Obesity-related Insulin Resistance Research Articles

A Pilot Study on the Proteomics Profile of Serum Exosome-Enriched Extracellular Vesicles from Normal versus Individuals with Obesity-Related Insulin Resistance.

Circulating exosome-enriched extracellular vesicles (EVs) have drawn considerable importance in obesity-related insulin-resistance (IR). We sought to compare the proteomics profile of serum exosomes from normal individuals and those with obesity and IR. We isolated serum exosomes from male subjects with obesity and insulin resistance (Ob-IR, HOMA-IR > 2.0) and lean/overweight insulin-sensitive (Normal (N), HOMA-IR < 2.0) individuals. The differential protein expression between the two groups was detected by a label-free quantitative mass spectrometry analysis followed by GO annotation and ingenuity pathway analysis (IPA). We identified 23 upregulated and 46 downregulated proteins between Ob-IR and N groups. Some of these proteins are involved in altering insulin signaling (VPS13C, TBC1D32, TTR, and ADIPOQ), inflammation (NFκB and CRP), and B-cell proliferation/activation (IGLV4-69, IGKV1D-13, and IGHV4-28). GO analysis revealed that the differentially expressed proteins (DEPs) are mainly involved in regulating immune cell activation and are located in extracellular space. IPA analysis showed that top molecules mediating IR, inflammation and B-cell activation were upregulated in Ob-IR subjects compared to N subjects. Serum exosomal proteins can be used as biomarkers to identify the future risk of diabetes and a therapeutic target to prevent or slow down the progression of diabetes in high-risk individuals.

Mechanistic insights into the role of USP14 in adipose tissue macrophage recruitment and insulin resistance in obesity

Diet-induced obesity can cause metabolic syndromes. The critical link in disease progression is adipose tissue macrophage (ATM) recruitment, which drives low-level inflammation, triggering adipocyte dysfunction. It is unclear whether ubiquitin-specific proteinase 14 (USP14) affects metabolic disorders by mediating adipose tissue inflammation. In the present study, we showed that USP14 is highly expressed in ATMs of obese human patients and diet-induced obese mice. Mouse USP14 overexpression aggravated obesity-related insulin resistance by increasing the levels of pro-inflammatory ATMs, leading to adipose tissue inflammation, excessive lipid accumulation, and hepatic steatosis. In contrast, USP14 knockdown in adipose tissues alleviated the phenotypes induced by a high-fat diet. Co-culture experiments showed that USP14 deficiency in macrophages led to decreased adipocyte lipid deposition and enhanced insulin sensitivity, suggesting that USP14 plays an important role in ATMs. Mechanistically, USP14 interacted with TNF receptor-associated 6, preventing K48-linked ubiquitination as well as proteasome degradation, leading to increased pro-inflammatory polarization of macrophages. In contrast, the pharmacological inhibition of USP14 significantly ameliorated diet-induced hyperlipidemia and insulin resistance in mice. Our results demonstrated that macrophage USP14 restriction constitutes a key constraint on the pro-inflammatory M1 phenotype, thereby inhibiting obesity-related metabolic diseases.

Restoring SRSF3 in Kupffer cells attenuates obesity-related insulin resistance.

In obesity, depletion of Kupffer cells (KCs) expressing CRIg (complement receptor of the immunoglobulin superfamily) leads to microbial DNA accumulation, which subsequently triggers tissue inflammation and insulin resistance. However, the mechanism underlying obesity-mediated changes in KC complement immune functions is largely unknown. Using KC-specific deactivated Cas9 (dCas9) transgenic mice treated with guide RNA, we assessed the effects of restoring CRIg or the serine/arginine-rich splicing factor 3 (SRSF3) abundance on KC functions and metabolic phenotypes in obese mice. The impacts of weight loss on KC responses were evaluated in a diet switch mouse model. The role of SRSF3 in regulating KC functions was also evaluated using KC-specific SRSF3 knockout mice. Here, we report that overexpression of CRIg in KCs of obese mice protects against bacterial DNA accumulation in metabolic tissues. Mechanistically, SRSF3 regulates CRIg expression, which is essential for maintaining the CRIg+ KC population. During obesity, SRSF3 expression decreases, but it is restored with weight loss through a diet switch, normalizing CRIg+ KCs. KC SRSF3 is also repressed in obese human livers. Lack of SRSF3 in KCs in lean and obese mice decreases their CRIg+ population, impairing metabolic parameters. During the diet switch, the benefits of weight loss are compromised due to SRSF3 deficiency. Conversely, SRSF3 overexpression in obese mice preserves CRIg+ KCs and improves metabolic responses. Restoring SRSF3 abundance in KCs offers a strategy against obesity-associated tissue inflammation and insulin resistance by preventing bacterial DNA accumulation.

