Search Results (14)

Peri- and postmenopausal women often experience unexplained weight gain despite maintaining consistent dietary and lifestyle habits. While the biological mechanisms underlying this phenomenon remain poorly understood, physiological and pathophysiological changes during the menopausal transition are likely contributors. Proteomic profiling holds potential for revealing key molecular pathways involved in the pathogenesis of obesity in this population. This review synthesizes current evidence on proteomic alterations linked to overweight and obesity in peri- and postmenopausal women. A structured literature search was performed across Ovid MEDLINE^®, EMBASE, the Cochrane Library, and Scopus for studies published between October 2010 and March 2025. Eligible studies included original research involving overweight or obese peri- or postmenopausal women that reported proteomic data. Extracted information encompassed study design, participant characteristics, sample types, and proteomic findings. Identified proteins were cross-referenced with a prior review of consistently dysregulated proteins in obesity. Five studies met the inclusion criteria, collectively revealing consistent proteomic patterns associated with inflammation, metabolic dysfunction, and endothelial dysregulation. These included C-reactive protein, Tissue necrotic factor-alpha, interleukins, adiponectin, and endocan. Notably, one study demonstrated that weight loss led to reductions in IL-6, IL-1 receptor antagonist, and CRP, suggesting that obesity-related inflammation may be at least partially reversible. This review provides preliminary evidence linking chronic inflammation, metabolic dysregulation, and vascular stress to obesity in peri- and postmenopausal women. These proteomic signatures enhance understanding of menopausal weight gain and highlight the potential of proteomics to guide personalized interventions. However, larger, well-designed prospective studies are needed to confirm these associations and clarify causal pathways. Full article

Background/Objectives: Previous studies have shown that adiponectin deficiency or blocking adiponectin receptors (AdipoRs) in the brain can lead to an Alzheimer’s disease (AD)-like neuropathology. While AdipoRs are abundantly expressed in peripheral tissues, the effects of blocking these receptors in the peripheral tissues on the brain are unclear. This study investigates the impacts of blocking AdipoRs with a peripheral administration of ADP400, an antagonist peptide that targets AdipoRs on cognitive performance, hippocampal adult neurogenesis, and AD-like neuropathology in mice. Methods: Adult mice were intraperitoneally administered with ADP400 peptide that blocks peripheral AdipoRs continuously for 21 days, followed by a battery of behavioral test for mood and memory performance. Results: ADP400-treated mice exhibited impaired memory performance and increased anxiety-like behaviors. Molecular analyses revealed heightened hyperphosphorylation of tau and increased β-amyloid levels, alongside decreased expression of AdipoRs and PP2A in the hippocampus, suggesting a critical role of AdipoRs in AD-like neuropathology. Furthermore, ADP400 treatment significantly reduced hippocampal adult neurogenesis, as indicated by decreased BrdU, Ki67, and DCX staining. Inhibiting peripheral adiponectin receptors could lead to tau hyperphosphorylation and accumulated β-amyloid levels. Conclusions: These findings highlight the critical role of peripheral manipulation of adiponectin receptors in modulating cognitive function and adult neurogenesis, offering insights into potential therapeutic strategies for AD and related cognitive disorders. Full article

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. Full article

Obesity is associated with chronic inflammation that may contribute to T2D among youth. We examined the association between inflammatory biomarkers and insulin sensitivity and β-cell function and response to lifestyle intervention among Latino youth with obesity. Latino youth (n = 64) were randomized to six months of lifestyle intervention (INT, n = 40) or usual care (UC, n = 24). INT included nutrition education and physical activity. UC involved meeting with a pediatric endocrinologist and registered dietitian to discuss healthy lifestyles. At baseline, multiple linear regression assessed fasting serum interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), high-molecular weight adiponectin (HMW Adpn), IL-10, IL-1 receptor antagonist (IL-1ra) as predictors of insulin sensitivity (whole-body insulin sensitivity index, WBISI) and β-cell function (oral disposition index, oDI). Changes in outcomes between groups were assessed using covariance pattern models. At baseline, MCP-1 (β ± SE, −0.12 ± 0.05, p = 0.027) and IL-1ra (−0.03 ± 0.01, p = 0.005) were negatively associated with WBISI. Treatment effects were not observed for inflammatory markers. WBISI was significantly increased among both INT (from 1.8 ± 0.2 to 2.6 ± 0.4, p = 0.005) and UC (from 1.6 ± 0.2 to 2.8 ± 0.5, p = 0.002) with no significant differences between the groups. Obesity-related inflammatory mediators were associated with T2D risk factors but were unaffected by lifestyle intervention among Latino youth. Full article

