Adiponectin Expression Research Articles

Hyperplasia of fat-containing cells with mature adipocyte marker is associated with pancreatic fat enlargement

Abstract Objectives: The purpose was to elucidate the specific characteristics of fat-containing cells in the pancreas and the mechanism of intra-pancreatic fat deposition (IPFD) in humans. Methods: 15 Japanese patients who had undergone pancreatic resection were enrolled and the normal region of pancreatic samples from each patient was examined. To evaluate the characteristics of fat-containing cells, immunostaining for adiponectin and perilipin 1 was performed and the relationships between the pancreatic fat-cell area or clinical parameters, and the density or the diameter of the fat cells was analyzed. Results: Expression of adiponectin in the cytoplasm and perilipin 1 along the plasma membrane were observed in fat-containing cells in the pancreas. The fat-containing cell area had a significant positive correlation with cell density (r = 0.58, p = 0.023). In addition, fat-containing cell density was significantly positively correlated with homeostasis model assessment insulin resistance (HOMA-IR) (r = 0.61, p = 0.045). Fat-containing cell area was not significantly correlated with cell diameter (r = 0.45, p = 0.095). The diameter of fat-containing cells had significant positive correlations with BMI (r = 0.79, p < 0.001), fasting immunoreactive insulin (r = 0.65, p = 0.029) and HOMA-IR (r = 0.80, p = 0.003). Of all fat-containing cells, 10.4% were intralobular cells, and the diameter of intralobular cells showed a tendency for positive correlation with age (r = 0.52, p = 0.057). Conclusions: The characteristics of fat-containing cells in the pancreas indicate that some of them may be mature adipocytes, and fat volume may be increased by hyperplasia of fat-containing cells associated with insulin resistance. Key terms: pancreatic fat, adipocytes markers, hyperplasia of fat-containing cells, insulin resistance.

Ponatinib exacerbate renal injury in systemic lupus erythematosus mouse model through PDGFR-PI3K/AKT pathway

Lupus nephritis (LN) is a common clinical complication of systemic lupus erythematosus (SLE). Proliferative lupus nephritis represents the gravest form of LN, and since effective drugs for its treatment are still lacking, tyrosine kinase inhibitors (TKIs) find extensive clinical utility due to their notable impact on suppressing cell proliferation and may serve as potential drugs for LN treatment. However, previous studies on the effects of TKI on LN have been controversial. Ponatinib, a third-generation TKI, lacks studies on its role in LN. This study aimed to investigate the impact of the ponatinib on LN. MRL/lpr mice were evaluated for renal function, autoimmune markers and histopathological changes after oral administration of ponatinib. RNA-seq analysis was performed to explore the molecular pathways involved in ponatinib-induced kidney injury. Ponatinib uniquely exacerbated renal damage in MRL/lpr mice, evidenced by a decline in renal function and acute pathological changes, without affecting lupus-related autoimmune markers. Differential expressed genes analysis and functional enrichment implicate ponatinib-induced renal damage in MRL/lpr mice associated with adiponectin. Furthermore, we verified ponatinib signaling the PI3K/AKT pathway through PDGFRα, potentially influencing high molecular weight adiponectin (HMW ADIPOQ) expression and exacerbating renal damage. In conclusion, this study demonstrates that ponatinib can up-regulate HMW ADIPOQ expression via the PI3K/AKT pathway by inhibiting PDGFRα phosphorylation, highlighting the potential nephrotoxic effects of ponatinib in lupus-prone mice, and underscoring the importance of monitoring renal function in systemic autoimmune diseases patients receiving ponatinib.

1α,25-Dihydroxyvitamin D Downregulates Adipocyte Impact on Breast Cancer Cell Migration and Adipokine Release.