A mandatory practice in type 2 diabetes mellitus to maintain quality of life

Nepalese owing to modern lifestyle and processed food are racially at an elevated risk of acquiring central obesity-related insulin resistance (IR) and thus Type 2 diabetes mellitus (T2DM) and Diabetic Kidney Disease (DKD). Low birth weight in utero and later becoming obese risks the development of T2DM. In a total of eighty-four newly diagnosed treatment-naive Nepalese T2DMs, incidence of IR, percentage beta-cell function (%BCF) and percentage insulin sensitivity (%IS) were determined using Homeostatic Model Assessment 2 (HOMA2-IR). Association of HOMA2-IR with albuminuria, kidney function, hs-CRP, fatty liver, fatty pancreas, several anthropometric and biochemical parameters were analyzed. Among the eighty-four T2DMs, fifty-four agreeing regular follow-ups were prescribed a low-carbohydrate diet (&amp;#60;130gm/day). At 6 months, their glycemic controls were monitored. From 84 newly diagnosed T2DMs, 56 (66.7%) were insulin resistant and 28(33.3%) insulin-sensitive on HOMA2-IR. There was a significant association of HOMA2-IR with albuminuria and declining kidney function (p=0.006 and 0.034 respectively) and most of them were at reversible stages. Waist circumference (WC), waist-hip ratio (WHR), lipid profile ratios, fatty liver and fatty pancreas were elucidated as potential markers for IR. The IS group (ISG) had significantly inadequate %BCF (p=0.001) but high %IS (p&amp;#60;0.001) has healthier WHR (p=0.001) and lipid profile ratios which are opposite to IR group (IRG). 13 ISG had raised hs-CRP and 15 normal and 21 IRG had normal hs-CRP and 35 raised. At 6 months, the IRG achieved significantly better postprandial glycemic goals (p=0.04) and significant improvement in WC and WHR (p=0.008 and 0.03 respectively) with a low-carbohydrate diet as compared to ISG. Severe insulin resistance and IR-associated DKD, fatty liver and fatty pancreas are highly prevalent from the time of diagnosis of T2DM in the Nepalese population. Thus inspecting for IR and its consequences mandatorily at diagnosis and applying precision therapies like adjustments in the quality and quantity of staple food carbohydrates significantly improves IR-related parameters and glycemia.

Integrated Analysis of Gut Microbiome and Adipose Transcriptome Reveals Beneficial Effects of Resistant Dextrin from Wheat Starch on Insulin Resistance in Kunming Mice.

Systemic chronic inflammation is recognized as a significant contributor to the development of obesity-related insulin resistance. Previous studies have revealed the physiological benefits of resistant dextrin (RD), including obesity reduction, lower fasting glucose levels, and anti-inflammation. The present study investigated the effects of RD intervention on insulin resistance (IR) in Kunming mice, expounding the mechanisms through the gut microbiome and transcriptome of white adipose. In this eight-week study, we investigated changes in tissue weight, glucose-lipid metabolism levels, serum inflammation levels, and lesions of epididymal white adipose tissue (eWAT) evaluated via Hematoxylin and Eosin (H&E) staining. Moreover, we analyzed the gut microbiota composition and transcriptome of eWAT to assess the potential protective effects of RD intervention. Compared with a high-fat, high-sugar diet (HFHSD) group, the RD intervention significantly enhanced glucose homeostasis (e.g., AUC-OGTT, HOMA-IR, p < 0.001), and reduced lipid metabolism (e.g., TG, LDL-C, p < 0.001) and serum inflammation levels (e.g., IL-1β, IL-6, p < 0.001). The RD intervention also led to changes in the gut microbiota composition, with an increase in the abundance of probiotics (e.g., Parabacteroides, Faecalibaculum, and Muribaculum, p < 0.05) and a decrease in harmful bacteria (Colidextribacter, p < 0.05). Moreover, the RD intervention had a noticeable effect on the gene transcription profile of eWAT, and KEGG enrichment analysis revealed that differential genes were enriched in PI3K/AKT, AMPK, in glucose-lipid metabolism, and in the regulation of lipolysis in adipocytes signaling pathways. The findings demonstrated that RD not only ameliorated IR, but also remodeled the gut microbiota and modified the transcriptome profile of eWAT.

