Obesity-related Insulin Resistance Research Articles

High tissue-sodium associates with systemic inflammation and insulin resistance in obese individuals

Background and aimsHigh sodium intake is associated with obesity and insulin resistance, and high extracellular sodium content may induce systemic inflammation, leading to cardiovascular disease. In this study, we aim to investigate whether high tissue sodium accumulation relates with obesity-related insulin resistance and whether the pro-inflammatory effects of excess tissue sodium accumulation may contribute to such association. Methods and resultsIn a cross-sectional study of 30 obese and 53 non-obese subjects, we measured insulin sensitivity determined as glucose disposal rate (GDR) using hyperinsulinemic euglycemic clamp, and tissue sodium content using 23Na magnetic resonance imaging. Median age was 48 years, 68% were female and 41% were African American. Median (interquartile range) BMI was 33 (31.5, 36.3) and 25 (23.5, 27.2) kg/m2 in the obese and non-obese individuals, respectively. In obese individuals, insulin sensitivity negatively correlated with muscle (r = −0.45, p = 0.01) and skin sodium (r = −0.46, p = 0.01). In interaction analysis among obese individuals, tissue sodium had a greater effect on insulin sensitivity at higher levels of high-sensitivity C-reactive protein (p-interaction = 0.03 and 0.01 for muscle and skin Na+, respectively) and interleukin-6 (p-interaction = 0.024 and 0.003 for muscle and skin Na+, respectively). In interaction analysis of the entire cohort, the association between muscle sodium and insulin sensitivity was stronger with increasing levels of serum leptin (p-interaction = 0.01). ConclusionsHigher muscle and skin sodium are associated with insulin resistance in obese patients. Whether high tissue sodium accumulation has a mechanistic role in the development of obesity-related insulin resistance through systemic inflammation and leptin dysregulation remains to be examined in future studies.Clinicaltrials.gov registration: NCT02236520.

Brain targeted peptide-functionalized chitosan nanoparticles for resveratrol delivery: Impact on insulin resistance and gut microbiota in obesity-related Alzheimer's disease

The pathology of Alzheimer's disease (AD) is highly correlated with obesity-induced insulin resistance. Resveratrol (Res) is a natural phenol that demonstrates a neuroprotective effect, but the bioactivity of Res is low in vivo. Here, chitosan (CS) was cross-linked with sodium tripolyphosphate (TPP) to encapsulate low water solubility Res. Next, a brain-targeted peptide (TG: TGNYKALHPHNG) was modified on the surface of Res-loaded CS/TPP nanoparticles (TG-Res-CS/TPP-NPs) to specifically deliver Res to the brain. Morris water maze results indicated that cognitive impairments were ameliorated by TG-Res-CS/TPP-NPs in obesity-related AD mice. Obesity-related insulin resistance promotes Tau phosphorylation and Aβ aggregation in the brain. Administration of TG-Res-CS/TPP-NPs alleviated lipid deposition-induced insulin resistance and decreased the level of phosphorylated Tau and Aβ aggregation via the JNK/AKT/GSK3β pathway. Additionally, TG-Res-CS/TPP-NPs transported across blood-brain barrier which in turn increased glucose transporter expression levels, antioxidant enzyme activity and inhibited microglial cell activation. Thus, TG-Res-CS/TPP-NPs were more effective than Res-CS/TPP-NPs at regulating glucose homeostasis, oxidative stress and neuroinflammation in the brain. Moreover, inflammatory, lipid metabolism and oxidative stress-related gut microbiota including Helicobacter, Colidextribacter, Anaerotruncus, Parasutterella, Allobaculum, Alloprevotella, Alistipes, Bifidobacterium and Candidatus_Saccharimonas were also regulated by TG-Res-CS/TPP-NPs. This work indicates the potential use of TG-Res-CS/TPP-NPs for the delivery of Res.

The HIF1α polymorphism rs2301104 is associated with obesity and obesity-related cytokines in Han Chinese population.