Excess adiposity is associated with a higher risk of breast cancer metastasis and mortality. Evidence suggests that dietary vitamin D inhibits breast cancer metastasis. However, the mechanistic link between vitamin D's regulation of adipocyte metabolism and metastasis has not been previously investigated. Therefore, the purpose of these experiments was to examine the effect of the active form of vitamin D, 1α,25-dihydroxyvitamin D (1,25(OH)2D), on adipocyte release of bioactive compounds and whether the impact on adipocytes leads to inhibition of breast cancer cell migration, an important step of metastasis. Differentiated 3T3-L1 adipocytes were treated with 1,25(OH)2D for two days, followed by either harvesting the adipocytes or collecting adipocyte-conditioned media without 1,25(OH)2D. A transwell migration assay was conducted with vehicle- or 1,25(OH)2D-conditioned media. In order to explore the mechanism underlying effects on breast cancer metastatic capability, the mRNA expression of leptin, adiponectin, insulin-like growth factor (IGF-1), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1) was measured in adipocytes following either vehicle or 1,25(OH)2D treatment. Conditioned media from 1,25(OH)2D-treated adipocytes inhibited the migration of metastatic MDA-MB-231 breast cancer cells compared to conditioned media from vehicle-treated adipocytes. Treatment of adipocytes with 1,25(OH)2D decreased mRNA expression of leptin, adiponectin, IGF-1, IL-6, and MCP-1. Consistent with mRNA expression, concentrations of leptin, adiponectin, IGF-1, and IL-6 in adipocyte-conditioned media were decreased with 1,25(OH)2D treatment, although MCP-1 remained unchanged. In summary, these results suggest that 1,25(OH)2D alters adipocyte secretions to prevent breast cancer metastasis.

Activation of G Protein-Coupled Estrogen Receptor 1 (GPER) Attenuates Obesity-Induced Asthma by Switching M1 Macrophages to M2 Macrophages.

The prevalence of obesity-induced asthma increases in women after menopause. We hypothesized that the increase in obese asthma in middle-aged women results from estrogen loss. In particular, we focused on the acute action of estrogen through the G protein-coupled estrogen receptor 1 (GPER), previously known as GPR30. We investigated whether GPER activation ameliorates obesity-induced asthma with a high-fat diet (HFD) using G-1, the GPER agonist, and G-36, the GPER antagonist. Administration of G-1 (0.5 mg/kg) suppressed HFD-induced airway hypersensitivity (AHR), and increased immune cell infiltration, whereas G-36 co-treatment blocked it. Histological analysis showed that G-1 treatment inhibited HFD-induced inflammation, fibrosis, and mucus hypersecretion in a GPER-dependent manner. G-1 inhibited the HFD-induced rise in the mRNA levels of pro-inflammatory cytokines in the gonadal white adipose tissue and lungs, whereas G-36 co-treatment reversed this effect. G-1 increased anti-inflammatory M2 macrophages and inhibited the HFD-induced rise in pro-inflammatory M1 macrophages in the lungs. In addition, G-1 treatment reversed the HFD-induced increase in leptin expression and decrease in adiponectin expression in the lungs and gonadal white adipose tissue. The results suggest that activation of GPER could be a therapeutic option for obesity-induced asthma.

Abstract P361: Characterization of a Constitutive Adiponectin-Cre Rat Reveals Expression in Adipocyte, Endothelial and Neuronal Lineages

Introduction: The Dahl salt-sensitive (DahlSS) rat is a valuable model for studying hypertension and blood pressure regulation. To create new genetic tools for probing gene function specifically within adipose tissues in this model, we engineered a constitutive Adipoq-Cre rat on a DahlSS genomic background using CRISPR-Cas9 genome editing. Methods: A P2A-Cre cassette was inserted in-frame with the endogenous Adiponectin gene (ENSRNOG00065003537) to enable bicistronic expression from the major transcript (Adipoq-201; ENSRNOT00060022350.1). CRISPR targeting was achieved by microinjecting rat zygotes with a ribonucleoprotein (RNP) complex consisting of Cas9 protein and single guide RNA with a target near the stop codon, and a homology-directed repair plasmid template carrying the Cre recombinase cassette. To evaluate the pattern of Cre expression, Adipoq-Cre DahlSS rats were crossed with a Rosa-CAG-LSL-tdTomato LE reporter line (RRRC#: 009389). The progeny were analyzed for tdTomato reporter expression by cryo-fluorescence tomography (CFT) at postnatal day 10 (P10) and 10 weeks of age, using a Xerra TM EMIT imaging platform (50um sections). A Zeiss LSM 880 system was used to image fresh Vectashield-mounted tissues with a Plan-Apochromat 20x objective and a 561nm laser. Results: Strong CFT signal was detected in all examined adipose depots including subcutaneous, gonadal, and retroperitoneal white adipose tissue, interscapular brown adipose tissue, and perivascular adipose tissue (PVAT). Expression was also detected in the CNS. Confocal imaging of mesenteric PVAT and thoracic aorta PVAT revealed expression in adipocytes, endothelial cells, and peripheral nerves. Conclusion: The newly developed constitutive DahlSS Adipoq-Cre recombinase knockin drives expression in white and brown adipose depots but the presence of expression in non-adipocyte cells suggests either developmental or adult adiponectin expression in endothelial and neuronal lineages, limiting its ability to drive strictly adipose-specific gene expression.