Cyclosorus Terminans Extract Alleviates Neuroinflammation in Insulin Resistant Rats.

High-fat diet consumption for an extended period causes obesity, systemic metabolic disturbance, and brain insulin resistance, resulting in neuroinflammation. Although the beneficial effect of Cyclosorus terminans extract on obesity-related insulin resistance has been demonstrated, little is known about how it affects neuroinflammation and brain insulin resistance in obese rats. Male Wistar rats were given either a normal diet (ND, n = 6) or a high-fat diet (HFD, n = 24) for a total of 14 weeks. At the beginning of the week, 13 rats in the ND group were given vehicle orally for 2 weeks, while rats on HFD diets were randomized to one of four groups and given either vehicle, 100 mg/kg/day of Cyclosorus terminans extract, 200 mg/kg/day of Cyclosorus terminans extract, or 20 mg/kg/day of pioglitazone orally for 2 weeks. After the experimental period, blood and brain samples were taken to assess metabolic and brain parameters. HFD-fed rats had obesity, systemic and brain insulin resistance, brain inflammation, microglial and astrocyte hyperactivity, and brain necroptosis. Treatment with 200 mg/kg/day of Cyclosorus terminans extract and pioglitazone equally attenuated obesity, insulin resistance, brain insulin dysfunction, and neuroinflammation in insulin resistant rats. Our findings suggest that Cyclosorus terminans extract may hold promise as a therapeutic agent for insulin resistance and neuroinflammation in obese conditions.

Sex-specific increases in myostatin and SMAD3 contribute to obesity-related insulin resistance in human skeletal muscle and primary human myotubes.

The purpose of the present study was to determine the effects of obesity and biological sex on myostatin expression in humans and to examine the direct effects of myostatin, SMAD2, and SMAD3 on insulin signaling in primary human skeletal muscle cells (HSkMCs). For cohort 1, 15 lean [body mass index (BMI): 22.1 ± 0.5 kg/m2; n = 8 males; n = 7 females] and 14 obese (BMI: 40.6 ± 1.4 kg/m2; n = 7 males; n = 7 females) individuals underwent skeletal muscle biopsies and an oral glucose tolerance test. For cohort 2, 14 young lean (BMI: 22.4 ± 1.9 kg/m2; n = 6 males; n = 8 females) and 14 obese (BMI: 39.3 ± 7.9 kg/m2; n = 6 males; n = 8 females) individuals underwent muscle biopsies for primary HSkMC experiments. Plasma mature myostatin (P = 0.041), skeletal muscle precursor myostatin (P = 0.048), and skeletal muscle SMAD3 (P = 0.029) were elevated in obese females compared to lean females, and plasma mature myostatin (r = 0.58, P = 0.029) and skeletal muscle SMAD3 (r = 0.56, P = 0.037) were associated with insulin resistance in females but not males. Twenty-four hours of myostatin treatment impaired insulin signaling in primary HSkMCs derived from females (P < 0.024) but not males. Overexpression of SMAD3, but not SMAD2, impaired insulin-stimulated AS160 phosphorylation in HSkMCs derived from lean females (-27%, P = 0.040), whereas silencing SMAD3 improved insulin-stimulated AS160 phosphorylation and insulin-stimulated glucose uptake (25%, P < 0.014) in HSkMCs derived from obese females. These results suggest for the first time that myostatin-induced impairments in skeletal muscle insulin signaling are sex specific and that increased body fat in females is associated with detrimental elevations in myostatin and SMAD3, which contribute to obesity-related insulin resistance.NEW & NOTEWORTHY Obesity is considered a main risk factor for the development of insulin resistance and type 2 diabetes. The present study utilizes in vivo and in vitro experiments in human skeletal muscle to demonstrate for the first time that females are inherently more susceptible to myostatin-induced insulin resistance, which is further enhanced with obesity due to increased myostatin and SMAD3 expression.

