important role in body fat distribution, our study aimed to determine whether differences in body fat distribution between black and white SA women were associated with subcutaneous adipose tissue (SAT) expression of oestrogen receptors (ERA and ERB) and aromatase (CYP19A1). Body fat distribution (DXA and CT) and ERA, ERB and CYP19A1 expression in abdominal and gluteal SAT were measured in 26 black and 22 white SA women. Abdominal SAT ERA and ERB did not differ by ethnicity or BMI. Gluteal ERA was higher (1.08 ± 0.06 vs 0.99 ± 0.05, P < 0.001) and ERB was lower (0.99 ± 0.06 vs 1.10 ± 0.07, P < 0.001) in black vs white SA women. CYP19A1 increased with obesity in all depots (P < 0.001). In both black and white SA women, gluteal ERA was associated with lower central fat mass (FM) and greater gynoid FM (P < 0.05), while the inverse association was shown for CYP19A1 in all depots (P < 0.01). In conclusion, ethnic differences in gluteal ERA expression were associated with differences in body fat distribution previously reported between black and white SA women.

An Exercise Intervention to Unravel the Mechanisms Underlying Insulin Resistance in a Cohort of Black South African Women: Protocol for a Randomized Controlled Trial and Baseline Characteristics of Participants.

BACKGROUND: The pathogenesis of type 2 diabetes (T2D) in black African women is complex and differs from that in their white counterparts. However, earlier studies have been cross-sectional and provide little insight into the causal pathways. Exercise training is consistently used as a model to examine the mechanisms underlying insulin resistance and risk for T2D. OBJECTIVE: The objective of the study was to examine the mechanisms underlying the changes in insulin sensitivity and secretion in response to a 12-week exercise intervention in obese black South African (SA) women. METHODS: A total of 45 obese (body mass index, BMI: 30-40 kg/m2) black SA women were randomized into a control (n=22) or experimental (exercise; n=23) group. The exercise group completed 12 weeks of supervised combined aerobic and resistance training (40-60 min, 4 days/week), while the control group maintained their typical physical activity patterns, and both groups were requested not to change their dietary patterns. Before and following the 12-week intervention period, insulin sensitivity and secretion (frequently sampled intravenous glucose tolerance test) and its primary and secondary determinants were measured. Dietary intake, sleep quality and quantity, physical activity, and sedentary behaviors were measured every 4 weeks. RESULTS: The final sample included 20 exercise and 15 control participants. Baseline sociodemographics, cardiorespiratory fitness, anthropometry, cardiometabolic risk factors, physical activity, and diet did not differ between the groups (P>.05). CONCLUSIONS: The study describes a research protocol for an exercise intervention to understand the mechanisms underlying insulin sensitivity and secretion in obese black SA women and aims to identify causal pathways underlying the high prevalence of insulin resistance and risk for T2D in black SA women, targeting specific areas for therapeutic intervention. TRIAL REGISTRATION: Pan African Clinical Trial Registry PACTR201711002789113; http://www.pactr.org/ATMWeb/ appmanager/atm/atmregistry?_nfpb=true&_pageLabel=portals_app_atmregistry_portal_page_13 (Archived by WebCite at http://www.webcitation.org/6xLEFqKr0).

Hypoxia and extra-cellular matrix gene expression in adipose tissue associates with reduced insulin sensitivity in black South African women.

Black South African women are more insulin resistant and have increased gluteal subcutaneous adipose tissue hypertrophy than white South African women. We tested the hypothesis that adipose tissue hypoxia and extracellular matrix gene expression in gluteal and abdominal subcutaneous adipose tissue is higher in black than white women, and associates with reduced insulin sensitivity in black women. Insulin sensitivity (frequently sampled intravenous glucose tolerance test), gluteal and abdominal subcutaneous adipose tissue mRNA levels of hypoxia- and extracellular matrix-related genes were measured in normal-weight and obese premenopausal black (n = 30) and white (n = 26) South African women at baseline, and in black women, at 5-year follow-up (n = 10). Compared to obese white women, obese black women had higher expression of hypoxia inducible factor 1, collagen Vα1 and collagen VIα1 and reduced vascular endothelial growth factor-α expression in gluteal (p < 0.05) but not abdominal subcutaneous adipose tissue depots. Independent of age and body fatness, gluteal expression of hypoxia inducible factor 1 (r = -0.55; p = 0.01), collagen Vα1 (r = -0.41; p = 0.05) and collagen VIα1 (r = -0.47; p = 0.03) correlated with reduced insulin sensitivity in black women only. Over a 5-year follow-up, changes in gluteal hypoxia inducible factor 1 (r = 0.77; p = 0.01) collagen Vα1 (r = 0.71; p = 0.02) and collagen VIα1 (r = 0.81; p < 0.01) expression correlated positively with the change in fasting insulin concentrations in black women. Compared to their white counterparts, black women expressed higher levels of genes associated with hypoxia and collagen deposition, and the associations between these genes and insulin sensitivity differed by ethnicity. We thus propose that insulin resistance in black women may be related to higher extracellular matrix and hypoxia gene expression.