To evaluate the association between genetic polymorphisms of HIF1α and obesity and obesity-related cytokines in the Han Chinese population. The study consisted of 160 subjects with obesity and 166 age- and gender-matched healthy controls. We genotyped three tag single nucleotide polymorphisms (SNPs) of HIF1α by using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS)-based genotyping technology. Plasma cytokine concentrations were determined on the Luminex platform. The genetic associations were analysed statistically. Obese subjects had significant obesity-related metabolic abnormalities, including hyperglycaemia, insulin resistance, and abnormalities in blood lipids, liver enzymes, and uric acid levels. SNP analysis of HIF1α revealed that the allele and genotype frequencies of rs2301104 were significantly associated with obesity. Our results suggest that the minor allele C of rs2301104 might be a protective mutation of obesity, and CC/CG genotypes of rs2301104 could be protective genotype of obesity. We also found that subjects with CC/CG genotypes of rs2301104 had significantly lower levels of IL-6, TNF-α, IL-1β, IL-8, and IL-10 than subjects with GG genotypes. This is the first study to report an association between HIF1α polymorphisms and obesity and obesity-related cytokines in a Han Chinese population. These results require replication in larger populations but suggest that HIF1α may play an important role in obesity development.

Abstract 10045: Higher Renal Vascular Resistance is Associated With Greater Body Mass Index in Children

Background: Obesity is associated with increased risk for cardiovascular and renal diseases, however, there has been little focus on renal vascular function. The purpose of this study is to assess renal vascular flow regulation and investigate their relation to cardiovascular risk factors in obese children. Methods: Noninvasive ultrasonographic measurements were made in 108 overweight/obese children aged 7 to 13 years (body mass index 18 to 33kg/m 2 ). Using color Doppler sonography, peak systolic (PSV), end-diastolic (EDV), and average peak flow (APV) velocities of renal artery were measured. Pulsatility index as a parameter of vascular resistance was calculated. Pulsatility index was defined as (PSV-EDV)/APV. Quantitative B-mode ultrasound scans were used to measure intima-media thickness and diameters of the common carotid artery. Plasma lipid concentrations, uric acid, homeostasis model assessment of insulin resistance, and high sensitivity C-reactive protein were assessed in the obese children. Results: Compared with overweight children with body mass index <25 kg/m 2 , pulsatility index in obese children with body mass index≥25 kg/m 2 was significantly higher (1.24 ±0.13 vs. 1.13 ±0.14 cm/sec, p < 0.01), because APV and EDV were significantly lower (35 ±3 vs. 38 ±7 cm/sec and 21± 3 vs. 25 ±5 cm/sec, p <0.05, respectively), although PSV was not significantly different. Pulsatility index correlated significantly with body mass index (r =0.58, p < 0.01), insulin (r = 0.24, p < 0.05), homeostasis model assessment of insulin resistance (r =0.25, p < 0.01), triglycerides (r = 0.26, p < 0.01), uric acid (r = 0.22, p < 0.05), systolic blood pressure (r = 0.31, p < 0.01), and carotid intima-media thickness (r = 0.36, p<0.01). Renal blood flow velocities did not correlate with high sensitivity C-reactive protein. Conclusions: The present study indicates that obesity can adversely affect renal vascular flow and resistance in children. Obesity-related insulin resistance may be a main risk factor for renal vascular flow changes. Obesity not only is a risk factor for later cardiovascular disease, but also is associated with significant impairment of renal arterial flow dynamics.

The Relationship between Serum Levels of Irisin with Cardiometabolic Biomarkers in Patients with Type 2 Diabetes

Background: Diabetes and obesity are associated with an increased risk of cardiovascular disease. Irisin is a newly recognized peptidic myokine with anti-obesity and anti-diabetic properties. This study aims to investigate the relationship between serum irisin levels with cardiometabolic biomarkers in patients with type 2 diabetes mellitus (T2DM).
 Methods: In this comparative cross- sectional study, 80 T2DM patients and 80 control participants (adjusted by age, body mass index (BMI), and physical activity) referring to Bou Ali Hospital in Zahedan, Iran, were enrolled. Serum irisin concentrations, anthropometric, and biochemical parameters were assessed.
 Results: Serum irisin level was significantly lower in T2DM patients compared to control group. Multiple linear regression analysis revealed that after adjustment for age, irisin was negatively associated with waist circumference (WC, P < 0.01) and waist to height ratio (WHtR, P < 0.01), homeostasis model assessment insulin resistance (HOMA-IR, P = 0.009), triglycerides (TG, P = 0.016), and positively associated with high density lipoprotein cholesterol (HDL-c, P = 0.03) in diabetic patients.
 Conclusion: The findings suggest that irisin can be used as a marker for predicting of obesity-related cardiometabolic biomarkers, insulin resistance, and incidentT2DM.

