Mechanisms of body fat distribution and gluteal-femoral fat protection against metabolic disorders.

Obesity is a major health problem that affects millions of individuals, and it is associated with metabolic diseases including insulin resistance (IR), type 2 diabetes (T2D), and cardiovascular diseases (CVDs). However, Body fat distribution (BFD) rather than crude obesity is now considered as a more accurate factor associated with these diseases. The factors affecting BFD vary, from genetic background, epigenetic factors, ethnicity, aging, hormonal changes, to lifestyle and medication consumptions. The main goal of controlling BFD comes from the fact that fat accumulation in different depots has a different effect on the overall health and metabolic health of individuals. It is well established that fat storage in the abdominal visceral depot is associated with metabolic disorder occurrence, while gluteal-femoral subcutaneous fat depot seems to be protective against these diseases. In this paper, we will summarize the factors affecting fat distribution. Then, we will present evidence connecting gluteal-femoral fat depot with protection against metabolic disorders including IR, T2D, and CVDs. Finally, we will list the suggested mechanisms that lead to this protective effect. The abstract is visualized in Graphical Abstract.

From an Apple to a Pear: Moving Fat around for Reversing Insulin Resistance.

Type 2 diabetes (T2D) is a chronic condition where the body is resistant to insulin, leading to an elevated blood glucose state. Obesity is a main factor leading to T2D. Many clinical studies, however, have described a proportion of obese individuals who express a metabolically healthy profile, whereas some lean individuals could develop metabolic disorders. To study obesity as a risk factor, body fat distribution needs to be considered rather than crude body weight. Different individuals' bodies favor storing fat in different depots; some tend to accumulate more fat in the visceral depot, while others tend to store it in the femoral depot. This tendency relies on different factors, including genetic background and lifestyle. Consuming some types of medications can cause a shift in this tendency, leading to fat redistribution. Fat distribution plays an important role in the progression of risk of insulin resistance (IR). Apple-shaped individuals with enhanced abdominal obesity have a higher risk of IR compared to BMI-matched pear-shaped individuals, who store their fat in the gluteal-femoral depots. This is related to the different adipose tissue physiology between these two depots. In this review, we will summarize the recent evidence highlighting the underlying protective mechanisms in gluteal-femoral subcutaneous adipose tissues compared to those associated with abdominal adipose tissue, and we will revise the recent evidence showing antidiabetic drugs that impact fat distribution as they manage the T2D condition.

In Vitro and In Vivo Validation of GATA-3 Suppression for Induction of Adipogenesis and Improving Insulin Sensitivity.

Impaired adipogenesis is associated with the development of insulin resistance and an increased risk of type 2 diabetes (T2D). GATA Binding Protein 3 (GATA3) is implicated in impaired adipogenesis and the onset of insulin resistance. Therefore, we hypothesize that inhibition of GATA3 could promote adipogenesis, restore healthy fat distribution, and enhance insulin signaling. Primary human preadipocytes were treated with GATA3 inhibitor (DNAzyme hgd40). Cell proliferation, adipogenic capacity, gene expression, and insulin signaling were measured following well-established protocols. BALB/c mice were treated with DNAzyme hgd40 over a period of 2 weeks. Liposomes loaded with DNAzyme hgd40, pioglitazone (positive), or vehicle (negative) controls were administered subcutaneously every 2 days at the right thigh. At the end of the study, adipose tissues were collected and weighed from the site of injection, the opposite side, and the omental depot. Antioxidant enzyme (superoxide dismutase and catalase) activities were assessed in animals' sera, and gene expression was measured using well-established protocols. In vitro GATA3 inhibition induced the adipogenesis of primary human preadipocytes and enhanced insulin signaling through the reduced expression of p70S6K. In vivo GATA3 inhibition promoted adipogenesis at the site of injection and reduced MCP-1 expression. GATA3 inhibition also reduced omental tissue size and PPARγ expression. These findings suggest that modulating GATA3 expression offers a potential therapeutic benefit by correcting impaired adipogenesis, promoting healthy fat distribution, improving insulin sensitivity, and potentially lowering the risk of T2D.

Blood Flow Disturbance and Morphological Alterations Following the Right Atrial Ligation in the Chick Embryo.