Dietary apigenin ameliorates obesity-related hypertension through TRPV4-dependent vasorelaxation and TRPV4-independent adiponectin secretion

BackgroundObesity-related hypertension is a major cardiovascular risk factor. Apigenin, a natural flavonoid in celery, induces vascular dilation via endothelial transient receptor potential channel vanilla 4 (TRPV4) channels. This study aimed to explore apigenin's potential to alleviate obesity-related hypertension in mice and its underlying mechanisms. MethodsThe C57BL/6 and TRPV4 knockout mice were fed a high-fat diet and subjected to dietary intervention with apigenin. Body weight and tail blood pressure of the mice were measured during the feeding. Vascular reactivity was assessed through a DMT wire myograph systems in vitro. The distribution and expression of adiponectin and pro-inflammatory markers in brown fat were detected. Injecting adeno-associated eight (AAV8) viruses into brown adipose tissue (BAT) to determine whether adiponectin is indispensable for the therapeutic effect of apigenin. Palmitic acid (PA) was used in mouse brown adipocytes to examine the detailed mechanisms regulating adiponectin secretion. ResultsApigenin improved vasodilation and reduced blood pressure in obese mice, effects partly blocked in TRPV4 knockout. It also reduced weight gain independently of TRPV4. Apigenin increased adiponectin secretion from BAT; knockdown of adiponectin weakened its benefits. Apigenin downregulated Cluster of differentiation 38 (CD38), restoring Nicotinamide adenine dinucleotide+ (NAD+) levels and activating the NAD+/Sirtuin 1 (SIRT1) pathway, enhancing adiponectin expression. ConclusionsOur study indicates that dietary apigenin is suitable as a nonpharmaceutical intervention for obesity-related hypertension. In mechanism, in addition to improving vascular relaxation through the activation of endothelial TRPV4 channels, apigenin also directly alleviated adipose inflammation and increased adiponectin levels by inhibiting CD38.

The contribution of adiponectin to diabetic retinopathy progression: Association with the AGEs-RAGE pathway

Diabetic retinopathy (DR) is a chronic complication of diabetes. Given that adiponectin plays a key role in DR progression, this study aims to elucidate the molecular mechanisms of sDR progression related to adiponectin. First, we extracted the microarray dataset GSE60436 from the Gene Expression Omnibus (GEO) database to identify hub genes associated with DR. Pathway enrichment analysis revealed a focus on inflammation, oxidative stress, and metabolic disease pathways. Gene Set Enrichment Analysis (GSEA) identified nine significant pathways related to DR. Immune infiltration analysis indicated increased infiltration of fibroblasts and endothelial cells in DR patients. Second, at the gene level, single-cell RNA sequencing (scRNA-seq) results showed a decrease in ADIPOQ gene expression as the disease progressed in our mouse models. At the protein level, ELISA results from sera of 31 patients and 11 control subjects demonstrated significantly lower adiponectin expression in the proliferative diabetic retinopathy (PDR) group compared to controls. Our findings reveal that adiponectin is involved in the advanced glycation end products (AGEs) and receptor of advanced glycation end products (RAGE) axis, as evidenced by hub gene analysis, scRNA-seq, and ELISA. In conclusion, adiponectin acts as a central molecule in the AGEs-RAGE axis, regulated by ADIPOQ, to influence DR progression.