Vaccarin improves insulin sensitivity and glucose uptake in diet-induced obese mice via activation of GPR120-PI3K/AKT/GLUT4 pathway

Insulin resistance is a risk factor for type 2 diabetes and is often associated with obesity. Vaccarin, a flavonoid found in vaccaria seeds, is commonly used in traditional Chinese medicine for activating blood circulation. Here, we showed that vaccarin ameliorates high-fat diet-induced obesity and insulin resistance in mice by reducing fat accumulation and improving insulin sensitivity in white adipose tissue. Further hyperinsulinemic-euglycemic clamp test revealed enhanced glucose uptake in vaccarin-treated WAT and skeletal muscle, consistent with activated insulin signaling pathway in these tissues. Mechanistically, vaccarin activates adipose tissue GPR120 and subsequently activating the PI3K/AKT/GLUT4 signaling pathway in 3T3-L1 cells. Together, these results reveal an undiscovered function of vaccarin in preventing obesity-related insulin resistance and advocates that vaccarin holds promise for further development as an innovative agent for the prevention of metabolic disorders.

Extracellular vesicles mediate the communication of adipose tissue with brain and promote cognitive impairment associated with insulin resistance

Type 2 diabetes with obesity-related insulin resistance as the main manifestation is associated with an increased risk of cognitive impairment. Adipose tissue plays an important role in this process. Here, we demonstrated that adipose tissue-derived extracellular vesicles (EVs) and their cargo microRNAs (miRNAs) mediate inter-organ communication between adipose tissue and the brain, which can be transferred into the brain in a membrane protein-dependent manner and enriched in neurons, especially in the hippocampus. Further investigation suggests that adipose tissue-derived EVs from high-fat diet (HFD)-fed mice or patients with diabetes induce remarkable synaptic loss and cognitive impairment. Depletion of miRNA cargo in these EVs significantly alleviates their detrimental effects on cognitive function. Collectively, these data suggest that targeting adipose tissue-derived EVs or their cargo miRNAs may provide a promising strategy for pharmaceutical interventions for cognitive impairment in diabetes.

Metabolic status is not related to dietary acid load in polycystic ovary syndrome

Aim:Women with polycystic ovary syndrome (PCOS) are at high risk for obesity-related disorders, insulin resistance (IR), and metabolic syndrome (MS). Adopting potent approaches to diet enhances cardiometabolic risk profile and reproductive function. Different types of diets have provided conflicting results so far. We aimed to investigate whether dietary acid load (DAL) contributed to the metabolic process in PCOS.
 Material and Method: This study included 46 newly diagnosed PCOS patients and 46 healthy individuals with matched age, sex, and BMI. Clinical, anthropometric, and biochemical measurements were obtained. We extracted net endogenous acid production (NEAP) and potential renal acid load (PRAL) scores from 24-hour dietary data recorded on a nutrient database program for three days (BeBiS software program).
 Results:We concluded no statistically significant difference between the groups by NEAP (p=0.569) and PRAL (p=0.969).Patients with PCOS had higher fasting insulin levels and HOMA-IR (p

Investigating the Expression and Function of the Glucose Transporter GLUT6 in Obesity.

