Search Results (128)

Background/Objectives: Numerous studies have documented cardioprotective effects of adiponectin in animal models of cardiometabolic disease (CMD). Adiponectin receptor agonist ALY688 has demonstrated functional significance against pressure overload-induced cardiac remodeling events in a mouse model of heart failure with reduced ejection fraction (HFrEF), potentially through modulation of the systemic metabolome. However, the specific metabolites and their pathophysiological contribution to cardioprotection in cardiac hypertrophy or heart failure remain unclear. This study aimed to characterize systemic metabolic alterations across five tissues in HFrEF and determine how ALY688 modifies these pathways to mediate cardioprotection in the transverse aortic constriction (TAC) model. Methods: Targeted metabolic profiling was performed on heart, liver, muscle, epididymal white adipose tissue (eWAT), and serum collected five weeks post-surgery from wild-type male C57BL/6 mice. Mice underwent either Sham or TAC-induced left ventricular pressure overload, with or without daily subcutaneous ALY688 administration. Metabolites were quantified using liquid chromatography–tandem mass spectrometry (LC–MS/MS) and statistically analyzed at the tissue level. Results: Consistent with pathological cardiac remodeling, the comprehensive metabolomic analysis revealed that TAC induced widespread disruption of systemic metabolic homeostasis. ALY688 treatment significantly modified several key metabolite classes, including triglycerides (TGs) and glycosylceramides (HexCer). Notably, ALY688 also altered multiple gut-derived metabolites, including trimethylamine N-oxide (TMAO), 5-aminovaleric acid (5-AVA), and glycodeoxycholic acid (GDCA), highlighting a potential gut–liver–heart axis mediating its cardioprotective effects. Conclusions: These findings demonstrate that ALY688 mitigates TAC-induced metabolic dysregulation across multiple tissues. The identified metabolic signatures suggest that ALY688 exerts cardioprotective effects, at least in part, through restoration of systemic metabolic homeostasis and engagement of a gut–liver–heart metabolic axis. These results provide mechanistic insight into adiponectin receptor agonism and support further exploration of ALY688 as a potential therapeutic strategy for HFrEF. Full article

Background: Excess accumulation of white adipose tissue is linked to the development of obesity and type 2 diabetes, both of which are associated with systemic metabolic dysfunction. One promising approach is to convert white adipocytes into beige adipocytes, which have greater thermogenic potential and improved insulin sensitivity. Trans-resveratrol (RES), a polyphenolic compound known to have multiple metabolic benefits, has been reported to promote browning of adipocytes and improve insulin signaling; however, it is unclear whether sex and diabetic status modify RES’s effects. Methods: We evaluated the ability of RES to induce browning and increase insulin sensitivity in adipose-derived stromal cells (ADSCs) derived from diabetic db/db mice and explored the extent to which these responses are modulated by sex and diabetic status. Subcutaneous ADSCs were isolated from wildtype (WT) and diabetic (db/db) male and female mice and then treated with RES during beige adipocyte differentiation. Results: RES enhanced the expression of Pgc1α and Ucp1 mRNA and increased mitochondrial proton leak in ADSCs of both WT and db/db mice. RES also enhanced insulin-induced AKT phosphorylation in all groups of ADSCs. Notably, the effects of RES on browning and insulin signaling were influenced by the sex and diabetic status of the mice, as ADSCs from female diabetic mice responded differently compared with those from their WT or male counterparts. Conclusions: These findings highlight the importance of considering sex and diabetic status when developing browning strategies to target obesity and type 2 diabetes. Full article

Background and Objectives: Chemical androgen deprivation and estrogenization are essential components of clinical treatment for advanced prostate cancer and male-to-female sex transition. The aim of this study was to determine the effects of these therapies on anthropometric parameters, liver histology, and biochemical parameters, with the goal of establishing experimental models that accurately represent current clinical practice. Materials and Methods: Young adult Wistar rats were divided into nine groups: intact control (IC), control vehicle (CV), cyproterone acetate-treated (CA), flutamide-treated (F), control sesame oil (CO), estradiol valerate-treated (E), combined control (CC), flutamide + estradiol valerate (F + E), and cyproterone acetate + estradiol valerate (CA + E)-treated groups. Treatments were administered by subcutaneous injection for four weeks. Results: The administration of estradiol valerate, alone or combined with antiandrogens, reduced final body mass and white adipose tissue mass. Notable changes were observed in absolute and relative pituitary, liver, prostate, and testis mass in the E, F + E and CA + E groups. There were no significant changes in liver histology or glycogen deposition; however, the combined treatment groups showed an increased volume density of binucleated hepatocytes and fibrotic tissue. Regarding biochemical parameters, androgen deprivation and/or estrogenization caused marked changes in serum triglyceride, LDL (low-density lipoproteins), ALP (alkaline phosphatase), AST (aspartate aminotransferase), ALT (alanine aminotransferase), Bil-T (bilirubin), creatinine, and urea levels. Conclusions: Given the importance of these therapies in clinical practice, providing a model based on the evaluated parameters offers a solid platform for future research. Full article

