Based on rodent studies, we examined the hypothesis that increased adipose tissue (AT) mass in obesity without an adequate support of vascularization might lead to hypoxia, macrophage infiltration, ...and inflammation.
Oxygen partial pressure (AT pO2) and AT temperature in abdominal AT (9 lean and 12 overweight/obese men and women) was measured by direct insertion of a polarographic Clark electrode. Body composition was measured by dual-energy X-ray absorptiometry, and insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp. Abdominal subcutaneous tissue was used for staining, quantitative RT-PCR, and chemokine secretion assay.
AT pO2 was lower in overweight/obese subjects than lean subjects (47 +/- 10.6 vs. 55 +/- 9.1 mmHg); however, this level of pO2 did not activate the classic hypoxia targets (pyruvate dehydrogenase kinase and vascular endothelial growth factor VEGF). AT pO2 was negatively correlated with percent body fat (R = -0.50, P < 0.05). Compared with lean subjects, overweight/obese subjects had 44% lower capillary density and 58% lower VEGF, suggesting AT rarefaction (capillary drop out). This might be due to lower peroxisome proliferator-activated receptor gamma1 and higher collagen VI mRNA expression, which correlated with AT pO2 (P < 0.05). Of clinical importance, AT pO2 negatively correlated with CD68 mRNA and macrophage inflammatory protein 1alpha secretion (R = -0.58, R = -0.79, P < 0.05), suggesting that lower AT pO2 could drive AT inflammation in obesity.
Adipose tissue rarefaction might lie upstream of both low AT pO2 and inflammation in obesity. These results suggest novel approaches to treat the dysfunctional AT found in obesity.
Reduced Adipose Tissue Oxygenation in Human Obesity
Evidence for Rarefaction, Macrophage Chemotaxis, and Inflammation Without an Angiogenic Response
Magdalena Pasarica ,
Olga R. Sereda ,
Leanne M. ...Redman ,
Diana C. Albarado ,
David T. Hymel ,
Laura E. Roan ,
Jennifer C. Rood ,
David H. Burk and
Steven R. Smith
From the Pennington Biomedical Research Center, Baton Rouge, Louisiana
Corresponding author: Steven R. Smith, smithsr{at}pbrc.edu
Abstract
OBJECTIVE— Based on rodent studies, we examined the hypothesis that increased adipose tissue (AT) mass in obesity without an adequate
support of vascularization might lead to hypoxia, macrophage infiltration, and inflammation.
RESEARCH DESIGN AND METHODS— Oxygen partial pressure (AT pO 2 ) and AT temperature in abdominal AT (9 lean and 12 overweight/obese men and women) was measured by direct insertion of a
polarographic Clark electrode. Body composition was measured by dual-energy X-ray absorptiometry, and insulin sensitivity
was measured by hyperinsulinemic-euglycemic clamp. Abdominal subcutaneous tissue was used for staining, quantitative RT-PCR,
and chemokine secretion assay.
RESULTS— AT pO 2 was lower in overweight/obese subjects than lean subjects (47 ± 10.6 vs. 55 ± 9.1 mmHg); however, this level of pO 2 did not activate the classic hypoxia targets (pyruvate dehydrogenase kinase and vascular endothelial growth factor VEGF).
AT pO 2 was negatively correlated with percent body fat ( R = −0.50, P < 0.05). Compared with lean subjects, overweight/obese subjects had 44% lower capillary density and 58% lower VEGF, suggesting
AT rarefaction (capillary drop out). This might be due to lower peroxisome proliferator–activated receptor γ1 and higher collagen
VI mRNA expression, which correlated with AT pO 2 ( P < 0.05). Of clinical importance, AT pO 2 negatively correlated with CD68 mRNA and macrophage inflammatory protein 1α secretion ( R = −0.58, R = −0.79, P < 0.05), suggesting that lower AT pO 2 could drive AT inflammation in obesity.
CONCLUSIONS— Adipose tissue rarefaction might lie upstream of both low AT pO 2 and inflammation in obesity. These results suggest novel approaches to treat the dysfunctional AT found in obesity.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 15 December 2008.
Clinical trials reg. no. NCT00704197, clinicaltrials.gov.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted December 9, 2008.
Received August 11, 2008.