A MUFA/carotenoid-rich oil ameliorated insulin resistance by improving inflammation and oxidative stress in obese rats

Obesity is associated with low-grade inflammation and oxidative stress, leading to insulin resistance and type II diabetes. Caryocar brasiliense pulp oil (pequi oil – PO) is rich in oleic acid and carotenoids and positively implicated in regulating inflammation and oxidative stress. This study investigated PO's antioxidant and anti-inflammatory effects in a diet-induced obesity model. Male Wistar rats were allocated into three experimental groups: Control (CD), Western Diet (WD), and Western Diet, with 27% of lard switched by PO (WDP). Metabolic, inflammatory, and oxidative stress biomarkers were evaluated after 12 weeks of diet protocols in liver and adipose tissue. WDP rats gained less body mass and epididymal fat, had less hepatic fat infiltration, and were more glucose-tolerant and insulin-sensitive than WD (p < 0.05). In the liver, the WDP group had the highest non-enzymatic antioxidant capacity, SOD and GPx activities, CAT, SOD II, and HSP72 expression compared to WD (p < 0.05). Adipose tissue IL-6 and TNF were reduced, and IL-10 was increased in WDP compared to WD (p < 0.05). Our data suggest that the partial replacement of lard by PO in a Western diet prevented visceral fat accumulation and contributed to reducing inflammation in adipose tissue and liver oxidative stress, improving obesity-related insulin resistance.

Thrombospondin1 antagonist peptide treatment attenuates obesity-associated chronic inflammation and metabolic disorders in a diet-induced obese mouse model

Thrombospondin1 (TSP1) is a multifunctional matricellular protein. Previously, we demonstrated that TSP1 plays a pivotal role in obesity-related inflammation and insulin resistance (IR) by modulating macrophage accumulation and activation in adipose tissue. Moreover, in our in vitro studies, a CD36-derived peptide, functioning as a TSP1 antagonist, effectively inhibited TSP1-induced proinflammatory macrophage activation. However, whether this CD36 peptide can inhibit obesity-induced inflammation and IR in vivo is unknown and determined in this study in a high fat diet-induced obese mouse model (DIO). CD36 peptide or control peptide was intraperitoneally administered into the established obese mice triweekly for 6 weeks. We found that CD36 peptide treatment didn’t affect obesity or weight gain but significantly reduced proinflammatory cytokine production systemically and in visceral fat tissue. Adipose tissue exhibited fewer crown-like structures and reduced macrophage infiltration. CD36 peptide treatment also attenuated the proinflammatory phenotype of bone marrow derived macrophages from obese mice. Furthermore, CD36 peptide treatment improved glucose tolerance and insulin sensitivity, and mitigated obesity-related fatty liver disease and kidney damage. Collectively, this study suggests that the CD36 peptide, as a TSP1 antagonist, shows promise as a novel therapeutic approach for managing obesity-related metabolic disorders.

A Drosophila model targets Eiger/TNFα to alleviate obesity-related insulin resistance and macrophage infiltration.

Obesity is associated with various metabolic disorders, such as insulin resistance and adipose tissue inflammation (ATM), characterized by macrophage infiltration into adipose cells. This study presents a new Drosophila model to investigate the mechanisms underlying these obesity-related pathologies. We employed genetic manipulation to reduce ecdysone levels to prolong the larval stage. These animals are hyperphagic and exhibit features resembling obesity in mammals, including increased lipid storage, adipocyte hypertrophy and high circulating glucose levels. Moreover, we observed significant infiltration of immune cells (hemocytes) into the fat bodies, accompanied by insulin resistance. We found that attenuation of Eiger/TNFα signaling reduced ATM and improved insulin sensitivity. Furthermore, using metformin and the antioxidants anthocyanins, we ameliorated both phenotypes. Our data highlight evolutionarily conserved mechanisms allowing the development of Drosophila models for discovering therapeutic pathways in adipose tissue immune cell infiltration and insulin resistance. Our model can also provide a platform to perform genetic screens or test the efficacy of therapeutic interventions for diseases such as obesity, type 2 diabetes and non-alcoholic fatty liver disease.