Background/Objectives: Increased fat intake and high content of saturated fatty acids in the diet are associated with higher body weight and an increased risk of obesity. This study aimed to determine the impact of a high-fat diet (HFD) on white adipose tissue (WAT) metabolism and to verify whether this effect depends on the sources of lipids in HFD. Methods: Male C57BL/6J mice, 7 weeks old, received a control (Ctrl.) or high-fat diet (HFD) with 10% and 45% energy from fat, respectively, for 15 weeks. Lard was used as the main dietary fat in the HFD group. Next, the HFD group was subdivided into HFD-L, HFD-CO, HFD-OO and HFD-FO groups differing in the lipid sources (lard, coconut oil, olive oil, fish oil, respectively). The experiment was continued for 12 consecutive weeks. The study analyzed the concentration of different fatty acids in visceral (VAT) and subcutaneous (ScAT) adipose tissue; the levels of autophagy markers: beclin1, Atg5, LC3, p62, AMPK; ER stress markers: phos-PERK, CHOP, XBP-1 and oxidative stress parameters: TAS and TBARS in VAT and ScAT. Results: Mice in all HFD groups showed increased body mass and adipose tissue hypertrophy. Blood glucose concentration remained elevated in the HFD-L group but normalized in other HFD groups by the end of the dietary intervention. Fatty acid content in VAT and ScAT reflected the dietary sources in HFD. The HFD-L, HFD-CO, HFD-OO groups showed increased beclin1, ATG5, and p62 levels in VAT but the LC3-II/LC3-I ratio was similar to the control, suggesting impaired autophagic flux. In the HFD-FO group, the LC-II/LC-I ratio was elevated, along with decreased p62 levels, indicating active autophagic degradation. Changes in autophagy activity were insignificant in ScAT. ER stress markers were also mostly unaffected by HFD in both adipose tissue depots. TAS and TBARS values in VAT and ScAT were similar in the HFD-L and HFD-CO groups, and the HFD-OO group showed increased TAS and decreased TBARS, while the HFD-FO reduced TBARS. Conclusions: Antioxidant capacity and autophagy activity in WAT depended on fat content and lipid source, especially in the visceral depot. Fish oil induced changes in cellular metabolism, especially in VAT, diminishing the detrimental effects of HFD. Full article

Background/Objectives: Rosiglitazone (RSG), a potent PPARγ agonist for type 2 diabetes mellitus (T2DM), induces adverse adipogenic effects that limit clinical use. We investigated whether emodin (1,3,8-trihydroxy-6-methylanthraquinone, EMO), a natural anthraquinone, mitigates RSG-induced complications while enhancing its insulin-sensitizing benefits in severe obesity. Methods: Male ob/ob mice with established obesity and diabetes were treated for 4 weeks with RSG (10 mg kg⁻¹ day⁻¹), EMO (200 or 400 mg kg⁻¹ day⁻¹) or their combination. Metabolic profiling, organ function, and adipose histology were analyzed. RNA sequencing and mechanistic studies (Western blot, RT-qPCR, luciferase assays) in inguinal subcutaneous adipose tissue (iSAT), epididymal white adipose tissue (eWAT), and 3T3-L1 adipocytes were used to define EMO’s actions. Results: EMO co-treatment dose-dependently reduced RSG-induced weight gain, visceral adiposity (iSAT and eWAT mass, p < 0.05), and ectopic lipid deposition while ameliorating hepatorenal dysfunction. EMO synergistically enhanced RSG’s glucose-lowering effects. Mechanistically, EMO suppressed sterol regulatory element-binding protein 1 (SREBP1)-mediated lipogenesis (Srebp1, Acc, Fasn, Scd1; p < 0.05) and enhanced PPARγ-peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α)-driven thermogenesis via enhanced PPARγ transactivation and nuclear translocation. Thermogenic genes (Ucp1, Ppargc1a, Cidea; p < 0.05) were upregulated, with maximal uncoupling protein 1 (UCP1) induction in iSAT at 400 mg/kg EMO. Conclusions: EMO selectively enhances RSG’s glycemic benefits while attenuating its adipogenic effects in severe obesity by dual PPARγ modulation-inhibiting adipogenic pathways while amplifying thermogenesis. This strategy mitigates RSG’s adverse effects while improving insulin sensitivity, supporting the potential of EMO as a PPARγ adjunct therapy. Full article

