Multipotent Stromal Cells from Subcutaneous Adipose Tissue of Normal Weight and Obese Subjects: Modulation of Their Adipogenic Differentiation by Adenosine A1 Receptor Ligands

Adenosine A1 receptor (A1R) activation, stimulating lipogenesis and decreasing insulin resistance, could be useful for metabolic syndrome management in obese subjects. Since full A1R agonists induce harmful side-effects, while partial agonists show a better pharmacological profile, we investigated the influence of two derivatives of the full A1R agonist 2-chloro-N6-cyclopentyladenosine (CCPA), C1 and C2 behaving as A1R partial agonists in animal models, on the adipogenic differentiation of stromal/stem cells (ASCs) from human subcutaneous adipose tissue, which mainly contribute to increase fat mass in obesity. The ASCs from normal-weight subjects showed increased proliferation and A1R expression but reduced adipogenic differentiation compared to obese individual-derived ASCs. Cell exposure to CCPA, C1, C2 or DPCPX, an A1R antagonist, did not affect ASC proliferation, while mainly C2 and DPCPX significantly decreased adipogenic differentiation of both ASC types, reducing the activity of glycerol-3-phosphate dehydrogenase and the expression of PPARγ and FABP-4, all adipogenic markers, and phosphorylation of Akt in the phosphatidylinositol-3-kinase pathway, which plays a key-role in adipogenesis. While requiring confirmation in in vivo models, our results suggest that A1R partial agonists or antagonists, by limiting ASC differentiation into adipocytes and, thereby, fat mass expansion, could favor development/worsening of metabolic syndrome in obese subjects without a dietary control.

Efficacy and Safety of GLP-1 Receptor Agonists in Patients With Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis

The prevalence of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM) is increasing and there is an urgent need for new treatment strategy to prevent progression of hepatic steatosis and fibrosis. We have performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the treatment of hepatic steatosis and fibrosis in patients with T2DM and NAFLD. The PubMed, Web of Science, Scopus, Embase and Cochrane Central Register of Controlled Trials databases were searched for articles that met the eligibility criteria to explore the efficacy and safety of GLP-1RAs in patients with T2DM and NAFLD. We assessed pooled data using a random/fixed-effects model according to the I2 and p-values. Eight trials that included a total of 468 participants were eligible for inclusion in the review. For primary outcomes, administration of GLP-1RAs significantly decreased the content of intrahepatic adipose (IHA)[p=0.007, weight mean difference (WMD) -3.01, 95% confidence interval (CI) -4.75, -1.28], subcutaneous adipose tissue (SAT) (p<0.00001,WMD -28.53,95%CI -68.09,-26.31), and visceral adipose tissue (VAT) (p<0.0001,WMD -29.05,95%CI -42.90,-15.9). For secondary outcomes, GLP-1RAs produced a significant decrease in levels of alanine aminotransferase(ALT)(p=0.02, WMD -3.82, 95%CI -7.04, -0.60), aspartate aminotransferase (AST) (p=0.03, WMD -2.4, 95%CI -4.55,-0.25, I2 = 49%), body weight (p<0.00001,WMD -3.48,95%CI -4.58,-2.37), body mass index (p<0.00001,WMD -1.07,95%CI -1.35,-0.78), circumference waist (p=0.0002,WMD -3.87, 95%CI -5.88, -1.86) fasting blood glucose (p=0.02, WMD -0.35, 95%CI -0.06, -0.05), HbA1c (p<0.00001,WMD -0.39,95%CI -0.56,-0.22), HoMA-IR(p=0.005, WMD-1.51, 95%CI-0.87,-0.16), total cholesterol (p=0.0008, WMD -0.31, 95%CI -0.48, 0.13) and triglycerides (p=0.0008, WMD -0.27, 95%CI -0.43,-0.11) in comparison with the control regimens. The main adverse events associated with GLP-1RAs included mild-to-moderate gastrointestinal discomfort and nonsense hypoglycemia that resolved within a few weeks. GLP-1RAs were an effective treatment that improved intrahepatic visceral and subcutaneous adipose tissue, inflammatory markers, the anthropometric profiles and some metabolic indices in patients with T2DM and NAFLD, GLP-1RAs could be considered for use in these if there are no contraindications. Further studies are needed to understand the direct and indirect effects of GLP-1RAs on NAFLD and the potential mechanism via which they prevent its progression.Systematic Review Registration: PROSPERO, identifier CRD42021265806.

Ultra-sound Shear Wave Elastography Tissue Stiffness and Thickness Assessment After Adjuvant Radiotherapy for Breast Cancer Treatment; An Exploratory Study.

Purpose: This research investigated the feasibility of using B-mode ultrasound with shear-wave elastography (SWE) to evaluate the structural and mechanical properties of multiple tissue layers in the pectoral region of women with chronic radiation fibrosis following breast cancer treatment. Method: Nine women between one and five years post unilateral conventional fractionated radiotherapy were evaluated. Both ultrasound and SWE were used to examine the thickness and stiffness of skin, subcutaneous adipose tissue, fascia and muscle in both their irradiated and non-irradiated sides. Linear mixed models were conducted to examine statistical differences in tissue thickness and stiffness between irradiated and non-irradiated sides with the arm resting by the side and also in abduction. Results: Significant differences were found between irradiated and non-irradiated tissues. Irradiated skin was significantly thicker (p=0.020) and stiffer (p<0.001) with the arm by the side. Irradiated subcutaneous adipose tissue was significantly thinner (p<0.001). Irradiated fascia and muscles thinned significantly with the arm moved out to abduction position. Irradiated pectoral muscle was significantly stiffer (p=0.004), this stiffness amplified with arm abduction (p<0.001) where the muscle thinned significantly (P<0.001).Conclusion: Ultrasound with SWE shows potential to provide novel objective evaluation of radiation induced soft tissue fibrosis at multiple tissue layers in the pectoral region. Tissue thickness changes in irradiated tissue were evident in ultrasound images. Quantifying these tissue changes supports research development and introduction of clinical interventions to ameliorate the symptoms of morbidity that is currently considered irreversible.

Experimental characterisation of porcine subcutaneous adipose tissue under blunt impact up to irreversible deformation

A deeper understanding of the mechanical characteristics of adipose tissue under large deformation is important for the analysis of blunt force trauma, as adipose tissue alters the stresses and strains that are transferred to subjacent tissues. Hence, results from drop tower tests of subcutaneous adipose tissue are presented (i) to characterise adipose tissue behaviour up to irreversible deformation, (ii) to relate this to the microstructural configuration, (iii) to quantify this deformation and (iv) to provide an analytical basis for computational modelling of adipose tissue under blunt impact. The drop tower experiments are performed exemplarily on porcine subcutaneous adipose tissue specimens for three different impact velocities and two impactor geometries. An approach based on photogrammetry is used to derive 3D representations of the deformation patterns directly after the impact. Median values for maximum impactor acceleration for tests with a flat cylindrical impactor geometry at impact velocities of 886 mm/s, 1253 mm/s and 2426 mm/s amount to 61.1 g, 121.6 g and 264.2 g, respectively, whereas thickness reduction of the specimens after impact amount to 16.7%, 30.5% and 39.3%, respectively. The according values for tests with a spherically shaped impactor at an impact velocity of 1253 mm/s are 184.2 g and 78.7%. Based on these results, it is hypothesised that, in the initial phase of a blunt impact, adipose tissue behaviour is mainly governed by the behaviour of the lipid inside the adipocytes, whereas for further loading, contribution of the extracellular collagen fibre network becomes more dominant.