Nano cerium oxide and cerium/zinc nanocomposites characterization and therapeutic role in combating obesity via controlling oxidative stress and insulin resistance in rat model

BackgroundCeO2NPs and ZnONPs can curb the increase of cholesterol and triglycerides observed in rats with non-alcoholic fatty liver disease. It was suggested that CeO2 NPs could potentially have an insulin-sensitizing effect, specifically on adipose tissue and skeletal muscle. It was reported that ZnONPs combat the increase of insulin resistance observed in obese rats and could be beneficial value in NAFLD. In our previous work, ZnO-NPs manifested valuable anti-obesity effects via lowering body weight gain, oxidative stress, BMI, lipids, and insulin resistance. MethodsIn the present study, cerium oxide nanoparticles (A-1) and cerium/zinc nanocomposites (A-2 and A-3) were synthesized by solgel to investigate their role on oxidative stress, adipocyte hormones, and insulin resistance in an obese rat model. X-ray diffraction, HRTEM, SEM, and XPS were carried out to confirm the crystal structure, the particle size, the morphology of the nanoparticles and the oxidation states. ResultsThe Rietveld refinement has also been executed on A-1 (chi2 = 1.00; average Bragg = 2.92%; R-factor = 2.45%) and on A-2 (Rw = 9.87%, Rex= 9.68%, χ2 = 1.04, GoF = 1.02). The XPS spectra indicated the presence of Ce in + 4 and + 3 oxidation states and Zn as ZnO and ZnO.OH. Cerium oxide and ZnO crystal sizes lie in the range 40.53–45.01 and 40.53–45.01 nm, respectively. The results indicated that treating obese rats with any of the tested nano compounds (5 mg or 10 mg/Kg) lowered plasma cholesterol, triglycerides, LDL, insulin resistance, glucose, and BMI significantly relative to obese group values. On the other hand, HDL increased significantly in obese rats after treatment with either A-2 or A-3 compared to obese rats. The current investigation showed antioxidant activities for A-1, A-2, and A3 as evidenced by the significant increase in GSH level and a significant decrease in MDA. ConclusionIt was found that A-1, A-2, and A-3 have an efficient therapeutic role in treating of obesity-related hyperlipidemia, oxidative stress and insulin resistance. The results of A-2 and A-3 were more pronounced than those of A-1. The use of Zn/Ce nanocomposite (that have positive characteristics) in combating obesity and its complications could be become a new trend in therapeutic application for a management of obesity.

1627-P: Enhancer Regulator MLL4 Programs Skeletal Muscle Metabolic Efficiency by Limiting AMPK-Mediated Fuel Catabolism

Skeletal muscle adapts to nutrient availability and physiological demands by fine-tuning gene expression patterns and metabolism to maximize metabolic efficiency. The mechanisms that enable and mediate muscle transcriptional and metabolic responses to environmental cues remain unclear, however. We have shown previously that enhancer regulator MLL4 is required for establishing and maintaining slow type I fiber program to ensure running endurance (J Clin Invest. 2020;130(9):4710-4725). Here, we report that MLL4 plays a critical role in directing muscle metabolic transcriptional adaptation that governs metabolic efficiency and systemic metabolism. MLL4 expression is regulated by nutrient availability, and skeletal muscle-specific ablation of MLL4 protects mice against diet-induced obesity and improves systemic glucose homeostasis despite reducing exercise endurance. Combining comprehensive metabolic and genomic analysis of the MLL4-depleted muscles using multidimensional ‘omics’ technologies, we gained insight into the molecular targets and biological functions of the MLL4 protein. Specifically, this seemingly paradoxical phenotype is due to markedly enhanced fuel catabolism in MLL4 deficient muscles, a favorable metabolic reprogramming caused by the activation of muscle AMPK. Isotopic 13C-glucose tracing experiments in myocyte provided further evidence that MLL4 exerts control upon muscle fuel catabolism. Remarkably, pharmacologic targeting the MLL4 pathway activates muscle AMPK, confers resistance to diet-induced obesity and ameliorates obesity-related insulin resistance and liver steatosis. These results identify an enhancer regulator limiting AMPK-mediated muscle fuel catabolism and offer a new potential therapeutic strategy for obesity-related metabolic disorders. Disclosure L.Yang: None. L.Liu: None. C.Ding: None. T.Fu: None. Z.Zhou: None. Z.Gan: None.