Adiponectin, a key metabolic hormone, is secreted into the circulation by fat cells where it enhances insulin sensitivity and stimulates glucose and fatty acid metabolism. Adiponectin receptors are highly expressed in the taste system; however, their effects and mechanisms of action in the modulation of gustatory function remain unclear. We utilized an immortalized human fungiform taste cell line (HuFF) to investigate the effect of AdipoRon, an adiponectin receptor agonist, on fatty acid-induced calcium responses. We showed that the fat taste receptors (CD36 and GPR120) and taste signaling molecules (Gα-gust, PLCβ2, and TRPM5) were expressed in HuFF cells. Calcium imaging studies showed that linoleic acid induced a dose-dependent calcium response in HuFF cells, and it was significantly reduced by the antagonists of CD36, GPR120, PLCβ2, and TRPM5. AdipoRon administration enhanced HuFF cell responses to fatty acids but not to a mixture of sweet, bitter, and umami tastants. This enhancement was inhibited by an irreversible CD36 antagonist and by an AMPK inhibitor but was not affected by a GPR120 antagonist. AdipoRon increased the phosphorylation of AMPK and the translocation of CD36 to the cell surface, which was eliminated by blocking AMPK. These results indicate that AdipoRon acts to increase cell surface CD36 in HuFF cells to selectively enhance their responses to fatty acids. This, in turn, is consistent with the ability of adiponectin receptor activity to alter taste cues associated with dietary fat intake. Full article

Decompensated liver cirrhosis is often complicated by refractory ascites, and intractable ascites are a predictor of poor prognosis in patients with liver cirrhosis. The treatment of ascites in patients with cirrhosis is based on the use of aldosterone blockers and loop diuretics, and occasionally vasopressin receptor antagonists are also used. Recent reports suggest that sodium–glucose cotransporter 2 (SGLT2) inhibitors may be a new treatment for refractory ascites with a different mechanism with respect to conventional agents. The main mechanisms of ascites reduction with SGLT2 inhibitors appear to be natriuresis and osmotic diuresis. However, other mechanisms, including improvements in glucose metabolism and nutritional status, hepatoprotection by ketone bodies and adiponectin, amelioration of the sympathetic nervous system, and inhibition of the renin–angiotensin–aldosterone system, may also contribute to the reduction of ascites. This literature review describes previously reported cases in which SGLT2 inhibitors were used to effectively treat ascites caused by liver cirrhosis. The discussion of the mechanisms involved is expected to contribute to establishing SGLT2 therapy for ascites in the future. Full article

It is estimated that in patients taking antipsychotic drugs (APDs), metabolic syndrome occurs 2–3 times more often than in the general population. It manifests itself in abdominal obesity, elevated glucose concentration, and dyslipidemia. Despite the high prevalence of this disorder, only a small percentage of patients receive appropriate and effective treatment, and none of the available methods for preventing or treating APD-induced metabolic side effects is satisfactory. A promising supplement to antipsychotic therapy appears to be ligands of the serotonin 6 (5-HT₆) receptor. The present study aimed to examine the chronic effects of the selected APDs (haloperidol, risperidone, olanzapine), administered alone and in combination with a selective 5-HT₆ agonist (WAY-181187) or antagonist (SB-742457), on weight gain, food intake, serum lipid profile, glucose level, and a spectrum of hormones derived from adipose (leptin, adiponectin) and gastrointestinal (insulin, ghrelin) tissue in rats. SB-742457 inhibited increased weight gain and alleviated hyperglycemia induced by APDs more strongly than did WAY-181187, but also intensified dyslipidemia. WAY-181187 tended to improve the lipid profile, but increased the glucose level. The greatest benefits were obtained when WAY-181187 or SB-742457 were co-administered with haloperidol. It is difficult to assess whether the modification of the serum levels of insulin, leptin, ghrelin, and adiponectin depended on the treatment applied or other drug-independent factors; therefore, further research is needed. Full article

