LKB1 Regulates Goat Intramuscular Adipogenesis Through Focal Adhesion Pathway

Intramuscular fat (IMF) deposition is one of the most important factors to affect meat quality in livestock and induce insulin resistance and adverse metabolic phenotypes for humans. However, the key regulators involved in this process remain largely unknown. Although liver kinase B1 (LKB1) was reported to participate in the development of skeletal muscles and classical adipose tissues. Due to the specific autonomic location of intramuscular adipocytes, deposited between or within muscle bundles, the exact roles of LKB1 in IMF deposition need further verified. Here, we cloned the goat LKB1 coding sequence with 1,317 bp, encoding a 438 amino acid peptide. LKB1 was extensively expressed in detected tissues and displayed a trend from decline to rise during intramuscular adipogenesis. Functionally, knockdown of LKB1 by two individual siRNAs enhanced the intramuscular preadipocytes differentiation, accompanied by promoting lipid accumulation and inducing adipogenic transcriptional factors and triglyceride synthesis-related genes expression. Conversely, overexpression of LKB1 restrained these biological signatures. To further explore the mechanisms, the RNA-seq technique was performed to compare the difference between siLKB1 and the control group. There were 1,043 differential expression genes (DEGs) were screened, i.e., 425 upregulated genes and 618 downregulated genes in the siLKB1 group. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis predicted that the DEGs were mainly enriched in the focal adhesion pathway and its classical downstream signal, the PI3K-Akt signaling pathway. Specifically, knockdown of LKB1 increased the mRNA level of focal adhesion kinase (FAK) and vice versa in LKB1-overexpressed cells, a key component of the activated focal adhesion pathway. Convincingly, blocking this pathway by a specific FAK inhibitor (PF573228) rescued the observed phenotypes in LKB1 knockdown adipocytes. In conclusion, LKB1 inhibited goat intramuscular adipogenesis through the focal adhesion pathway. This work expanded the genetic regulator networks of IMF deposition and provided theoretical support for improving human health and meat quality from the aspect of IMF deposition.

Impact of subclinical inflammatory markers on the development of cardiovascular pathology in patients with the metabolic syndrome

Metabolic syndrome currently remains one of the most pressing problems in medicine, since it makes its decisive contribution to the development of cardiovascular diseases and cerebral complications. Another important problem of modern medicine is arterial hypertension, which is one of the constituent criteria of metabolic syndrome, whose mechanism of development is due to a disruption in the work of the renin-angiotensin-aldosterone system, the sympathoadrenal system, an increased content of pro-inflammatory cytokines, as well as an imbalance in the adipokine system. Adipose tissue now acts not just as a structure that provides our body with energy only, but now it acts as an organ of the endocrine system, producing a large number of metabolically active substances. Patients with metabolic syndrome have been found to have elevated levels of proinflammatory cytokines were increased: monocytic chemotactic protein-1 (MCP-1), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). These cytokines are thought to be synthesised by adipose tissue macrophages and are involved in the pathogenesis of the metabolic syndrome. Oxidative stress can induce insulin resistance in adipocytes. The pathogenesis of oxidative stress in adipocytes in MS is still a mystery. This knowledge would be very useful in developing new approaches to MS therapy. Given the significant effect of chemokines in MS on the development of systemic inflammation, insulin resistance, and arterial hypertension, scientists have an important task not only to describe the actions of individual chemokines in hypertension, but also to characterize how the effect on one chemokine modulates the expression and/or function of other chemokines and their related receptors.

Raloxifene Ameliorates Glucosamine-Induced Insulin Resistance in Ovariectomized Rats