Enhancing de novo ceramide synthesis induced by bisphenol A exposure aggravates metabolic derangement during obesity

ObjectiveExposure to bisphenol A (BPA) has been shown to increase the prevalence of obesity and its related insulin resistance (IR). Ceramide is a sphingolipid known to facilitate the production of proinflammatory cytokines and subsequently exacerbate inflammation and IR during the progression of obesity. Here, we investigated the effects of BPA exposure on ceramide de novo synthesis and whether increased ceramides aggravate adipose tissue (AT) inflammation and obesity-related IR. MethodsA population-based case–control study was conducted to explore the relationship between BPA exposure and IR and the potential role of ceramide in AT in obesity. Next, we used mice reared on a normal chow diet (NCD) or a high-fat diet (HFD) to verify the results from the population study and then investigated the role of ceramides in low-level BPA exposure with HFD-induced IR and AT inflammation in mice treated with or without myriocin (an inhibitor of the rate-limiting enzyme in de novo ceramide synthesis). ResultsBPA levels are higher in obese individuals and are significantly associated with AT inflammation and IR. Specific subtypes of ceramides mediated the associations between BPA and obesity, obesity-related IR and AT inflammation in the obesity group. In animal experiments, BPA exposure facilitated ceramide accumulation in AT, activated PKCζ, promoted AT inflammation, increased the expression and secretion of proinflammatory cytokines via the JNK/NF-κB pathway, and lowered insulin sensitivity by disrupting IRS1-PI3K-AKT signaling in mice fed a HFD. Myriocin suppressed BPA-induced AT inflammation and IR. ConclusionThese findings indicate that BPA aggravates obesity-induced IR, which is partly via increased de novo synthesis of ceramides and subsequent promotion of AT inflammation. Ceramide synthesis could be a potential target for the prevention of environmental BPA exposure-related metabolic diseases.

Mitochondrial Cholesterol Metabolites in a Bile Acid Synthetic Pathway Drive Nonalcoholic Fatty Liver Disease: A Revised “Two-Hit” Hypothesis

The rising prevalence of nonalcoholic fatty liver disease (NAFLD)-related cirrhosis highlights the need for a better understanding of the molecular mechanisms responsible for driving the transition of hepatic steatosis (fatty liver; NAFL) to steatohepatitis (NASH) and fibrosis/cirrhosis. Obesity-related insulin resistance (IR) is a well-known hallmark of early NAFLD progression, yet the mechanism linking aberrant insulin signaling to hepatocyte inflammation has remained unclear. Recently, as a function of more distinctly defining the regulation of mechanistic pathways, hepatocyte toxicity as mediated by hepatic free cholesterol and its metabolites has emerged as fundamental to the subsequent necroinflammation/fibrosis characteristics of NASH. More specifically, aberrant hepatocyte insulin signaling, as found with IR, leads to dysregulation in bile acid biosynthetic pathways with the subsequent intracellular accumulation of mitochondrial CYP27A1-derived cholesterol metabolites, (25R)26-hydroxycholesterol and 3β-Hydroxy-5-cholesten-(25R)26-oic acid, which appear to be responsible for driving hepatocyte toxicity. These findings bring forth a “two-hit” interpretation as to how NAFL progresses to NAFLD: abnormal hepatocyte insulin signaling, as occurs with IR, develops as a “first hit” that sequentially drives the accumulation of toxic CYP27A1-driven cholesterol metabolites as the “second hit”. In the following review, we examine the mechanistic pathway by which mitochondria-derived cholesterol metabolites drive the development of NASH. Insights into mechanistic approaches for effective NASH intervention are provided.