Metabolic responses to albumin deficiency differ distinctly between partial and full ablation of albumin expression in mice

It had been observed that homozygous albumin knockout mice (Alb−/−) exhibit low plasma free fatty acid (FFA) concentration and improved blood glucose regulation. However, it was not yet known to what extent heterozygous albumin knockout (Alb+/−) mice would display a similar phenotype. Alb−/−, Alb+/−, and wild-type (WT) female mice were studied on a low-fat diet (LFD) or high-fat diet (HFD). On both diets, decreased plasma FFA concentration, and improved glucose tolerance test were observed in Alb−/−, but not in Alb+/−, compared to WT. Plasma adiponectin concentration showed greater elevation in Alb−/− than Alb+/−. Consistent with that, adiponectin gene expression was significantly higher in Alb−/− mice than in Alb+/− and WT mice. A dose-dependent response was observed for hepatic Acadl gene expression showing higher Acadl gene expression in Alb−/− mice than in Alb+/− and WT mice. In conclusion, although female Alb+/− mice exhibited some slight differences from WT mice (e.g., increased plasma adiponectin and hepatic Acadl gene expression), Alb+/− mice did not exhibit improved glucoregulation in comparison to WT mice, indicating that a minor suppression of albumin expression is not sufficient to improve glucoregulation. Furthermore, it is now clear that although the response of female mice to HFD might be unique from how males generally respond, still the complete albumin deficiency in Alb−/− mice and the associated FFA reduction is capable of improving glucoregulation in females on this diet. The present results have implications for the role of albumin and FFA in the regulation of metabolism.

Effects of Exhaustive Exercise on Adiponectin and High-Molecular-Weight Oligomer Levels in Male Amateur Athletes.

Physical activity promotes metabolic health and prevents lifestyle-related diseases. Adiponectin is specifically produced by adipose tissue and comes in three forms, differing in terms of weight: trimers (LMW), hexamers (MMW), and high-molecular-weight (HMW) oligomers. The oligomers are associated with the beneficial effects of adiponectin. In this study, we aimed to investigate the impact of a single bout of exhaustive exercise on adiponectin expression in 25 male amateur athletes, divided into two groups, one comprising young adults (YAs) (n = 15), and the other comprising middle-aged adults (MAs) (n = 10). Body fat was estimated through skinfold thickness. Adiponectin levels were assessed at baseline and at 15 min and 24 h post-exercise, while HMW oligomer levels were evaluated at baseline and at 24 h post-exercise. We observed a significant increase in total adiponectin at both 15 min and 24 h after exercise, with there being a more evident effect among the YA subjects. HMW oligomers also increased significantly after exercise both in the total sample and among the YA subjects, but this was not the case in the MA subjects. The increase in adiponectin levels was significantly associated with Powerpeak. Furthermore, a significant inverse correlation was found between basal adiponectin and VO2peak and Powerpeak. In conclusion, a single bout of exhaustive exercise can rapidly and significantly enhance the basal circulating adiponectin concentration, which seems to be negatively associated with maximal aerobic capacity.

Testosterone with Silymarin Improves Diabetes-obesity Comorbidity Complications by Modulating Inflammatory Responses and CYP7A1/ACC Gene Expressions in Rats.

The co-morbidity of DMOB has become increasingly problematic among the world's population because of a high-calorie diet and sedentary lifestyle. DMOB is associated with lower testosterone (TN) levels, the male sex hormone. The phytochemical compound silymarin (SN) exerts antidiabetic activity by modifying β-cells and anti-obesity activity by inhibiting adipogenesis by methylxanthine. The goal of this study was to find out how well testosterone (TN) with silymarin (SN) protects against oxidative stress and inflammation in the liver of the experimental rats with type 2 diabetes (T2D) and obesity (DMOB). The present study evaluates the efficacy of TN and SN combination (TNSN) on the levels of the potential parameters, such as body mass, serum marker enzymes, fasting glucose levels, HbA1c levels, lipid profile, enzymatic and non-enzymatic antioxidants, proinflammatory cytokines, gene expression pathways, and histopathology in a DMOB comorbidity rat model. Male Sprague-Dawley (SD) rats were fed a high-fat diet (HFD) for 20 weeks with an administration of a single dose of streptozotocin (STZ) i.p. injection (30 mg/kg) on the 9th week of the study. The procedure was to develop the DMOB co-morbidity model in the experimental animals. Co-treatment of TN and SN administration were followed throughout the experiment. Rats were sacrificed after overnight fasting to collect serum and liver tissue samples. Samples were analyzed using a clinical chemistry automated analyzer, spectrophotometry, and quantitative real-time PCR (qPCR) methods and protocols. Analyses of body mass changes, serum marker enzymes, fasting glucose levels, HbA1c levels, lipid profiles, enzymatic and non-enzymatic antioxidants, TNF-α, IL-6, adiponectin, CYP7A1, ACC expression pathways, and histopathology showed significant abnormal levels (P ≤ 0.05) in the pathological group. These were efficiently treated to normal by the administration of TNSN. These results concluded that TNSN exerted protective efficacy against the liver abnormalities in the co-morbidity of the DMOB rat model.

