The Multi-Level Action of Fatty Acids on Adiponectin Production by Fat Cells

Current epidemics of diabetes mellitus is largely caused by wide spread obesity. The best-established connection between obesity and insulin resistance is the elevated and/or dysregulated levels of circulating free fatty acids that cause and aggravate insulin resistance, type 2 diabetes, cardiovascular disease and other hazardous metabolic conditions. Here, we investigated the effect of a major dietary saturated fatty acid, palmitate, on the insulin-sensitizing adipokine adiponectin produced by cultured adipocytes. We have found that palmitate rapidly inhibits transcription of the adiponectin gene and the release of adiponectin from adipocytes. Adiponectin gene expression is controlled primarily by PPARγ and C/EBPα. Using mouse embryonic fibroblasts from C/EBPα-null mice, we have determined that the latter transcription factor may not solely mediate the inhibitory effect of palmitate on adiponectin transcription leaving PPARγ as a likely target of palmitate. In agreement with this model, palmitate increases phosphorylation of PPARγ on Ser273, and substitution of PPARγ for the unphosphorylated mutant Ser273Ala blocks the effect of palmitate on adiponectin transcription. The inhibitory effect of palmitate on adiponectin gene expression requires its intracellular metabolism via the acyl-CoA synthetase 1-mediated pathway. In addition, we found that palmitate stimulates degradation of intracellular adiponectin by lysosomes, and the lysosomal inhibitor, chloroquine, suppressed the effect of palmitate on adiponectin release from adipocytes. We present evidence suggesting that the intracellular sorting receptor, sortilin, plays an important role in targeting of adiponectin to lysosomes. Thus, palmitate not only decreases adiponectin expression at the level of transcription but may also stimulate lysosomal degradation of newly synthesized adiponectin

Susceptibility of Pancreatic Beta Cells to Fatty Acids Is Regulated by LXR/PPARα-Dependent Stearoyl-Coenzyme A Desaturase

Chronically elevated levels of fatty acids-FA can cause beta cell death in vitro. Beta cells vary in their individual susceptibility to FA-toxicity. Rat beta cells were previously shown to better resist FA-toxicity in conditions that increased triglyceride formation or mitochondrial and peroxisomal FA-oxidation, possibly reducing cytoplasmic levels of toxic FA-moieties. We now show that stearoyl-CoA desaturase-SCD is involved in this cytoprotective mechanism through its ability to transfer saturated FA into monounsaturated FA that are incorporated in lipids. In purified beta cells, SCD expression was induced by LXR- and PPARα-agonists, which were found to protect rat, mouse and human beta cells against palmitate toxicity. When their SCD was inhibited or silenced, the agonist-induced protection was also suppressed. A correlation between beta cell-SCD expression and susceptibility to palmitate was also found in beta cell preparations isolated from different rodent models. In mice with LXR-deletion (LXRβ-/- and LXRαβ-/-), beta cells presented a reduced SCD-expression as well as an increased susceptibility to palmitate-toxicity, which could not be counteracted by LXR or PPARα agonists. In Zucker fatty rats and in rats treated with the LXR-agonist TO1317, beta cells show an increased SCD-expression and lower palmitate-toxicity. In the normal rat beta cell population, the subpopulation with lower metabolic responsiveness to glucose exhibits a lower SCD1 expression and a higher susceptibility to palmitate toxicity. These data demonstrate that the beta cell susceptibility to saturated fatty acids can be reduced by stearoyl-coA desaturase, which upon stimulation by LXR and PPARα agonists favors their desaturation and subsequent incorporation in neutral lipids

Экспериментальная оценка устройства механической поддержки сердца на основе дискового насоса вязкого трения