Diet-induced obesity (DIO) reduces fatty acid oxidation in skeletal muscle and decreases circulating levels of adiponectin. Endocannabinoid signaling is overactive in obesity, with some effects abated by antagonism of cannabinoid receptor 1 (CB₁). This research aimed to determine if treatment with the global CB₁ antagonist/inverse agonist, AM251, in high-fat diet (HFD) fed rats influenced adiponectin signaling in skeletal muscle and a “browning” of white adipose tissue (WAT) defined by UCP1 expression levels. Male Sprague Dawley rats consumed an HFD (21% fat) for 9 weeks before receiving daily intraperitoneal injections with vehicle or AM251 (3 mg/kg) for 6 weeks. mRNA expression of genes involved in metabolic functions were measured in skeletal muscle and adipose tissue, and blood was harvested for the measurement of hormones and cytokines. Muscle citrate synthase activity was also measured. AM251 treatment decreased fat pad weight (epididymal, peri-renal, brown), and plasma levels of leptin, glucagon, ghrelin, and GLP-1, and increased PAI-1 along with a range of pro-inflammatory and anti-inflammatory cytokines; however, AM251 did not alter plasma adiponectin levels, skeletal muscle citrate synthase activity or mRNA expression of the genes measured in muscle. AM251 treatment had no effect on white fat UCP1 expression levels. AM251 decreased fat pad mass, altered plasma hormone levels, but did not induce browning of WAT defined by UCP1 mRNA levels or alter gene expression in muscle treated acutely with adiponectin, demonstrating the complexity of the endocannabinoid system and metabolism. The CB₁ ligand AM251 increased systemic inflammation suggesting limitations on its use in metabolic disorders. Full article

Noting the worldwide rapid increase in the prevalence of overweight and obesity new effective drugs are now being sought to combat these diseases. Histamine H₃ receptor antagonists may represent an effective therapy as they have been shown to modulate histamine synthesis and release and affect a number of other neurotransmitters (norepinephrine, acetylcholine, γ-aminobutyric acid, serotonin, substance P) thus influencing the food intake. Based on the preliminary studies determining affinity, intrinsic activity, and selected pharmacokinetic parameters, two histamine H₃ receptor ligands were selected. Female rats were fed palatable food for 28 days and simultaneously administered the tested compounds intraperitoneally (i.p.) at a dose of 10 or 1 mg/kg b.w./day. Weight was evaluated daily and calorie intake was evaluated once per week. The plasma levels of cholesterol, triglycerides, leptin, adiponectin, ghrelin, corticosterone, CRP and IL-6 were determined at the end of experiment. The glucose tolerance test was also performed. To exclude false positives, the effect of tested compounds on spontaneous activity was monitored during the treatment, as well as the amount of consumed kaolin clay was studied as a reflection of possible gastrointestinal disturbances comparable to nausea. The histamine H₃ receptor antagonists KSK-59 and KSK-73 administered i.p. at a dose of 10 mg/kg b.w. prevented weight gain in a rat model of excessive eating. They reduced adipose tissue deposits and improved glucose tolerance. Both compounds showed satisfying ability to penetrate through biological membranes determined in in vitro studies. Compound KSK-73 also reduced the caloric intake of the experimental animals what indicates its anorectic effect. These results show the pharmacological properties of histamine H₃ receptor antagonists, (4-pyridyl)piperazine derivatives, as the compounds causing not only slower weight gain but also ameliorating some metabolic disorders in rats having the opportunity to overeat. Full article

