Early mitochondrial adaptations in skeletal muscle to diet-induced obesity are strain dependent and determine oxidative stress and energy expenditure but not insulin sensitivity

This study sought to elucidate the relationship between skeletal muscle mitochondrial dysfunction, oxidative stress, and insulin resistance in two mouse models with differential susceptibility to diet-induced obesity. We examined the time course of mitochondrial dysfunction and insulin resistance in obesity-prone C57B and obesity-resistant FVB mouse strains in response to high-fat feeding. After 5 wk, impaired insulin-mediated glucose uptake in skeletal muscle developed in both strains in the absence of any impairment in proximal insulin signaling. Impaired mitochondrial oxidative capacity preceded the development of insulin resistant glucose uptake in C57B mice in concert with increased oxidative stress in skeletal muscle. By contrast, mitochondrial uncoupling in FVB mice, which prevented oxidative stress and increased energy expenditure, did not prevent insulin resistant glucose uptake in skeletal muscle. Preventing oxidative stress in C57B mice treated systemically with an antioxidant normalized skeletal muscle mitochondrial function but failed to normalize glucose tolerance and insulin sensitivity. Furthermore, high fat-fed uncoupling protein 3 knockout mice developed increased oxidative stress that did not worsen glucose tolerance. In the evolution of diet-induced obesity and insulin resistance, initial but divergent strain-dependent mitochondrial adaptations modulate oxidative stress and energy expenditure without influencing the onset of impaired insulin-mediated glucose uptake.     

Leptin signaling in adipose tissue: role in lipid accumulation and weight gain

Rationale: The link between obesity, hyperleptinemia, and development of cardiovascular disease is not completely understood. Increases in leptin have been shown to impair leptin signaling via caveolin-1-dependent mechanisms. However, the role of hyperleptinemia versus impaired leptin signaling in adipose tissue is not known. Objective: To determine the presence and significance of leptin-dependent increases in adipose tissue caveolin-1 expression in humans. Methods and Results: We designed a longitudinal study to investigate the effects of increases in leptin on adipose tissue caveolin-1 expression during weight gain in humans. Ten volunteers underwent 8 weeks of overfeeding, during which they gained an average weight of 4.1±1.4 kg, with leptin increases from 7±3.8 to 12±5.7 ng/mL. Weight gain also resulted in changes in adipose tissue caveolin-1 expression, which correlated with increases in leptin (rho=0.79, P=0.01). In cultured human white preadipocytes, leptin increased caveolin-1 expression, which in turn impaired leptin cellular signaling. Functionally, leptin decreased lipid accumulation in differentiating human white preadipocytes, which was prevented by caveolin-1 overexpression. Further, leptin decreased perilipin and fatty acid synthase expression, which play an important role in lipid storage and biogenesis. Conclusions: In healthy humans, increases in leptin, as seen with modest weight gain, may increase caveolin-1 expression in adipose tissue. Increased caveolin-1 expression in turn impairs leptin signaling and attenuates leptin-dependent lowering of intracellular lipid accumulation. Our study suggests a leptin-dependent feedback mechanism that may be essential to facilitate adipocyte lipid storage during weight gain.     

Thioredoxin interacting protein genetic variation is associated with diabetes and hypertension in the Brazilian general population

ObjectiveTo investigate the relationship between TXNIP polymorphisms, diabetes and hypertension phenotypes in the Brazilian general population.MethodsFive hundred seventy-six individuals randomly selected from the general urban population according to the MONICA-WHO project guidelines were phenotyped for cardiovascular risk factors. A second, independent, sample composed of 487 family-trios from a different site was also selected. Nine TXNIP polymorphisms were studied. The potential association between TXNIP variability and glucose-phenotypes in children was also explored. TXNIP expression was quantified by real-time PCR in 53 samples from human smooth muscle cells primary culture.ResultsTXNIP rs7211 and rs7212 polymorphisms were significantly associated with glucose and blood pressure related phenotypes. In multivariate logistic regression models the studied markers remained associated with diabetes even after adjustment for covariates. TXNIP rs7211 T/rs7212 G haplotype (present in approximately 17% of individuals) was significantly associated to diabetes in both samples. In children, the TXNIP rs7211 T/rs7212 G haplotype was associated with fasting insulin concentrations. Finally, cells harboring TXNIP rs7212 G allele presented higher TXNIP expression levels compared with carriers of TXNIP rs7212 CC genotype (p = 0.02).ConclusionCarriers of TXNIP genetic variants presented higher TXNIP expression, early signs of glucose homeostasis derangement and increased susceptibility to chronic metabolic conditions such as diabetes and hypertension. Our data suggest that genetic variation in the TXNIP gene may act as a “common ground” modulator of both traits: diabetes and hypertension.     