Improved ovarian adiponectin system expression in polycystic ovary syndrome treated with exenatide.

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder that can cause infertility. This experimental study was conducted to elucidate the role of adiponectin signaling in rats with PCOS treated with exenatide. Twenty-eight adult female Wistar rats were divided into four groups of seven. The normal group did not receive any drug. The PCOS+vehicle (Veh) group received estradiol valerate to induce PCOS, then was divided into PCOS +E50 and PCOS+E100 groups and treated with 50 or 100 mg/kg doses of exenatide, respectively. The mRNA expression of adiponectin and adiponectin receptor 1 (Adipo-R1) was evaluated using a semi-quantitative real-time polymerase chain reaction. The results indicated that the level of adiponectin diminished in the PCOS rats while exenatide increased adiponectin expression at both doses. Adiponectin receptor mRNA levels were higher in the PCOS rats than in the normal rats (p<0.05). In addition, exenatide decreased the levels of Adipo-R1 expression. Taken together, our results showed that exenatide may improve PCOS characteristics in rats through the molecular regulation of adiponectin and its receptor.

Adiponectin Prevents Skin Inflammation in Rosacea by Suppressing S6 Phosphorylation in Keratinocytes

Numerous recent evidence highlights epidemiological connections between rosacea and metabolic disorders. However, the precise path through which metabolic factors impact rosacea risk is still unclear. Therefore, this study aims to investigate the role of adiponectin, a crucial adipokine that regulates metabolic homeostasis, in the pathogenesis of rosacea. We elucidated a detrimental feedback loop between rosacea-like skin inflammation and decreased levels of skin adiponectin. To elaborate, rosacea lesional skin exhibits diminished adiponectin expression compared to non-lesional areas in the same patients. Induction of rosacea-like inflammation reduced adiponectin levels in the skin by generating inflammatory cytokines that suppress adiponectin production from subcutaneous adipocytes. Conversely, complete depletion of adiponectin exacerbated rosacea-like features in the mouse model. Mechanistically, adiponectin deficiency led to heightened S6 phosphorylation, a marker of the mTORC1 signaling pathway, in the epidermis. Adiponectin significantly inhibited S6 phosphorylation in cultured keratinocytes. Notably, replenishing adiponectin whole protein or topically applying an agonist for adiponectin receptor 1 successfully improved rosacea-like features in mice. This study contributes to understanding the role of adiponectin in skin inflammation associated with rosacea pathophysiology, suggesting that restoring adiponectin function in the skin could be a potential therapeutic strategy.

Renal denervation alleviates vascular remodeling in spontaneously hypertensive rats by regulating perivascular adipose tissue.

Vascular remodeling is the main pathological process that causes the damage of the target organ of hypertension. Perivascular adipose tissue (PVAT) surrounds blood vessels and plays a key role in the pathogenesis of various cardiovascular diseases. This study aimed to investigate the effects of renal denervation (RDN) on hypertensive vascular remodeling and to elucidate the role of PVAT in this process. Male spontaneously hypertensive rat (SHR) and Wistar-Kyoto (WKY) rat were selected. Aortic vascular remodeling was evaluated using hematoxylin and eosin (H&E) staining and Masson's trichrome staining. Morphological changes in the PVAT were observed through H&E and Oil Red O staining. Dihydroethidium was used to measure oxidative stress levels in PVAT, while western blot analysis was used to determine the expression levels of proteins associated with vascular remodeling. The results showed that the aortic medial thickness, media thickness/lumen diameter, collagen volume fraction, and reactive oxygen species (ROS) level in PVAT were significantly higher in the SHR group than in the WKY group. The indexes mentioned above were lower in the SHR-RDN group than in the SHR group. H&E staining revealed that fat droplets in PVAT in the SHR-RDN group became smaller and browning occurred. Moreover, the protein expression of uncoupling protein-1 (UCP-1) and neuregulin 4 (Nrg4) was significantly increased in the SHR-RDN group. In addition, the expression of adiponectin increased and the expression of leptin decreased in the SHR-RDN group compared to the SHR group. In conclusion, RDN can relieve hypertensive vascular remodeling, which may be associated with PVAT.