Glucocorticoids (GCs), a class of corticosteroids produced by the adrenal cortex in response to stress, exert obesity-promoting effects. Although adaptive thermogenesis has been considered an effective approach to counteract obesity, whether GCs play a role in regulating cold stress-induced thermogenesis remains incompletely understood. Here, we show that the circulating levels of stress hormone corticosterone (GC in rodents) were significantly elevated, whereas the levels of adiponectin, an adipokine that was linked to cold-induced adaptive thermogenesis, were decreased 48 h post cold exposure. The administration of a glucocorticoid hydrocortisone downregulated adiponectin protein and mRNA levels in both WAT and white adipocytes, and upregulated thermogenic gene expression in inguinal fat. In contrast, mifepristone, a glucocorticoid receptor antagonist, enhanced adiponectin expression and suppressed energy expenditure in vivo. Mechanistically, hydrocortisone suppressed adiponectin expression by antagonizing PPARγ in differentiated 3T3-L1 adipocytes. Ultimately, adiponectin deficiency restored mifepristone-decreased oxygen consumption and suppressed the expression of thermogenic genes in inguinal fat. Taken together, our study reveals that the GCs/adiponectin axis is a key regulator of beige fat thermogenesis in response to acute cold stress. Full article

Obesity is a worldwide chronic metabolic disease characterized by an abnormal fat accumulation and represents one of the main risk factors for several diseases. White adipose tissue is the primary site for energy storage in the form of triglycerides, whereas brown adipose tissue does not store energy-providing lipids but rather dissipates it by producing heat. White-to-brown adipocyte trans-differentiation could represent a new target of anti-obesity strategies and result in fat reduction. Previous studies indicated that adenosine receptor activation induces trans-differentiation of white adipocytes to brown adipocytes. The aim of this study was to evaluate the effects of polydeoxyribonucleotide (PDRN), an A_2Ar receptor agonist, in an in vitro model of browning. Mouse 3T3-L1 pre-adipocytes were differentiated in mature adipocytes with specific culture media and then treated with PDRN (10 µg/mL), PDRN + ZM241385 (1 µM), CGS21680 (1 µM) and CGS + ZM241385 for 24 h. Cell viability was studied by MTT assay, and browning induction was evaluated by Oil Red O staining and by RT-qPCR to study gene expression of browning markers. PDRN, as well as CGS21680, reduced the accumulation of lipids, cell volume and lipid droplet size; increased the expression of UCP1, PRDM16 and DIO2, considered as browning markers; and reduced the expression of FASn and FABP4, considered as whitening markers. In addition, PDRN decreased leptin expression and enhanced adiponectin mRNA levels. All these effects were abrogated when PDRN was co-incubated with the A_2Ar antagonist ZM241385. In conclusion, these results suggest that PDRN is able to induce the white-to-brown adipose differentiation through A_2Ar stimulation. Since PDRN is a safe drug already available in the market for other therapeutic indications, its “anti-obesity” potential warrants investigation in a clinical scenario. Full article

Hyperglycemia linked to diabetes results in endothelial dysfunction. In the present work, we comprehensively characterized effects of short-term hyperglycemia induced by administration of an insulin receptor antagonist, the S961 peptide, on endothelium and perivascular adipose tissue (PVAT) in mice. Endothelial function of the thoracic and abdominal aorta in 12-week-old male C57Bl/6Jrj mice treated for two weeks with S961 infusion via osmotic pumps was assessed in vivo using magnetic resonance imaging and ex vivo by detection of nitric oxide (NO) production using electron paramagnetic resonance spectroscopy. Additional methods were used to analyze PVAT, aortic segments and endothelial-specific plasma biomarkers. Systemic disruption of insulin signaling resulted in severe impairment of NO-dependent endothelial function and a loss of vasoprotective function of PVAT affecting the thoracic as well as abdominal parts of the aorta, however a fall in adiponectin expression and decreased uncoupling protein 1-positive area were more pronounced in the thoracic aorta. Results suggest that dysfunctional PVAT contributes to vascular pathology induced by altered insulin signaling in diabetes, in the absence of fat overload and obesity. Full article