Obesity-related insulin resistance is a highly prevalent and growing health concern, which places stress on the pancreatic islets of Langerhans by increasing insulin secretion to lower blood glucose levels. The glucose transporters GLUT1 and GLUT3 play a key role in glucose-stimulated insulin secretion in human islets, while GLUT2 is the key isoform in rodent islets. However, it is unclear whether other glucose transporters also contribute to insulin secretion by pancreatic islets. Herein, we show that SLC2A6 (GLUT6) is markedly upregulated in pancreatic islets from genetically obese leptin-mutant (ob/ob) and leptin receptor-mutant (db/db) mice, compared to lean controls. Furthermore, we observe that islet SLC2A6 expression positively correlates with body mass index in human patients with type 2 diabetes. To investigate whether GLUT6 plays a functional role in islets, we crossed GLUT6 knockout mice with C57BL/6 ob/ob mice. Pancreatic islets isolated from ob/ob mice lacking GLUT6 secreted more insulin in response to high-dose glucose, compared to ob/ob mice that were wild type for GLUT6. The loss of GLUT6 in ob/ob mice had no adverse impact on body mass, body composition, or glucose tolerance at a whole-body level. This study demonstrates that GLUT6 plays a role in pancreatic islet insulin secretion in vitro but is not a dominant glucose transporter that alters whole-body metabolic physiology in ob/ob mice.

A bioactive component of Portulaca Oleracea L., HM-chromanone, improves palmitate-induced insulin resistance by inhibiting mTOR/S6K1 through activation of the AMPK pathway in L6 skeletal muscle cells.

Increased free fatty acid levels in the blood are common in obesity and cause insulin resistance associated with type 2 diabetes in the muscles. Previous studies have confirmed the antidiabetic and anti-obesity potential of (E)-5-hydroxy-7-methoxy-3-(2-hydroxybenzyl)-4-chromanone (HM-chromanone). However, it is unknown how HM-chromanone alleviates obesity-related insulin resistance in L6 skeletal muscle cells. Palmitate induced insulin resistance and reduced glucose uptake, whereas HM-chromanone significantly increased glucose uptake. In palmitate-treated L6 skeletal muscle cells, HM-chromanone stimulated liver kinase B1 (LKB1) and 5'-adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. The AMPK inhibitor compound C, and the LKB1 inhibitor radicicol blocked the effects of HM-chromanone. Furthermore, HM-chromanone significantly inhibited mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase 1 (S6K1) activation, but there was no change in protein kinase C θ (PKC θ) expression. When pAMPK was inhibited with compound C, the effect of HM-chromanone on the inhibition of mTOR and S6K1 was significantly diminished. This indicates that HM-chromanone inhibits mTOR and S6K1 activation through pAMPK activation. Inhibition of mTOR and S6K1 by HM-chromanone significantly reduced IRS-1Ser307 and IRS-1Ser632 phosphorylation, leading to insulin resistance. This resulted in an increase in PM-GLUT4 (glucose transporter 4) expression, thereby stimulating glucose uptake in insulin-resistant muscle cells. HM-chromanone can improve palmitate-induced insulin resistance by inhibiting mTOR and S6K1 through activation of the AMPK pathway in L6 skeletal muscle cells. These results show the therapeutic potential of HM-chromanone for improving insulin resistance in type 2 diabetes.

Possible Role of GnIH as a Novel Link between Hyperphagia-Induced Obesity-Related Metabolic Derangements and Hypogonadism in Male Mice.

Gonadotropin-inhibitory hormone (GnIH) is a reproductive inhibitor and an endogenous orexigenic neuropeptide that may be involved in energy homeostasis and reproduction. However, whether GnIH is a molecular signal link of metabolism and the reproductive system, and thus, regulates reproductive activity as a function of the energy state, is still unknown. In the present study, we investigated the involvement of GnIH in glycolipid metabolism and reproduction in vivo, and in the coupling between these two processes in the testis level. Our results showed that chronic intraperitoneal injection of GnIH into male mice not only increased food intake and altered meal microstructure but also significantly elevated body mass due to the increased mass of liver and epididymal white adipose tissue (eWAT), despite the loss of testicular weight. Furthermore, chronic intraperitoneal administration of GnIH to male mice resulted in obesity-related glycolipid metabolic derangements, showing hyperlipidemia, hyperglycemia, glucose intolerance, and insulin resistance through changes in the expression of glucose and lipid metabolism-related genes in the pancreas and eWAT, respectively. Interestingly, the expression of GnIH and GPR147 was markedly increased in the testis of mice under conditions of energy imbalance, such as fasting, acute hypoglycemia, and hyperglycemia. In addition, chronic GnIH injection markedly inhibited glucose and lipid metabolism of mice testis while significantly decreasing testosterone synthesis and sperm quality, inducing hypogonadism. These observations indicated that orexigenic GnIH triggers hyperphagia-induced obesity-related metabolic derangements and hypogonadism in male mice, suggesting that GnIH is an emerging candidate for coupling metabolism and fertility by involvement in obesity and metabolic disorder-induced reproductive dysfunction of the testes.