Effect of tannic acid on adiponectin and gonads in male Brandt’s voles (Lasiopodomys brandtii)

Adiponectin regulates steroid production and influences gonadal development. This study examined the effects of tannic acid (TA) on the adiponectin levels and gonads of male Brandt’s voles. Male Brandt’s voles aged 90 d were randomly separated into three groups: a control group (provided distilled water), a group given 600 mg∙kg-1 TA, and a group that received 1200 mg∙kg-1 TA (continuous gavage for 18 d). In this study, we examined the effects of TA on the adiponectin, antioxidant, and inflammatory levels in the testes. Furthermore, we examined the expression of important regulatory elements that influence adiponectin expression and glucose utilisation. In addition, the body weight, reproductive organ weight, and testicular shape were assessed. Our study observed that TA treatment increased serum adiponectin levels, DsbA-L and Ero1-Lα transcription levels, and AdipoR1, AMPK, GLUT1, and MCT4 expression levels in testicular tissue. TA enhanced pyruvate and lactic acid levels in the testicular tissue, boosted catalase activity, and reduced MDA concentrations. TA reduced the release of inflammatory factors in the testicular tissues of male Brandt’s voles. TA increased the inner diameter of the seminiferous tubules. In conclusion, TA appears to stimulate adiponectin secretion and gonadal growth in male Brandt’s voles while acting as an antioxidant and anti-inflammatory agent.

Regional adiposity and insulin sensitivity - interactions with menopause and HIV in middle-aged Black African women.

To explore depot-specific functional aspects of adipose tissue, examining the putative role for menopause and HIV status on insulin sensitivity (SI) and beta-cell function in Black South African women. Women (n = 92) from the Middle-Aged Soweto Cohort, including premenopausal HIV-negative (n = 21); premenopausal women living with HIV (WLWH; n = 11); postmenopausal HIV-negative (n = 42); postmenopausal WLWH (n = 18) underwent the following tests: body composition (dual energy x-ray absorptiometry); fasting bloods for sex hormones, inflammation and adipokines; frequently sampled intravenous glucose tolerance test for SI and beta-cell function (disposition index, DI); abdominal (aSAT) and gluteal subcutaneous adipose tissue (gSAT) biopsies for cell size and mRNA expression of adipokines, inflammation, and estrogen receptors [ER]. Depot-specific associations between gene expression and insulin parameters did not differ by HIV or menopause status. Pooled analysis showed significant models for SI (P = 0.002) and DI (P = 0.003). Higher SI was associated with lower leptin and CD11c expression in aSAT and higher adiponectin in gSAT. Higher DI was associated with higher aSAT and gSAT expression of adiponectin, LPL, ERα, and PPARγ, and lower leptin in aSAT. WLWH had higher expression of adiponectin and lower expression of leptin in both aSAT (P = 0.002 and P = 0.005) and gSAT (P = 0.004 and P = 0.002), respectively, and a larger proportion of smaller cells in aSAT (P < 0.001). Insulin sensitivity and beta cell function were distinctively associated with aSAT and gSAT. While menopause did not influence these relationships, HIV had a significant effect on adipose tissue, characterised by variations in cell size distribution and transcript levels within the depots.

Novel role of Quercetin in ameliorating metabolic syndrome via VDR mediated activation of adiponectin/AdipoR2 signaling