Collectively known as congenital heart defects (CHDs), cardiac abnormalities at birth are the most common forms of neonatal defects. Being principally responsible for the heart's pumping power, ventricles are particularly affected by developmental abnormalities, such as flow disturbances or genomic defects. Hypoplastic Right Heart Syndrome (HRHS) is a rare disease where the right ventricle is underdeveloped. In this study, we introduce a surgical procedure performed on chick embryo, termed right atrial ligation (RAL) for disturbing hemodynamics within the right heart aiming in order to generate an animal model of HRHS. RAL is a new surgical manipulation, similar to the well-studied left atrial ligation (LAL) surgery but it induces the hemodynamic change into the right side of the heart. After inducing RAL, We utilized techniques such as Doppler ultrasound, x-ray micro-CT, histology, and computational fluid dynamics (CFD) analysis, for a comprehensive functional and structural analysis of a developing heart. Our results displayed that RAL does not induce severe flow disturbance and ventricular abnormalities consistent with clinical findings. This study allows us to better understand the hemodynamics-driven CHD development and sensitivities of ventricles under disturbed flows.

Multifunctional Oil Absorption with Macroporous Polystyrene Fibers Incorporating Silver-Doped ZnO.

Hydrophobic microporous polystyrene (PS) fibers are fabricated by a solvent-induced phase-separation-assisted electrospinning method. Zinc oxide (ZnO) and silver-doped zinc oxide (Ag-ZnO) nanomaterials with variable morphologies are added to the PS fibers, to investigate the influence of multifunctional nanofiller addition on the porosity and consequent oil-adsorbing properties for different oil types. The doping of silver as well as the uniformity in particle distribution are confirmed by scanning electron microscopy and the energy-dispersive spectral analyses. The porosity of the fibers and their crystallinity effect depend on the hydrophobicity and surface properties of these microporous nanofilled fibers. Ag-ZnO, specifically in 2 wt %, enhanced the pore size and distribution in PS porous fibers, thereby enhancing the oil-adsorbing property and its hydrophobicity. In-depth analysis of the oil adsorption mechanism is done for the fibers, both qualitatively and quantitatively, to demonstrate its correlation with the structural integrity of the fibers. The PS/2Ag-ZnO composite also exhibits the highest antibacterial performance against Staphylococcus aureus, a general indication of antibiological fouling properties of these oil-separating films. The antifouling/antibacterial activity of the nanoparticles and high oil sorption capacity of the highly porous PS composites show great potential for use in water-treatment-related applications.

Mechanosensitive Pathways in Heart Development: Findings from Chick Embryo Studies.

The heart is the first organ that starts to function in a developing embryo. It continues to undergo dramatic morphological changes while pumping blood to the rest of the body. Genetic regulation of heart development is partly governed by hemodynamics. Chick embryo is a major animal model that has been used extensively in cardiogenesis research. To reveal mechanosensitive pathways, a variety of surgical interferences and chemical treatments can be applied to the chick embryo to manipulate the blood flow. Such manipulations alter expressions of mechanosensitive genes which may anticipate induction of morphological changes in the developing heart. This paper aims to present different approaches for generating clinically relevant disturbed hemodynamics conditions using this embryonic chick model and to summarize identified mechanosensitive genes using the model, providing insights into embryonic origins of congenital heart defects.

Effect of left atrial ligation-driven altered inflow hemodynamics on embryonic heart development: clues for prenatal progression of hypoplastic left heart syndrome.

Congenital heart defects (CHDs) are abnormalities in the heart structure present at birth. One important condition is hypoplastic left heart syndrome (HLHS) where severely underdeveloped left ventricle (LV) cannot support systemic circulation. HLHS usually initiates as localized tissue malformations with no underlying genetic cause, suggesting that disturbed hemodynamics contribute to the embryonic development of these defects. Left atrial ligation (LAL) is a surgical procedure on embryonic chick resulting in a phenotype resembling clinical HLHS. In this study, we investigated disturbed hemodynamics and deteriorated cardiac growth following LAL to investigate possible mechanobiological mechanisms for the embryonic development of HLHS. We integrated techniques such as echocardiography, micro-CT and computational fluid dynamics (CFD) for these analyses. Specifically, LAL procedure causes an immediate flow disturbance over atrioventricular (AV) cushions. At later stages after the heart septation, it causes hemodynamic disturbances in LV. As a consequence of the LAL procedure, the left-AV canal and LV volume decrease in size, and in the opposite way, the right-AV canal and right ventricle volume increase. According to our CFD analysis, LAL results in an immediate decrease in the left AV canal WSS levels for 3.5-day (HH21) pre-septated hearts. For 7-day post-septated hearts (HH30), LAL leads to further reduction in WSS levels in the left AV canal, and relatively increased WSS levels in the right AV canal. This study demonstrates the critical importance of the disturbed hemodynamics during the heart valve and ventricle development.