DIABETES
Metabolic flexibility of skeletal muscle, that is, the preference for fat oxidation (FOx) during fasting and for carbohydrate oxidation in response to insulin, is decreased during insulin resistance. ...The aim of this study was to test the hypothesis that the capacity of myotubes to oxidize fat in vitro reflects the donor's metabolic characteristics. Insulin sensitivity (IS) and metabolic flexibility of 16 healthy, young male subjects was determined by euglycemic hyperinsulinemic clamp. Muscle samples were obtained from vastus lateralis, cultured, and differentiated into myotubes. In human myotubes in vitro, we measured suppressibility (glucose suppression of FOx) and adaptability (an increase in FOx in the presence of high palmitate concentration). We termed these dynamic changes in FOx metabolic switching. In vivo, metabolic flexibility was positively correlated with IS and maximal oxygen uptake and inversely correlated with percent body fat. In vitro suppressibility was inversely correlated with IS and metabolic flexibility and positively correlated with body fat and fasting FFA levels. Adaptability was negatively associated with percent body fat and fasting insulin and positively correlated with IS and metabolic flexibility. The interindividual variability in metabolic phenotypes was preserved in human myotubes separated from their neuroendocrine environment, which supports the hypothesis that metabolic switching is an intrinsic property of skeletal muscle.
Insulin resistance is associated with metabolic inflexibility, impaired switching of substrate oxidation from fatty acids to glucose in response to insulin. Impaired switching to fat oxidation in ...response to a high-fat diet (HFD) is hypothesized to contribute to insulin resistance. The objective of this study was to test the hypothesis that defects in substrate switching in response to insulin and a HFD are linked to reduced mitochondrial biogenesis and occur before the development of diabetes. Metabolic flexibility was measured in young sedentary men with (n = 16) or without (n = 34) a family history of diabetes by euglycemic-hyperinsulinemic clamp. Flexibility correlated with fat oxidation measured in a respiratory chamber after a 3-day HFD. Muscle mitochondrial content was higher in flexible subjects with high fat oxidation after a HFD and contributed 49% of the variance. Subjects with a family history of diabetes were inflexible and had reduced HFD-induced fat oxidation and muscle mitochondrial content but did not differ in the amount of body or visceral fat. Metabolic inflexibility, lower adaptation to a HFD, and reduced muscle mitochondrial mass cluster together in subjects with a family history of diabetes, supporting the role of an intrinsic metabolic defect of skeletal muscle in the pathogenesis of insulin resistance.
Abstract
Background
Longer-term humoral responses to 2-dose coronavirus disease 2019 (COVID-19) vaccines remain incompletely characterized in people living with human immunodeficiency virus (HIV) ...(PLWH), as do initial responses to a third dose.
Methods
We measured antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor-binding domain, angiotensin-converting enzyme 2 (ACE2) displacement, and viral neutralization against wild-type and Omicron strains up to 6 months after 2-dose vaccination, and 1 month after the third dose, in 99 PLWH receiving suppressive antiretroviral therapy and 152 controls.
Results
Although humoral responses naturally decline after 2-dose vaccination, we found no evidence of lower antibody concentrations or faster rates of antibody decline in PLWH compared with controls after accounting for sociodemographic, health, and vaccine-related factors. We also found no evidence of poorer viral neutralization in PLWH after 2 doses, nor evidence that a low nadir CD4+ T-cell count compromised responses. Post–third-dose humoral responses substantially exceeded post–second-dose levels, though Omicron-specific responses were consistently weaker than responses against wild-type virus. Nevertheless, post–third-dose responses in PLWH were comparable to or higher than controls. An mRNA-1273 third dose was the strongest consistent correlate of higher post–third-dose responses.
Conclusion
PLWH receiving suppressive antiretroviral therapy mount strong antibody responses after 2- and 3-dose COVID-19 vaccination. Results underscore the immune benefits of third doses in light of Omicron.
People living with human immunodeficiency virus with well-controlled viral loads on antiretroviral therapy and preserved CD4+ T-cell counts mount strong, functional antibody responses to 2- and 3-dose coronavirus disease 2019 vaccination, including to Omicron. Monitoring responses over time remains important.
Maximal mitochondrial ATP synthesis, measured by dynamic 31P magnetic resonance spectroscopy, is reduced in type 2 diabetes but is not associated with insulin resistance.
Objective:
The objective of ...this study was to determine the role of maximum mitochondrial capacity on the variation in insulin sensitivity within a population of patients with type 2 diabetes mellitus (T2DM).
Research Design and Methods:
Fifty-eight participants enrolled in a cross-sectional design: eight active controls maximum aerobic capacity (VO2max) > 40 ml/kg · min, 17 healthy sedentary controls without a family history (FH−) and seven with a family history (FH+) of diabetes, four obese participants, and 21 patients with T2DM. Mitochondrial capacity was measured noninvasively using 31P magnetic resonance spectroscopy of the vastus lateralis. Maximal ATP synthetic rate (ATPmax) was determined from the rate of phosphocreatine (PCr) recovery after short-term isometric exercise.