Cardiovascular Disease Risk Reduction and Body Mass Index.

Anti-hypertensive and lipid lowering therapy addresses only half of the cardiovascular disease risk in patients with body mass index > 30kg/m2, i.e., obesity. We examine newer aspects of obesity pathobiology that underlie the partial effectiveness of anti-hypertensive lipid lowering therapy for the reduction of cardiovascular disease risk in obesity. Obesity-related insulin resistance, vascular endothelium dysfunction, increased sympathetic nervous system/renin-angiotensin-aldosterone system activity, and glomerulopathy lead to type 2 diabetes, coronary atherosclerosis, and chronic disease kidney disease that besides hypertension and dyslipidemia increase cardiovascular disease risk. Obesity increases cardiovascular disease risk through multiple pathways. Optimal reduction of cardiovascular disease risk in patients with obesity is likely to require therapy targeted at both obesity and obesity-associated conditions.

Obesity-related prepartal insulin resistance in dairy cows is associated with increased lipin 1 and decreased FATP 1 expression in skeletal muscle

A number of alterations have been identified in lipid metabolism within adipose tissue and liver in obesity. Less is known about the capacity of skeletal muscle for the metabolism of fatty acids in obesity-related insulin resistance, though it is evident that dry cow muscles may contain increased triglyceride content. The current study was therefore undertaken to evaluate the skeletal muscle expression of proteins of the fatty acid metabolism in dry cows with different body condition scores (BCS). Sixteen Holstein-Friesian close-up cows were divided into 2 equal groups based on their BCS as optimal (3.25 ≤ BCS ≤ 3.5) and high (4.0 ≤ BCS ≤ 4.25). Blood samples collection and skeletal muscle biopsies were carried out at day 10 before calving. Blood serum was assayed for concentration of resistin using a bovine specific ELISA. Protein expression of insulin receptor beta subunit (IRβ), glucose transporter 4 (GLUT4), fatty acid translocase (FAT/CD36), fatty acid transporter 1 (FATP1), carnitine palmitoyltransferase 1 (CPT1), AMP-acitvated protein kinase (AMPK) and lipin 1 were analyzed in semitendinosus muscle by immunoblot. Resistin differed non-significantly between high-BCS and optimal-BCS cows. Insulin-resistant lipid metabolism in obese cows was paralleled with increased skeletal muscle expression of lipin 1 and GLUT4, and decreased expression of IRβ and FATP1. These data suggest that in obesity-related insulin resistance, metabolic capacity in dry cow skeletal muscles appears to be organized towards the synthesis of signaling intermediates rather than fatty acids oxidation and that altered fatty acid uptake does not contribute to this disposition.

225-OR: 5-Methoxytryptamine Improves Obesity-Related Inflammation and Insulin Resistance by Regulating M1/M2 Macrophage Polarization

In our previous study, we demonstrated that hypoglycemic agent DPP-4i changed the gut microbiota composition in diabetic patients and mice, and the DPP-4i-altered microbiome improved glucose tolerance in colonized mice. However, the mediators and their mechanisms remain to be elucidated. Comparing the intestinal metabolite profiles of HFD mice treated with or without sitagliptin (Sit) , we identified tryptophan derivative 5-methoxytryptomine (5-MT) was obviously increased after Sit treatment. In HFD and db/db mice, 5-MT treatment significantly reduced the body weight, improved glucose tolerance and insulin resistance, and ameliorated hepatic steatosis and inflammation. Drug affinity responsive target stability (DARTS) assay demonstrated the interaction between 5-MT and Aryl hydrocarbon receptor (AhR) . Specific inhibition of AhR attenuated the effects of 5-MT on improving insulin resistance. Furthermore, molecular mechanism exploration revealed that 5-MT promoted the expression and secretion of chemokine Cxcl14, which promoted macrophages maturation into alternative activation (M2-like) , subsequently inhibiting the production of inflammatory factors. These data demonstrate novel beneficial roles of 5-MT in improving obesity-related inflammation, insulin resistance and hepatic steatosis. Funding National Science Fund for Distinguished Young Scholars of China (No.81925007) , National Natural Science Foundation of China (No.81700757)