Osteoarthritis (OA) and osteoporosis (OP) are common among older women, especially postmenopausal women. Glucosamine (GlcN) is a common medication for OA, but it may induce insulin resistance and β-cell dysfunction, especially if ovarian hormones are lacking. Raloxifene (RLX) is a selective estrogen receptor modulator and also an OP drug. Previously, we found that estrogen could improve GlcN-induced insulin resistance in ovariectomized (OVX) rats. Here, we further hypothesized that RLX, similarly to estrogen, can ameliorate GlcN-induced insulin resistance in OVX rats. We used GlcN to induce insulin resistance in OVX rats as a model for evaluating the protective effects of RLX in vivo. We used a pancreatic β-cell line, MIN-6, to study the mechanisms underlying the effect of RLX in GlcN-induced β-cell dysfunction in vitro. Increases in fasting plasma glucose, insulin, and homeostasis model assessments of insulin resistance in OVX Sprague Dawley rats treated with GlcN were reversed by RLX treatment (n = 8 in each group). Skeletal muscle GLUT-4 increased, liver PEPCK decreased, pancreatic islet hypertrophy, and β-cell apoptosis in OVX rats treated with GlcN was ameliorated by RLX. The negative effects of GlcN on insulin secretion and cell viability in MIN-6 cells were related to the upregulation of reticulum (ER) stress-associated proteins (C/EBP homologous protein, phospho-extracellular signal-regulated kinase, phospho-c-JunN-terminal kinase), the expression of which was reduced by RLX. Pretreatment with estrogen receptor antagonists reversed the protective effects of RLX. GlcN can induce insulin resistance, β-cell dysfunction, and apoptosis in OVX rats and increase ER stress-related proteins in β-cells, whereas RLX can reverse these adverse effects. The effects of RLX act mainly through estrogen receptor α; therefore, RLX may be a candidate drug for postmenopausal women with OA and OP.

Potential Physical Health Changes during the Covid-19 Confinement in Pakistan

Background: The Coronavirus outbreak was declared a pandemic by the WHO in March 2020 and entire population was asked to self-isolate and live in home-confinement for several weeks to months. This has had collateral effects on many parameters of the isolatedindividuals health. A short term sedentary lifestyle is sufficient to induce insulin resistance and fat deposition which in turn increases the risk of multiple metabolic disorders. Aim: To investigate the potential physical health changes that occurred during the CoVID-19 quarantine/isolation period in Pakistan. Methods:A descriptive cross-sectional study was conducted during social isolation, from 27th May to 1st July, 2020. The study was initiated after approval from the institutional ethical review committee of Health Research Solutions. Stratified sampling technique was used to collect the data from the census organisation committee in Pakistan. Results: The sample of respondents in the data analysis included : N=553 (63.5% women 36.5% men). The findings explore the health impacts of several weeks of a reduction in physical activity and daily step-count combined with altered eating habits and sleep hygiene. Conclusion: The findings of the current study may contribute to a better understanding of the novel coronavirus effects on lifestyle especially physical activities and sedentary behaviour. It concludes that certain health aspects that have been explored in this research can be improved through methods developed to increase participation in activities during current and future pandemics. Keywords: CoVID-19 Coronavirus, WHO

Uremic Toxins and Their Relation with Oxidative Stress Induced in Patients with CKD

The presence of toxins is believed to be a major factor in the development of uremia in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD). Uremic toxins have been divided into 3 groups: small substances dissolved in water, medium molecules: peptides and low molecular weight proteins, and protein-bound toxins. One of the earliest known toxins is urea, the concentration of which was considered negligible in CKD patients. However, subsequent studies have shown that it can lead to increased production of reactive oxygen species (ROS), and induce insulin resistance in vitro and in vivo, as well as cause carbamylation of proteins, peptides, and amino acids. Other uremic toxins and their participation in the damage caused by oxidative stress to biological material are also presented. Macromolecules and molecules modified as a result of carbamylation, oxidative stress, and their adducts with uremic toxins, may lead to cardiovascular diseases, and increased risk of mortality in patients with CKD.

Strategy for the Micro-Elimination of Hepatitis C among Patients with Diabetes Mellitus—A Hospital-Based Experience

Hepatitis C virus (HCV) infection can induce insulin resistance, and patients with diabetes mellitus (DM) have a higher prevalence of HCV infection. Patient outcomes improve after HCV eradication in DM patients. However, HCV micro-elimination targeting this population has not been approached. Little is known about using electronic alert systems for HCV screening among patients with DM in a hospital-based setting. We implemented an electronic reminder system for HCV antibody screening and RNA testing in outpatient departments among patients with DM. The screening rates and treatment rates at different departments before and after system implementation were compared. The results indicated that the total HCV screening rate increased from 49.3% (9505/19,272) to 78.2% (15,073/19,272), and the HCV-RNA testing rate increased from 73.4% to 94.2%. The anti-HCV antibody seropositive rate was 5.7%, and the HCV viremia rate was 62.7% in our patient population. The rate of positive anti-HCV antibodies and HCV viremia increased with patient age. This study demonstrates the feasibility and usefulness of an electronic alert system for HCV screening and treatment among DM patients in a hospital-based setting.