A sedentary lifestyle and physical inactivity leads to metabolic syndrome-associated comorbidities involving abdominal obesity, type 2 diabetes, hyperlipidaemia associated Cardiovascular Diseases (CVDs), and Metabolic dysfunction-associated fatty liver disease (MAFLD). In this study, we evaluated the novel hepato/cardio/adipo-protective role of Quercetin via Vitamin D Receptor, and elucidated its underlying mechanisms in reducing lipotoxicity, inflammation and fibrosis in high calorie diet induced metabolic syndrome. Male Swiss albino mice were fed with western diet and sugar water for multiple time intervals. Anti-lipotoxicity, anti-inflammatory, and anti-fibrotic effect of Quercetin was assessed by Oil Red O, H&E and TMS staining at different time points. The lipid profile, mRNA expression of inflammatory markers (TNF- α, IL-1β, IL-6 and MCP-1), fibrotic markers (α-SMA, COL1A1, COL1A2), adiponectin, AdipoR2, and VDR expression levels were measured from RNA pools of adipose, liver and heart tissues. Also, lipid-lowering and anti-steatohepatitic effects of Quercetin was assessed using mouse 3T3-L1 adipocytes, rat H9c2 cardiac cells, and human HepG2 hepatocytes. Our results indicate that, western diet fed mice with Quercetin ameliorated lipid profile and lipotoxicity. Histopathological examination and gene expression data revealed that Quercetin reduced hepatic and cardiac inflammation and fibrosis-associated markers. Interestingly, Quercetin treatment increased the serum levels of adiponectin and mRNA expressions of AdipoR2 and VDR. In-vitro experiments revealed the reduction in lipid accumulation of 3T3-L1 and fatty-acid-treated hepatic and cardiac cells following Quercetin treatment. These findings indicate that Quercetin exhibits a protective role on multiple organs through VDR activation and subsequent Adipo/AdipoR2 signaling in metabolic syndrome associated obesity, hepatic injury, and cardiac dysfunction.

AdipoRon, an adiponectin receptor agonist, modulates AMPK signaling pathway and alleviates ovalbumin-induced airway inflammation in a murine model of asthma

Asthma is a long-term disease that causes airways swelling and inflammation and in turn airway narrowing. AdipoRonis an orally active synthetic small molecule that acts as a selective agonist at theadiponectin receptor 1 and 2. The aim of the current study is to delineate the protective effect and the potential underlying mechanism ofadipoRon inairway inflammationinduced byovalbumin (OVA) in comparison withdexamethasone. Adult maleSwiss Albino micewere sensitized to OVA on days 0 and 7, then challenged with OVA on days 14, 15 and 16. AdipoRon was administered orally for 6 days starting from the 11th day till the 16th and 1 h prior to OVA in the challenge days. Obtained results from asthmatic control group showed a significant decrease in serum adiponectin concentration, an increase in inflammatory cell counts inthe bronchoalveolar lavage fluid(BALF), CD68 protein expression, inflammatory cytokine concentration and oxidative stress as well. Administration of adipoRon enhanced antioxidant mechanisms limiting oxidative stress by significantly increasing reduced glutathione (GSH) pulmonary content, decreasing serum lactate dehydrogenase (LDH) together with malondialdehyde (MDA) significant reduction in lung tissue. In addition, it modulated the levels of serum immunoglobulin E (IgE), pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-13, nuclear factor kappa B (NF-κB) and the anti-inflammatory one IL-10 improving lung inflammation as revealed by histopathological evaluation. Furthermore, lung tissue expression of nuclear factor erythroid 2-related factor (Nrf2) and 5′AMP-activated protein kinase (AMPK) were significantly increased adipoRon. Notably, results of adipoRon received group were comparable to those of dexamethasone group. In conclusion, our study demonstrates that adipoRon can positively modulate adiponectin expression with activation of AMPK pathway and subsequent improvement in inflammatory and oxidative signaling.

Competing endogenous RNA networks were associated with fat accumulation in skeletal muscle of aged male mice

Muscle aging contributed to morbidity and mortality in the elderly adults by leading to severe outcomes such as frailty, falls and fractures. Post-transcriptional regulation especially competing endogenous RNA (ceRNA) mechanism may modulate the process of skeletal muscle aging. RNA-seq was performed in quadriceps of 6-month-old (adult) and 22-month-old (aged) male mice to identify differentially expressed ncRNAs and mRNAs and further construct ceRNA networks. Decreased quadriceps-body weight ratio and muscle fiber cross-sectional area as well as histological characteristics of aging were observed in the aged mice. Besides, there were higher expressions of atrogin-1 and MuRF-1 and lower expression of Myog, Myf4 and Myod1 in the quadriceps of aged mice relative to that of adult mice. The expression of 85 lncRNAs, 52 circRNAs, 10 miRNAs and 277 mRNAs were significantly dysregulated in quadriceps between the two groups, among which two ceRNA networks lncRNA 2700081O15Rik/circRNA_0000820-miR-673–3p-Tmem120b were constructed. Level of triglycerides and expression of PPARγ, C/EBPα, FASN and leptin were elevated and the expression of adiponectin was reduced in quadriceps of aged mice compared with that of adult mice. LncRNA 2700081O15Rik/circRNA_0000820-miR-673–3p-Tmem120b were possibly associated with the adipogenesis and fat accumulation in skeletal muscle of age male mice.