233-LB: Ranolazine Fails to Improve Glycemia in Obese Liver-Specific Pyruvate Dehydrogenase–Deficient Mice

Background: Nonalcoholic fatty liver disease (NAFLD) increases risk for obesity-related insulin resistance and type 2 diabetes. Recent studies have demonstrated that stimulating pyruvate dehydrogenase (PDH) , the rate-limiting enzyme in glucose oxidation, can reverse obesity-induced NAFLD. Moreover, our lab has observed that treatment with the antianginal drug, ranolazine, augments hepatic PDH activity, leading to a reversal of obesity-induced glucose intolerance and NAFLD in mice. Our aim herein was to determine whether ranolazine's ability to mitigate obesity-induced NAFLD and hyperglycemia requires increases in hepatic PDH activity. Methods: We generated liver-specific PDH deficient (PDHLiver-/-) mice by crossing floxed Pdha1 mice with albumin-Cre (Alb-Cre) mice. PDHLiver-/- and Alb-Cre mice were placed on a high-fat diet for 12-weeks to induce obesity, whereas their lean controls were fed a low-fat diet. Mice were randomized to treatment with either vehicle control or ranolazine (50 mg/kg) once daily via oral gavage for 5-weeks, following which we assessed glucose homeostasis and hepatic steatosis. Results: Lean PDHLiver-/- mice exhibited no overt phenotypic differences (e.g. adiposity, glucose tolerance) from their Alb-Cre littermates, though a mild but nonsignificant worsening of pyruvate tolerance was observed. Similar findings were observed in obese PDHLiver-/- mice compared to their Alb-Cre littermates. Of interest, ranolazine treatment produced mild improvements in glucose tolerance in obese Alb-Cre mice, but not in obese PDHLiver-/- mice. However, this improvement in ranolazine treated Alb-Cre mice appears to be independent of decreases in hepatic triacylglycerol content. Conclusions: Although hepatic PDH activity appears to contribute to the glucose-lowering actions of ranolazine, this appears to be dissociated from its actions on hepatic steatosis, and impaired hepatic PDH activity per se is not sufficient to produce an NAFLD phenotype. Disclosure C. T. Saed: None. S. Tabatabaei dakhili: None. A. A. Greenwell: None. J. S. F. Chan: None. K. Yang: None. K. Gopal: None. F. Eaton: None. J. R. Ussher: None.

Human umbilical cord-derived mesenchymal stem cells alleviate insulin resistance in diet-induced obese mice via an interaction with splenocytes