Effect of obstructive sleep apnea on mitral valve tenting

Obstructive apneas produce high negative intrathoracic pressure that imposes an afterload burden on the left ventricle. Such episodes might produce structural changes in the left ventricle over time. Doppler echocardiograms were obtained within 2 months of attended polysomnography. Patients were grouped according to apnea-hypopnea index (AHI): mild/no obstructive sleep apnea (OSA; AHI <15) and moderate/severe OSA (AHI ≥15). Mitral valve tenting height and area, left ventricular (LV) long and short axes, and LV end-diastolic volume were measured in addition to tissue Doppler parameters. Comparisons of measurements at baseline and follow-up between and within groups were obtained; correlations between absolute changes (Δ) in echocardiographic parameters were also performed. After a mean follow-up of 240 days mitral valve tenting height increased significantly (1.17 ± 0.12 to 1.28 ± 0.17 cm, p = 0.001) in moderate/severe OSA as did tenting area (2.30 ± 0.41 to 2.66 ± 0.60 cm(2), p = 0.0002); Δtenting height correlated with ΔLV end-diastolic volume (rho 0.43, p = 0.01) and Δtenting area (rho 0.35, p = 0.04). In patients with mild/no OSA there was no significant change in tenting height; there was a borderline significant increase in tenting area (2.20 ± 0.44 to 2.31 ± 0.43 cm(2), p = 0.05). Septal tissue Doppler early diastolic wave decreased (8.04 ± 2.49 to 7.10 ± 1.83 cm/s, p = 0.005) in subjects with moderate/severe OSA but not in in those with mild/no OSA. In conclusion, in patients with moderate/severe OSA, mitral valve tenting height and tenting area increase significantly over time. This appears to be related, at least in part, to changes in LV geometry.     

Evidence for stopping mass drug administration for lymphatic filariasis in some, but not all local government areas of plateau and nasarawa States, Nigeria

Abstract. An average of six annual rounds of ivermectin and albendazole were distributed in Plateau and Nasarawa States, Nigeria, to eliminate lymphatic filariasis. From 2007 to 2008, population-based surveys were implemented in all 30 local government areas (LGAs) of the two states to determine the prevalence of Wuchereria bancrofti antigenemia to assess which LGA mass drug administration (MDA) could be halted. In total, 36,681 persons from 7,819 households were examined for filarial antigen as determined by immunochromatographic card tests. Overall antigen prevalence was 3.05% (exact upper 95% confidence interval [CI] = 3.41%) with an upper 95% CI range by LGA of 0.50-19.3%. Among 3,233 children 6-7 years of age, overall antigen prevalence was 1.71% (exact upper 95% CI = 2.19%), too high to recommend generally halting MDA in the two-state area. However, based on criteria of < 2% antigenemia among persons > 2 years of age, stopping MDA was recommended for 10 LGAs.     

Prevalence of neuropathic pain among black African patients suffering from common low back pain

To study the prevalence and semiotic characteristics of neuropathic pain in the common low back pain to the Black African subject. This was a prospective cross-sectional survey carried on from April 1 2009 to August 31 2009 in consultations of rheumatology, neurology, and neurosurgery at the University Hospital Yalgado Ouédraogo in Ouagadougou (Burkina Faso). All patients with a low back pain or a common lomboradiculalgie were included. DN4 questionnaire was used for the diagnosis of neuropathic pain. One hundred and seven patients have been recruited during the study period; Sixty-four (59.80%) were female (sex ratio M/F: 0.67). The average age was 34.11?±?13.46?years of age with extremes of 20 and 79. The average duration of disease was 48.53?months with extremes of 10?days and 50?years. Eighty-seven patients (81.31%) had a disease duration, which was 3?months longer. Sixty-six patients (61.70%) had a predominant lomboradiculalgie; among the remaining 41, low back pain predominated. Average intensity of pain was 62.81?±?22.43 (on a scale of 100). A sign of Lasèque was present in the 41 (38.30%) patients. Fifty-three (49.5%) patients had a neuropathic pain. The prevalence of neuropathy signs according to the DN4 questionnaire was as follows: burning (n?=?37; 34.58%), painful cold (n?=?13; 12.15%), electric shocks (n?=?31; 38.97%), pins and needles (n?=?34; 31.77%), tingling (n?=?35; 32.71%), numbness (n?=?45; 42.05%), itching (n?=?18; 16.82%), touch hypoesthesia (n?=?35; 32.71%), pinprick (n?=?33; 30.84%), and tactile allodynia (n?=?21; 19.62%). Among the studied variables, the presence of a radiculalgy was statistically associated with neuropathic pain. The lomboradiculalgie of the Black African subject associates neuropathic pain observed in half of patients. Treatment must therefore always take account of this association. However, further studies are needed before any definitive conclusion.