Aim. Experimental evaluation of the viscous friction disk pump efficiency, studying the relationship between inter-disk clearance and sizes of input and output ports and pump performance parameters.Materials and methods. To assess the characteristics and to optimize the disk friction pump design the pump model and experimental stand were created. Pump dimensions were set on the basis of medical and biological requirements for mechanical heart support systems and with due consideration of the experimental studies of our colleagues from Pennsylvania. Flow volume of the working fluid was measured by float rotameter Krohne VA-40 with measurement error of not more than 1%. The pressure values in the hydrodynamic circuit were measured using a monitor manufactured by Biosoft-M. Expansion device allowed changing the flow resistance of the system simulating the total peripheral resistance of the circulatory system.Results. Linear direct correlation between the pump performance and the pressure drop of liquid being created at the inlet and outlet of the pump was obtained. The required flow rate (5–7 l/min) and pressure (90–100 mmHg) were reached when the rotor speed was in the range of 2500–3000 rev/min. It has been shown that the increase of the inlet diameter to 15 mm has not resulted in a significant increase in the pump performance, and that the highest efficiency values can be obtained for the magnitude of inter-disk gap of 0.4–0.5 mm.Conclusion. Designed and manufactured experimental disc pump model for pumping fluid has showed the fundamental possibility to use this model as a system for mechanical support of the heart.Цель: экспериментальная оценка производительности дискового насоса вязкого трения, изучение взаимосвязи междискового зазора и размеров входных и выходных отверстий и параметров производительности насоса.Материалы и методы. Для изучения характеристик и оптимизации конструкции дискового насоса трения, предназначенного для перекачивания крови, был изготовлен макет насоса и стенд для его испытания. Габариты насоса задавались, исходя из медико-биологических требований для систем механической поддержки сердца и с учетом экспериментальных исследований наших коллег из Пенсильвании. Объемный расход рабочей жидкости измерялся поплавковым ротаметром Krohne VA-40 c погрешностью измерений не более 1%. Значения давления в гидродинамическом контуре измерялись при помощи монитора производства фирмы «Биософт-М». Дросселирующее устройство позволяло менять гидравлическое сопротивление системы, имитируя общее периферическое сопротивление сердечно-сосудистой системы человека.Результаты. В ходе эксперимента получена линейная прямая зависимость между производительностью насоса и создаваемым им перепадом давления жидкости на входе и выходе на насосе. Требуемые значения расхода (5–7 л/мин) и давления (90–100 мм рт. ст.) достигаются при частоте вращения ротора в диапазоне 2500–3000 об/мин. Показано, что увеличение входного диаметра до 15 мм не привело к значимому увеличению производительности насоса, а наибольшие значения производительности можно получить для величины междискового зазора 0,4–0,5 мм.Заключение. Спроектированный и изготовленный экспериментальный макет дискового насоса для перекачивания жидкости показал принципиальную возможность использовать такую модель в качестве системы для механической поддержки сердца

ER stress in rodent islets of langerhans is concomitant with obesity and β-cell compensation but not with β-cell dysfunction and diabetes

Objective: The objective of this study was to determine whether ER stress correlates with β-cell dysfunction in obesity-associated diabetes. Methods: Quantitative RT-PCR and western blot analysis were used to investigate changes in the expression of markers of ER stress, the unfolded protein response (UPR) and β-cell function in islets isolated from (1) non-diabetic Zucker obese (ZO) and obese female Zucker diabetic fatty (fZDF) rats compared with their lean littermates and from (2) high-fat-diet-fed fZDF rats (HF-fZDF), to induce diabetes, compared with age-matched non-diabetic obese fZDF rats. Results: Markers of an adaptive ER stress/UPR and β-cell function are elevated in islets isolated from ZO and fZDF rats compared with their lean littermates. In islets isolated from HF-fZDF rats, there was no significant change in the expression of markers of ER stress compared with age matched, obese, non-diabetic fZDF rats. Conclusions: These results provide evidence that obesity-induced activation of the UPR is an adaptive response for increasing the ER folding capacity to meet the increased demand for insulin. As ER stress is not exacerbated in high-fat-diet-induced diabetes, we suggest that failure of the islet to mount an effective adaptive UPR in response to an additional increase in insulin demand, rather than chronic ER stress, may ultimately lead to β-cell failure and hence diabetes

Comparison of meconium and neonatal hair analysis for detection of gestational exposure to drugs of abuse

Background: Meconium and hair are two biological markers of in utero exposure to illicit drugs. Objective: To compare the sensitivity of the two tests for different drugs. Setting: Motherisk laboratory which tests in utero drug exposure in Toronto. Methods: Cocaine, benzoylecgonine, opiates, cannabis, benzodiazepines, methadone, and barbiturates were measured in pairs of hair and meconium samples from the same neonates. Results: Meconium was marginally more sensitive than neonatal hair for detection of cocaine and cannabis, possibly because it may detect second trimester exposure whereas hair grows only during the third trimester of pregnancy. There was a significant correlation between hair and meconium concentrations of cocaine, cannabis, and opiates. Conclusion: In cases of clinical suspicion and a negative neonatal urine test, both meconium and hair are effective biological markers of in utero illicit drug exposure. Meconium may be more sensitive, but neonatal hair is available for three months whereas meconium is available for only one or two days. In contrast, the use of meconium, being a discarded material, is more acceptable to some parents than hair testing, which entails cutting scalp hair from the newborn

The results of transcatheter mitral valve replacement

Mitral insufficiency is one of the most common valvular pathology. In almost half of the patients, standard mitral valve replacement using extracorporeal circulation cannot be used due to the high risk of complications. In recent years, for this category of patients a method for transcatheter mitral valve replacement has been proposed. Now it is known about a few transcatheter prostheses for implantation into the native mitral valve that are at the stage of preclinical or clinical trials. This article analyzes the results of the clinical use of prostheses for transcatheter mitral valve replacement