BackgroundPrevious research has demonstrated that the spleen plays an important role in mesenchymal stem cell (MSC)-mediated alleviation of acute inflammation, as MSC infusion increases the spleen-derived anti-inflammatory cytokine interleukin 10 (IL-10) levels. However, studies on splenic involvement in MSC-induced protection against chronic inflammatory diseases are limited. Obesity is characterized by chronic low-grade inflammation, a key driver of insulin resistance. This study aims to evaluate the effects of MSCs on obesity-related insulin resistance and explore the underlying mechanism, particularly regarding splenic involvement.MethodsWe induced obesity in mice by feeding them high-fat diets for 20 weeks. Human umbilical cord-derived MSCs (UC-MSCs) were systemically infused into the obese mice once per week for 6 weeks. Systemic glucose metabolic homeostasis and insulin sensitivity in epididymal adipose tissue (EAT) were evaluated. Then, we conducted in vivo blockade of IL-10 during UC-MSC infusion by intraperitoneally administrating an IL-10-neutralizing antibody twice per week. We also investigated the therapeutic effects of UC-MSCs on obese mice after removal of the spleen by splenectomy.ResultsUC-MSC infusions improved systemic metabolic homeostasis and alleviated insulin resistance in EAT but elicited no change in weight. Despite rare engraftment of UC-MSCs in EAT, UC-MSC infusions attenuated insulin resistance in EAT by polarizing macrophages into the M2 phenotype, coupled with elevated serum IL-10 levels. In vivo blockade of IL-10 blunted the effects of UC-MSCs on obese mice. Furthermore, UC-MSCs overwhelmingly homed to the spleen, and the ability of UC-MSCs to elevate serum IL-10 levels and alleviate insulin resistance was impaired in the absence of the spleen. Further in vivo and in vitro studies revealed that UC-MSCs promoted the capacity of regulatory T cells (Treg cells) to produce IL-10 in the spleen.ConclusionsOur results demonstrated that UC-MSCs elevated serum IL-10 levels and subsequently promoted macrophage polarization, leading to alleviation of insulin resistance in EAT. The underlying mechanism was that UC-MSCs improved the capacity of Treg cells to produce IL-10 in the spleen. Our findings indicated that the spleen played a critical role in amplifying MSC-mediated immunomodulatory effects, which may contribute to maximizing MSC efficacy in clinical applications in the future.

Biological Importance, Therapeutic Benefit, and Medicinal Importance of Flavonoid, Cirsiliol for the Development of Remedies against Human Disorders

Background: Phytochemicals are pure chemical compounds found to be present in different plants part such as leaves, fruit, flower, seeds and the whole plant. These pure plant-based chemicals are having power to treat all disorders of the human beings and other higher animal species on earth. Flavonoidal compounds are responsible for the attractive color and important biological properties of plant material. Flavonoids are having a potential role in the treatment of numerous health complications of human beings. Antioxidant properties are one of the best pharmacological properties of all classes of flavonoidal compounds. A significant amount of these flavonoidal compounds are needed in our daily routine diet. Methods: Cirsiliol also called 5,3′,4′-trihydroxy-6,7-dimethoxyflavone is a flavonoidal class chemical found to be present in different plants including Salvia guaranitica. Various literature databases have been searched to know the biological potential of the cirsiliol in medicine. Different scientific research data of cirsiliol have been collected from various literature sources and analyzed in the present work. Detail pharmacological activities of cirsiliol in medicine have been evaluated in the present work through literature data analysis of various scientific research works. However analytical data has also been collected and analyzed in the present work through different literature sources. Results: From the collected data, it was found that cirsiliol is present in the plants such as Artemisia campestris, Artemisia scoparia, Centaurea jacea, Centaurea phyllocephala, Crossostephium chinense, Dracocephalum tanguticum, Eupatorium lindleyanum, Hyptis pectinata, and Iris germanica. Pharmacological data analysis revealed the biological importance of cirsiliol against cancer, inflammatory diseases, obesity-related insulin resistance, and respiratory disorders. However, the biological potential on ileum, benzodiazepine receptor, arachidonate 5-lipoxygenase, and xanthine oxidase has also been well summarized in the present investigation. High-performance liquid chromatography, bioactivity-guided isolation techniques, UPLC-ESI-MS/MS, LCMS and HPLC, and other forms of chromatographic techniques have been applicable for the analysis of cirsiliol in the various plants material. Conclusion: The present investigation revealed the biological importance and therapeutic benefit of cirsiliol in medicine for the development of better remedies against human disorders.

Oxidative stress in obesity and insulin resistance

Since obesity is one of the main factors in the development of insulin resistance (IR) and is also associated with increased oxidative stress (OxS) rate, this study aims to review the published literature to collate and provide a comprehensive summary of the studies related to the status of the OxS in the pathogenesis of obesity and related IR. OxS represents an imbalance between the production of reactive oxygen and nitrogen species (RONS) and the capacity of the antioxidant defense system (AOS) to neutralize RONS. A steady-state of RONS level is maintained through endogenous enzymatic and non-enzymatic AOS components. Three crucial enzymes, which suppress the formation of free radicals, are superoxide dismutases, catalases, and glutathione peroxidases. The second line of AOS includes non-enzymatic components such as vitamins C and E, coenzyme Q, and glutathione which neutralizes free radicals by donating electrons to RONS. Emerging evidence suggests that high RONS levels contribute to the progression of OxS in obesity by activating inflammatory pathways and thus leading to the development of pathological states, including IR. In addition, decreased level of AOS components in obesity increases the susceptibility to oxidative tissue damage and further progression of its comorbidities. Increased OxS in accumulated adipose tissue should be an imperative target for developing new therapies in obesity-related IR.