Loss of STAT5 in adipocytes increases subcutaneous fat mass via sex-dependent and depot-specific pathways

SUMMARYThe STAT (Signal Transducers and Activators of Transcription) family of transcription factors contributes to adipocyte development and function. STAT5A and STAT5B are induced during adipocyte differentiation and are primarily activated by growth hormone (GH). Studies in mice lacking adipocyte GH receptor or STAT5 support their roles in lipolysis-mediated reduction of adipose tissue mass. We have generated a mouse model lacking both STAT5 genes specifically in adipocytes (STAT5AKO). Notably, both sexes of STAT5AKO mice have increased inguinal adipose tissue without any changes in gonadal fat mass. However, both depots exhibit substantial differences in fat cell size. Study of STAT5AKO mice also have revealed that GH’s ability to induce insulin resistance is dependent upon STAT5 in adipocytes, but its ability to reduce adipose tissue mass is STAT5 independent. Additional observations, which were not predicted, indicate that the causes and regulation of increased fat mass in STAT5AKO mice are sex- and depot-dependent.

Naringenin ameliorates palmitic acid-induced fatty acid stress in 5 hepatocytes

: Type 2 diabetes is strongly associated with the development of insulin resistance in metabolically active tissues. Non-alcoholic fatty liver disease (NAFLD) is considered to be a manifestation of hepatic insulin resistance. Saturated fatty acids such as palmitic acid (PA) induce insulin resistance, which may be studied for therapeutic prevention by herbal agents. In the present study, the role of naringenin, a bioflavonoid, is examined in PA-induced cytotoxicity in human hepatocellular carcinoma (HepG2) cells. PA causes significant inflammation and apoptosis in these cells primarily by inhibiting phosphorylation of Akt at serine 473 residue. Apoptosis assay, mitochondrial transmembrane potential measurement and immunoblotting for protein expressions have been used for demonstrating PA-induced abnormalities. Naringenin treatment effectively inhibits the fatty acid-induced inflammation and cytotoxicity, along with improvement of insulin signaling. Naringenin has a potential to prevent the fatty acid-induced stresses in hepatocytes, and may be beneficial for improving hepatic insulin sensitivity and mitigating lipotoxicity.

Putative Role of Protein Palmitoylation in Cardiac Lipid-Induced Insulin Resistance

In the heart, inhibition of the insulin cascade following lipid overload is strongly associated with contractile dysfunction. The translocation of fatty acid transporter CD36 (SR-B2) from intracellular stores to the cell surface is a hallmark event in the lipid-overloaded heart, feeding forward to intracellular lipid accumulation. Yet, the molecular mechanisms by which intracellularly arrived lipids induce insulin resistance is ill-understood. Bioactive lipid metabolites (diacyl-glycerols, ceramides) are contributing factors but fail to correlate with the degree of cardiac insulin resistance in diabetic humans. This leaves room for other lipid-induced mechanisms involved in lipid-induced insulin resistance, including protein palmitoylation. Protein palmitoylation encompasses the reversible covalent attachment of palmitate moieties to cysteine residues and is governed by protein acyl-transferases and thioesterases. The function of palmitoylation is to provide proteins with proper spatiotemporal localization, thereby securing the correct unwinding of signaling pathways. In this review, we provide examples of palmitoylations of individual signaling proteins to discuss the emerging role of protein palmitoylation as a modulator of the insulin signaling cascade. Second, we speculate how protein hyper-palmitoylations (including that of CD36), as they occur during lipid oversupply, may lead to insulin resistance. Finally, we conclude that the protein palmitoylation machinery may offer novel targets to fight lipid-induced cardiomyopathy.