Norisoboldine, a Natural Alkaloid from Lindera aggregata (Sims) Kosterm, Promotes Osteogenic Differentiation via S6K1 Signaling Pathway and Prevents Bone Loss in OVX Mice.

Norisoboldine (NOR) is a major isoquinoline alkaloid component in the traditional Chinese herbal plant Lindera aggregata (Sims) Kosterm, with previously reported anti-osteoclast differentiation and antiarthritis properties. However, the roles of NOR on osteoblasts, bone marrow mesenchymal stem cells (BMSCs), and osteoporosis in vivo have never been well established. This study investigates the ability of NOR to improve bone formation in vitro and in vivo. Osteoblasts and BMSCs are used to study the effect of NOR on osteogenic and adipogenic differentiation. It finds that NOR promotes osteogenic differentiation of osteoblasts and BMSCs, while inhibiting adipogenic differentiation of BMSCs by reducing the relative expression of peroxisome proliferator-activated receptorγ (Ppar-γ) and adiponectin, C1Q and collagen domain containing (Adipoq). Mechanistic studies show that NOR increases osteoblast differentiation through the mechanistic target of rapamycin kinase (mTOR)/ribosomal protein S6 kinase; polypeptide 1 (S6K1) pathway, and treatment with an mTOR inhibitor rapamycin blocked the NOR-induced increase in mineral accumulation. Finally, the study evaluates the therapeutic potential of NOR in a mouse model of ovariectomy (OVX)-induced bone loss. NOR prevents bone loss in both trabecular and cortical bone by increasing osteoblast number and phospho-S6K1 (p-S6K1) expression in osteoblasts. NOR effects in enhancing osteoblast-induced bone formation via S6K1 pathway, suggesting the potential of NOR in osteoporosis treatment by increasing bone formation.

Dietary Supplementation with Naringin Improves Systemic Metabolic Status and Alleviates Oxidative Stress in Transition Cows via Modulating Adipose Tissue Function: A Lipid Perspective.

Dairy cows face metabolic challenges around the time of calving, leading to a negative energy balance and various postpartum health issues. Adipose tissue is crucial for cows during this period, as it regulates energy metabolism and supports immune function. Naringin, one of the main flavonoids in citrus fruit and their byproducts, is a potent antioxidant and anti-inflammatory phytoconstituent. The study aimed to evaluate the effects of supplemental naringin on performance, systemic inflammation, oxidative status, and adipose tissue metabolic status. A total of 36 multiparous Holstein cows (from ~21 d prepartum through 35 d postpartum) were provided a basal control (CON) diet or a CON diet containing naringin (NAR) at 30 g/d per cow. Supplemental NAR increased the yield of raw milk and milk protein, without affecting dry matter intake. Cows fed NAR showed significantly lower levels (p < 0.05) of serum non-esterified fatty acid (NEFA), C-reactive protein, IL-1β, IL-6, malonaldehyde, lipopolysaccharide (LPS), aspartate aminotransferase, and alanine aminotransferase, but increased (p < 0.05) glutathione peroxidase activity relative to those fed CON. Supplemental NAR increased (p < 0.05) adipose tissue adiponectin abundance, decreased inflammatory responses, and reduced oxidative stress. Lipidomic analysis showed that cows fed NAR had lower concentrations of ceramide species (p < 0.05) in the serum and adipose tissue than did the CON-fed cows. Adipose tissue proteomics showed that proteins related to lipolysis, ceramide biosynthesis, inflammation, and heat stress were downregulated (p < 0.05), while those related to glycerophospholipid biosynthesis and the extracellular matrix were upregulated (p < 0.05). Feeding NAR to cows may reduce the accumulation of ceramide by lowering serum levels of NEFA and LPS and increasing adiponectin expression, thereby decreasing inflammation and oxidative stress in adipose tissue, ultimately improving their systemic metabolic status. Including NAR in periparturient cows' diets improves lactational performance, reduces excessive lipolysis in adipose tissue, and decreases systemic and adipose tissue inflammation and oxidative stress. Integrating lipidomic and proteomic data revealed that reduced ceramide and increased glycerophospholipids may alleviate metabolic dysregulations in adipose tissue, which in turn benefits systemic metabolic status.