Suppression of RIP1 activity via S415 dephosphorylation ameliorates obesity-related hepatic insulin resistance.

Receptor-interacting serine/threonine-protein kinase 1 (RIP1) is a well-documented key regulator of TNFα-mediated inflammation, apoptosis, and necroptosis, which contribute to the development of obesity-related metabolic diseases such as nonalcoholic steatohepatitis. However, the mechanism regarding how RIP1 influences obesity-related insulin resistance remains elusive. Primary hepatocytes with necrostatin 1 treatment or RIP1 expression were exposed to palmitic acid (PA), prior to the examination of cellular insulin signaling. Phosphorylation sites of RIP1 were detected by liquid chromatography with tandem mass spectrometry, and RIP1 variants with mutated phosphorylation sites were overexpressed in hepatocytes to identify the specific residue that influenced the RIP1-mediated insulin resistance. Adenovirus expressing RIP1 (S415A) mutant were administered into diet-induced obese mice to assess the effects on insulin sensitivity. This study uncovered an aberrant increase in RIP1 activity during the development of obesity-induced insulin resistance. Inhibition of RIP1 activity with necrostatin 1 ameliorated PA- or high-fat diet-caused hepatic insulin resistance. With liquid chromatography with tandem mass spectrometry analysis and mutagenesis screening, S415, a novel phosphorylation site of RIP1, was identified to be responsible for RIP1-mediated insulin resistance. Loss-of-function mutation of S415 efficiently blunted RIP1-evoked insulin resistance in PA-treated hepatocytes or diet-induced obese mice. These findings highlight the diabetogenic role of RIP1 S415 and propose RIP1 as a promising therapeutic target for type 2 diabetes.

PM20D1 is a circulating biomarker closely associated with obesity, insulin resistance and metabolic syndrome.

Peptidase M20 domain containing 1 (PM20D1), a secreted enzyme catalysing condensation of fatty acids and amino acids into the bioactive lipids N-acyl amino acids (NAAA), induces uncoupling protein 1 (UCP1)-independent adaptive thermogenesis in brown/beige adipocytes in mice. This study aimed to explore the associations of the circulating levels of PM20D1 and major NAAA with obesity-related metabolic complications in humans. Serum concentrations of PM20D1 and NAAA (C18:1-Leu and C18:1-Phe) in 256 Chinese subjects, including 78 lean and 178 overweight/obese individuals with or without diabetes, were measured with immunoassays and liquid chromatography-mass spectrometry, respectively. The impact of sulfonylurea and rosiglitazone on their circulating levels was examined in 62 patients with type 2 diabetes. Serum PM20D1 level was significantly elevated in overweight/obese individuals and was closely associated with circulating levels of C18:1-Leu and C18:1-Phe. Furthermore, serum PM20D1, C18:1-Leu and C18:1-Phe concentrations correlated positively with several parameters of adiposity as well as fasting and 2 h postprandial glucose, HbA1c, fasting insulin and HOMA-IR independent of BMI and age. Moreover, a significant elevation in PM20D1, C18:1-Leu and C18:1-Phe concentrations corresponding with increases in the number of components of the metabolic syndrome (MetS) was observed. Treatment with sulfonylurea significantly decreased circulating PM20D1, C18:1-Leu and C18:1-Phe in patients with type 2 diabetes. Increased serum levels of PM20D1 and its catalytic products NAAA are closely associated with obesity-related glucose dysregulation, insulin resistance and MetS and can be potentially used as clinical biomarkers for diagnosing and monitoring these disorders.