Associations between body fat distribution, insulin resistance and dyslipidaemia in black and white South African women.

AIM: The aim was to examine differences in body fat distribution between premenopausal black and white South African (SA) women and explore the ethnic-specific associations with cardiometabolic risk. METHODS: Body composition, using dual-energy X-ray absorptiometry (DXA) and computerised tomography, insulin resistance (HOMA-IR) and lipid levels were assessed in 288 black and 197 white premenopausal SA women. RESULTS: Compared to the white women, black women had less central and more peripheral (lower-body) fat, and lower serum lipid and glucose concentrations, but similar homeostasis models for insulin resistance (HOMA-IR) values. The associations between body fat distribution and HOMA-IR, triglyceride and high-density lipoprotein cholesterol concentrations were similar, while the associations with fasting glucose, total and low-density lipoprotein cholesterol levels differed between black and white women. CONCLUSION: Ethnic differences in body fat distribution are associated, in part, with differences in cardiometabolic risk between black and white SA women.

Ethnic differences in the association between lipid metabolism genes and lipid levels in black and white South African women.

OBJECTIVE: Dyslipidaemia can lead to the development of atherosclerosis and cardiovascular disease (CVD), however its prevalence has been shown to differ between ethnic groups in South Africa (SA). Therefore the aim of this study was to investigate ethnic differences in the association between serum lipid levels and polymorphisms within genes involved in lipid metabolism in black and white SA women. METHODS: In a convenient sample of 234 white and 209 black SA women of Xhosa ancestry, body composition (DXA) and fasting serum lipids were measured. Participants were genotyped for the cholesteryl ester transfer protein (CETP, rs708272, B1/B2), lipoprotein lipase (LPL, rs328, S/X), hepatic lipase (LIPC, rs1800588, C/T) and proprotein convertase subtilisin/kexin type 9 (PCSK9, rs28362286, C/X) polymorphisms. RESULTS: Compared to white women, black women had lower concentrations of serum total cholesterol (TC, P < 0.001), low density lipoprotein cholesterol (LDL-C, P < 0.001), high density lipoprotein cholesterol (HDL-C, P < 0.001) and triglycerides (TG, P < 0.001). There were significant differences in the genotype and allele frequency distributions between black and white women for the LPL S/X (P < 0.001), PCSK9 C679X (P = 0.002) and LIPC 514C/T (P < 0.001) polymorphisms. In black women only, there were genotype effects on serum lipid levels. Specifically, women with the LPL SX genotype had lower TC and LDL-C and higher HDL-C concentrations than those with the SS genotype and women with the CETP B2 allele had lower LDL-C concentrations than those with the B1B1 genotype. CONCLUSION: Polymorphisms within the LPL and CETP genes were associated with a more protective lipid profile in black, but not white SA women. This supports the hypothesis that the more favorable lipid profile of black compared to white SA women is associated with polymorphisms in lipid metabolism genes, specifically the LPL and CETP genes.

The role of adipose tissue in insulin resistance in women of African ancestry.

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.

Reduced gluteal expression of adipogenic and lipogenic genes in Black South African women is associated with obesity-related insulin resistance.

CONTEXT: Black South African women are less insulin sensitive than their White counterparts, despite less central and greater peripheral fat deposition. We hypothesized that this paradox may be explained, in part, by differences in the adipogenic capacity of sc adipose tissue (SAT). OBJECTIVE: Our objective was to measure adipogenic and lipogenic gene expression in abdominal and gluteal SAT depots and determine their relationships with insulin sensitivity (S(I)) in South African women. PARTICIPANTS AND DESIGN: Fourteen normal-weight [body mass index (BMI) <25 kg/m(2)] Black, 13 normal-weight White, 14 obese (BMI >30 kg/m(2)) Black, and 13 obese White premenopausal South African women participated in this cross-sectional study. MAIN OUTCOMES: S(I) (frequently sampled i.v. glucose tolerance test) in relation to expression of adipogenic and lipogenic genes in abdominal and gluteal SAT depots. RESULTS: With increasing BMI, Black women had less visceral fat (P = 0.03) and more abdominal (P = 0.017) and gynoid (P = 0.041) SAT but had lower S(I) (P < 0.01) than White women. The expression of adipogenic and lipogenic genes was proportionately lower with obesity in Black but not White women in the gluteal and deep SAT depots (P < 0.05 for ethnicity × BMI effect). In Black women only, the expression of these genes correlated positively with S(I) (all P < 0.05), independently of age and fat mass. CONCLUSIONS: Obese Black women have reduced SAT expression of adipogenic and lipogenic genes compared with White women, which associates with reduced S(I). These findings suggest that obesity in Black women impairs SAT adipogenesis and storage, potentially leading to insulin resistance and increased risk of type 2 diabetes.