Background and Objectives: Insulin resistance (IR) is a serious condition leading to development of diabetes and cardiovascular complications. Hyper-activation of cannabinoid receptors-1 (CB1) has been linked to the development of metabolic disorders such as IR. Therefore, the effect of blocking CB1 on the development of IR was investigated in the present study. Materials and Methods: A 12-week high-fructose/high-salt feeding model of metabolic syndrome was used to induce IR in male Wistar rats. For this purpose, two different CB1-antagonists were synthesized and administered to the rats during the final four weeks of the study, AM6545, the peripheral neutral antagonist and AM4113, the central neutral antagonist. Results: High-fructose/salt feeding for 12 weeks led to development of IR while both AM6545 and AM4113, administered in the last 4 weeks, significantly inhibited IR. This was correlated with increased animal body weight wherein both AM6545 and AM4113 decreased body weight in IR animals but with loss of IR/body weight correlation. While IR animals showed significant elevations in serum cholesterol and triglycerides with no direct correlation with IR, both AM6545 and AM4113 inhibited these elevations, with direct IR/cholesterol correlation in case of AM6545. IR animals had elevated serum uric acid, which was reduced by both AM6545 and AM4113. In addition, IR animals had decreased adiponectin levels and elevated liver TNFα content with strong IR/adiponectin and IR/TNFα correlations. AM6545 inhibited the decreased adiponectin and the increased TNFα levels and retained the strong IR/adiponectin correlation. However, AM4113 inhibited the decreased adiponectin and the increased TNFα levels, but with loss of IR/adiponectin and IR/TNFα correlations. Conclusions: Both CB1 neutral antagonists alleviated IR peripherally, and exerted similar effects on rats with metabolic syndrome. They also displayed anti-dyslipidemic, anti-hyperurecemic and anti-inflammatory effects. Overall, these results should assist in the development of CB1 neutral antagonists with improved safety profiles for managing metabolic disorders. Full article

The increased number of patients with type 2 diabetes (T2D) has become a worldwide problem, and insulin sensitizers such as thiazolidinediones (TZDs) are used as therapeutic agents. We found that extracts of Vitex trifolia L. (V. trifolia), a medicinal plant from Myanmar, induced adipogenesis similar to rosiglitazone (ROS), which is a TZD, in 3T3-L1 preadipocytes. In the present study, we attempted to isolate from V. trifolia those compounds that showed ROS-like effects. Among the extracts of hexane, ethyl acetate, and methanol obtained from V. trifolia, the ethyl acetate extract with the strongest ROS-like effects was purified by various chromatographic methods to obtain three known compounds: vitexilactone (1), vitexicarpin (2) and oleanolic acid (3). Among the isolated compounds, the ROS-like action of 1 was the strongest. The effects of 1 on 3T3-L1 cells during adipogenesis were compared with those of ROS. Both 1 and ROS increased lipid accumulation, the expression of adiponectin and GLUT4 in the cell membrane and decreased both the size of adipocytes and the phosphorylation of IRS-1, ERK1/2 and JNK in 3T3-L1 cells. In contrast, unlike ROS, the induction of proteins involved in lipogenesis was partial. ROS-like effects of 1 in 3T3-L1 cells were suppressed by the addition of bisphenol A diglycidyl ether (BADGE), one of a peroxisome proliferator-activated receptor γ (PPARγ) antagonists, suggesting that the action of 1 on adipocytes is mediated by PPARγ. From the results of the present study, it can be concluded that 1 is a novel insulin sensitizer candidate. Full article