Nitric Oxide Releasing Hydrogel Nanoparticles Decreases Epithelial Cell Injuries Associated With Airway Reopening.

Acute respiratory distress syndrome (ARDS) is an acute inflammatory lung condition. It is characterized by disruption of gas exchange inside the alveoli, accumulation of protein edema, and an increase in lung stiffness. One major cause of ARDS is a lung infection, such as SARS-COV-2 infection. Lungs of ARDS patients need to be mechanically ventilated for airway reopening. Consequently, ventilation might damage delicate lung tissue leading to excess edema, known as ventilator-induced lung injury (VILI). Mortality of COVID-19 patients under VILI seems to be higher than non-COVID patients, necessitating effective preventative therapies. VILI occurs when small air bubbles form in the alveoli, injuring epithelial cells (EPC) due to shear stress. Nitric oxide (NO) inhalation was suggested as a therapy for ARDS, however, it was shown that it is not effective because of the extremely short half-life of NO. In this study, NO-releasing nanoparticles were produced and tested in an in vitro model, representing airways in the deep lung. Cellular injuries were quantified via fluorescent live/dead assay. Atomic force microscopy (AFM) was used to assess cell morphology. qRT-PCR was performed to assess the expression of inflammatory markers, specifically IL6 and CCL2. ELISA was performed to assess IL6 and confirm qRT-PCR results at the protein level. Finally, ROS levels were assessed in all groups. Here, we show that NO delivery via nanoparticles enhanced EPC survival and recovery, AFM measurements revealed that NO exposure affect cell morphology, while qRT-PCR demonstrated a significant downregulation in IL6 and CCL2 expression when treating the cells to NO both before and after shear exposure. ELISA results for IL6 confirmed qRT-PCR data. ROS experiment results support our findings from previous experiments. These findings demonstrate that NO-releasing nanoparticles can be used as an effective delivery approach of NO to deep lung to prevent/reduce ARDS associated inflammation and cell injuries. This information is particularly useful to treat severe ARDS due to COVID-19 infection. These nanoparticles will be useful when clinically administrated to COVID-19 patients to reduce the symptoms originating from lung distress.

Adaptation of a Mice Doppler Echocardiography Platform to Measure Cardiac Flow Velocities for Embryonic Chicken and Adult Zebrafish.

Ultrasonography is the most widely used imaging technique in cardiovascular medicine. In this technique, a piezoelectric crystal produces, sends, and receives high frequency ultrasound waves to the body to create an image of internal organs. It enables practical real time visualization in a non-invasive manner, making the modality especially useful to image dynamic cardiac structures. In the last few decades, echocardiography has been applied to in vivo cardiac disease models, mainly to rodents. While clinical echocardiography platforms can be used for relatively large animals such as pigs and rats, specialized systems are needed for smaller species. Theoretically, as the size of the imaged sample decreases, the frequency of the ultrasound transducer needed to image the sample increases. There are multiple modes of echocardiography imaging. In Doppler mode, erythrocytes blood flow velocities are measured from the frequency shift of the sent ultrasound waves compared to received echoes. Recorded data are then used to calculate cardiac function parameters such as cardiac output, as well as the hemodynamic shear stress levels in the heart and blood vessels. The multi-mode (i.e., b-mode, m-mode, Pulsed Doppler, Tissue Doppler, etc.) small animal ultrasound systems in the market can be used for most in vivo cardiac disease models including mice, embryonic chick and zebrafish. These systems are also associated with significant costs. Alternatively, there are more economical single-mode echocardiography platforms. However, these are originally built for mice studies and they need to be tested and evaluated for smaller experimental models. We recently adapted a mice Doppler echocardiography system to measure cardiac flow velocities for adult zebrafish and embryonic chicken. We successfully assessed cardiac function and hemodynamic shear stress for normal as well as for diseased embryonic chicken and zebrafish. In this paper, we will present our detailed protocols for Doppler flow measurements and further cardiac function analysis on these models using the setup. The protocols will involve detailed steps for animal stabilization, probe orientation for specific measurements, data acquisition, and data analysis. We believe this information will help cardiac researchers to establish similar echocardiography platforms in their labs in a practical and economical manner.