Results:
ATPmax was lower (P < 0.001) in T2DM and higher (P < 0.001) in active as compared with healthy sedentary FH− (active, 1.01 ± 0.2; FH−, 0.7 ± 0.2; FH+, 0.6 ± 0.1; obese, 0.6 ± 0.1; T2DM, 0.5 ± 0.2 mm ATP/sec; ANOVA P < 0.0001). Insulin sensitivity, measured by euglycemic-hyperinsulinemic (80 mIU/m2 · min) clamp was also reduced in T2DM (P < 0.001) (active, 12.0 ± 3.2; FH−, 7.8 ± 2.2; FH+, 6.8 ± 3.5; obese, 3.1 ± 1.0; T2DM, 3.4 ± 1.6; mg/kg estimated metabolic body size · min; ANOVA P < 0.0001). Unexpectedly, there was a broad range of ATPmax within the T2DM population where 52% of subjects with T2DM had ATPmax values that were within the range observed in healthy sedentary controls. In addition, 24% of the T2DM subjects overlapped with the active control group (range, 0.65–1.27 mm ATP/sec). In contrast to the positive correlation between ATPmax and M-value in the whole population (r2 = 0.35; P < 0.0001), there was no correlation between ATPmax and M-value in the patients with T2DM (r2 = 0.004; P = 0.79).
Conclusions:
Mitochondrial capacity is not associated with insulin action in T2DM.
BackgroundUkraine has the highest HIV prevalence in Europe, with young people disproportionately represented among populations at high risk. One particularly vulnerable group comprises adolescents ...who live or work on the streets. This study aimed to measure the extent and distribution of HIV risk behaviours among street-based adolescents in four Ukrainian cities as part of a regional UNICEF HIV prevention programme for most-at-risk adolescents.MethodsA cross-sectional behavioural survey was conducted of 805 adolescents (aged 10–19 years) in the cities of Kiev, Donetsk, Dnepropetrovsk and Nikolaev. Using location-based network and convenience sampling, 200 adolescents were reached in each site and were administered a standardised questionnaire on drug use, sexual behaviour, condom use, HIV knowledge, access to prevention services, experience of violence and contact with state institutions and police.ResultsConsiderable levels of HIV risk behaviour were found, including injecting drug use among 15.5% of the sample. Almost three-quarters of adolescents had experienced sexual debut, most before the age of 15 years. Male-to-male sexual behaviour was reported by just under 10% of boys. Condom use was low although varied by partner type. There were high rates of forced sex, and 75.5% of respondents reported police harassment.ConclusionsStreet-based adolescents in Ukraine are at significant risk of contracting HIV due to involvement in injecting drug use and unprotected sex in personal and commercial exchanges, including male-to-male sex. This group initiates risk behaviours at early ages, and does not appear to have good access to prevention and other health services.
Abstract Aims Pioglitazone (Pio) is known to improve insulin sensitivity in skeletal muscle. However, the role of Pio in skeletal muscle lipid metabolism and skeletal muscle oxidative capacity is not ...clear. The aim of this study was to determine the effects of chronic Pio treatment on skeletal muscle mitochondrial activity in individuals with type 2 diabetes (T2D). Materials and Methods Twenty-four participants with T2D (13 M/11F 53.38 ± 2.1 years; BMI 36.47 ± 1.1 kg/m2 ) were randomized to either a placebo (CON, n = 8) or a pioglitazone (PIO, n = 16) group. Following 12 weeks of treatment, we measured insulin sensitivity by hyperinsulinemic–euglycemic clamp (clamp), metabolic flexibility by calculating the change in respiratory quotient (ΔRQ) during the steady state of the clamp, intra- and extra-myocellular lipid content (IMCL and EMCL, respectively) by1 H magnetic resonance spectroscopy (1 H-MRS) and muscle maximal ATP synthetic capacity (ATPmax) by31 P-MRS. Results Following 12 weeks of PIO treatment, insulin sensitivity ( p < 0.0005 vs. baseline) and metabolic flexibility ( p < 0.05 vs. CON) significantly increased. PIO treatment significantly decreased IMCL content and increased EMCL content in gastrocnemius, soleus and tibialis anterior muscles. ATPmax was unaffected by PIO treatment. Conclusions These results suggest that 12 weeks of pioglitazone treatment improves insulin sensitivity, metabolic flexibility and myocellular lipid distribution without any effect on maximal ATP synthetic capacity in skeletal muscle. Consequently, pioglitazone-induced enhancements in insulin responsiveness and fuel utilization are independent of mitochondrial function.
PDF