Perirenal adipose tissue (PRAT)-derived asprosin as a potential doorway to obesity-related insulin resistance in male mice

PRAT, a mixture of white (WAT) and brown adipose tissue (BAT), has been increasingly recognized as a metabolically active tissue able to secrete a series of adipokines. In obesity, PRAT undergoes changes in its secretory profile. Recent studies have reported that asprosin, a newly discovered adipokine secreted by white adipocytes, is elevated in obese individuals. Whether PRAT secretes asprosin remains unknown. We hypothesized that in obesity, PRAT undergoes phenotypic changes which lead to increased asprosin expression in association with insulin resistance. To address our hypothesis, eight-week-old male C57BL/6 mice were randomized into two experimental groups. The Control Group (n=7) received a standard chow diet (5% fat, 48.7% carbohydrates [3.2% sucrose]) and the Obese Group (n=11) received a Western Diet (WD) (40% fat, 43% carbohydrates [34% sucrose]) for 38 weeks. Our experimental model was validated by the presence of central obesity which was confirmed by increased waist circumference (10.79 ± 0.25 cm vs. 8.70 ± 0.16 cm controls, p&lt;0.0001) and increased body weight (45.39 ± 1.98 g vs. 29.21 ± 0.79 g controls, p&lt;0.0001). Metabolic studies revealed that obese mice developed an intolerance to glucose as determined by the glucose tolerance test (40907 ± 5324 a.u vs. 26741 ± 2380 a.u controls, p&lt;0.05), elevated fasting blood glucose (116.9 ± 4.58 mg/dL vs. 88.0 ± 8.51 mg/dL controls, p&lt;0.05) and high serum insulin levels (3.52 ± 0.63 ng/mL vs. 0.91 ± 0.36 ng/mL controls, n=6, p&lt;0.01). Insulin resistance in the obese group was further confirmed by the increased homeostasis model assessment for insulin resistance (HOMA-IR) (35.99 ± 6.08 a.u vs. 4.24 ± 1.71 a.u controls, n=5, p&lt;0.01). As expected, greater PRAT mass was detected in the obese group (17.42 ± 2.34 mg/g vs. 2.92 ± 0.43 mg/g controls, p&lt;0.05) compared to controls. Histological analysis of PRAT stained with H&amp;E demonstrated a marked reduction of BAT and expansion of WAT with increased size of white adipocytes (6555 ± 1253 μm2 vs 493.7 ± 15.33 μm2 controls, p&lt;0.05) in association with inflammatory mononuclear cell infiltration. Strikingly, higher serum levels of asprosin (4.39 ± 0.07 pg/mL vs. 3.81 ±0.18 pg/mL controls, n=3, p&lt;0.05) in obese mice was accompanied by increased asprosin expression within PRAT (1.28 ± 0.18 a.u vs. 0.63 ± 0.11 a.u, n=3, p&lt;0.05). Since asprosin has been linked to insulin resistance in humans, our results suggest that insulin resistance observed in our male obese mice may be a result of increased circulating asprosin. The novelty of our findings indicate that PRAT may be a potential tissue contributing to the elevated circulating levels of asprosin in obesity. Diabetes Action to Maria Alicia Carrillo Sepulveda This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Glucocorticoid activation of anti-inflammatory macrophages protects against insulin resistance

Insulin resistance (IR) during obesity is linked to adipose tissue macrophage (ATM)-driven inflammation of adipose tissue. Whether anti-inflammatory glucocorticoids (GCs) at physiological levels modulate IR is unclear. Here, we report that deletion of the GC receptor (GR) in myeloid cells, including macrophages in mice, aggravates obesity-related IR by enhancing adipose tissue inflammation due to decreased anti-inflammatory ATM leading to exaggerated adipose tissue lipolysis and severe hepatic steatosis. In contrast, GR deletion in Kupffer cells alone does not alter IR. Co-culture experiments show that the absence of GR in macrophages directly causes reduced phospho-AKT and glucose uptake in adipocytes, suggesting an important function of GR in ATM. GR-deficient macrophages are refractory to alternative ATM-inducing IL-4 signaling, due to reduced STAT6 chromatin loading and diminished anti-inflammatory enhancer activation. We demonstrate that GR has an important function in macrophages during obesity by limiting adipose tissue inflammation and lipolysis to promote insulin sensitivity.

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 &lt;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 &lt; 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 &lt;0.05, respectively), although PSV was not significantly different. Pulsatility index correlated significantly with body mass index (r =0.58, p &lt; 0.01), insulin (r = 0.24, p &lt; 0.05), homeostasis model assessment of insulin resistance (r =0.25, p &lt; 0.01), triglycerides (r = 0.26, p &lt; 0.01), uric acid (r = 0.22, p &lt; 0.05), systolic blood pressure (r = 0.31, p &lt; 0.01), and carotid intima-media thickness (r = 0.36, p&lt;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.