Exogenous estrogen use in male-to-female individuals has been linked to increased cardiovascular disease risk, though the mechanisms remain unclear. This study examines the effects of 17β-estradiol (E₂) on metabolic and aortic function in castrated (CAS) male Sprague Dawley rats. CAS rats received subcutaneous E₂ (CAS + E₂) or placebo (CAS + PL) pellets for ~35 days, with intact males serving as controls. Endothelium-dependent vasorelaxation (EDV) in response to acetylcholine and contractile responses to phenylephrine were measured in aorta before and after pharmacological inhibitors. Metabolic parameters and expression of proteins associated with vascular and insulin signaling were also determined in aorta and white adipose tissue (WAT). E₂ treatment reduced body weight, improved HbA1c and enhanced glucose tolerance in CAS rats compared to the CAS + PL group. Improved glucose homeostasis was associated with upregulation of estrogen receptor alpha, phosphorylated Akt/Akt, and glucose transporter-4 expression in WAT. However, E₂ increased plasma triglyceride and impaired EDV, indicating compromised vascular function. Our results suggest that impaired aortic relaxation in the CAS + E₂ group may be partly attributable to increased contractility. Additionally, we observed reduced G protein-coupled estrogen receptor and elevated inducible nitric oxide synthase expression, warranting further investigation into whether these factors contribute to the effects of E₂ on aortic relaxation. Full article

The circadian rhythm of the central brain clock in the suprachiasmatic nucleus (SCN) is synchronized by light. White adipose tissue (WAT) is one of the metabolic endocrine organs containing a molecular clock, and it is synchronized by the SCN. Excess WAT is a risk factor for health issues including type 2 diabetes mellitus (DM2). We hypothesized that bright-light exposure would affect the human WAT transcriptome. Therefore, we analyzed WAT biopsies from two previously performed randomized cross-over trials (trial 1: n = 8 lean, healthy men, and trial 2: n = 8 men with obesity and DM2). From 7:30 h onwards, all the participants were exposed to either bright or dim light. Five hours later, we performed a subcutaneous abdominal WAT biopsy. RNA-sequencing results showed major group differences between men with obesity and DM2 and lean, healthy men as well as a differential effect of bright-light exposure. For example, gene sets encoding proteins involved in oxidative phosphorylation or respiratory chain complexes were down-regulated under bright-light conditions in lean, healthy men but up-regulated in men with obesity and DM2. In addition to evident group differences between men with obesity and DM2 and healthy lean subjects, autonomic or neuroendocrine signals resulting from bright-light exposure also differentially affect the WAT transcriptome. Full article

Background/Objectives: Obesity is a chronic metabolic disorder characterized by the excessive expansion of adipose tissue and impaired energy homeostasis. Natural products, such as plant extracts, are gaining attention as potential anti-obesity agents. This study aimed to evaluate and compare the anti-obesity effects of ginger (Zingiber officinale Roscoe) extract alone and as a mixture with long pepper (Piper longum L.) extract in a mouse model of high-fat diet-induced obesity. Methods: Male ICR mice were fed a high-fat diet to induce obesity and were orally administered ginger extract (60 mg/kg/day) or a 1:1 mixture of ginger and long pepper extracts (30 mg/kg/day each) for 8 weeks. Body weight, fat mass, glucose tolerance, and serum lipid levels were measured. Results: Ginger extract alone significantly reduced body weight gain and visceral and subcutaneous fat accumulation and improved glucose homeostasis and serum lipid profiles compared to the high-fat diet group. These effects were more pronounced than those observed with the mixture group. Ginger extract upregulated lipolytic markers via activation of the protein kinase A (PKA) signaling pathway and increased expression of uncoupling protein 1 (UCP1), indicating browning of white adipose tissue. Conclusions: Ginger extract alone exhibited significant anti-obesity effects compared to the mixture with long pepper extract. These findings suggest that ginger extract may serve as a promising natural agent for the prevention and management of obesity-related metabolic dysfunction. Full article

Adipose tissue exhibits dynamic metabolic and structural changes in response to environmental stimuli, including temperature fluctuations. While continuous cold exposure has been extensively studied, the molecular effects of prolonged intermittent cold exposure (ICE) remain poorly characterized. Here, we present a proteomic analysis of inguinal white adipose tissue (IWAT) from mice subjected to a 16-week regimen of short-term daily ICE (6 °C for 6 h, 5 days per week) without compensatory caloric intake. Mass spectrometry identified 1108 proteins, with 140 differentially expressed between experimental and control groups. ICE significantly upregulated mitochondrial proteins associated with lipid and carbohydrate catabolism, the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, and lipogenesis, including LETM1, AIFM1, PHB, PHB2, ACOT2, NDUA9, and ATP5J. These changes reflect enhanced metabolic activity and mitochondrial remodeling. In contrast, proteins linked to oxidative stress, insulin resistance, inflammation, and extracellular matrix remodeling were downregulated, such as HMGB1, FETUA, SERPH1, RPN1, and AOC3. Notably, gamma-synuclein (SYUG), which inhibits lipolysis, was undetectable in ICE-treated samples. Our findings support the hypothesis that ICE promotes thermogenic reprogramming and metabolic rejuvenation in subcutaneous fat through activation of futile cycles and mitochondrial restructuring. This study offers molecular insights into adaptive thermogenesis and presents intermittent cold exposure as a potential strategy to mitigate adipose tissue aging. Full article

The metabolic hyperactivity of tumor cells demands a substantial amount of energy and molecules to build new cells and expand the tumor, diverting these resources from healthy cells. Amino acids (AAs) are the only totipotent and essential molecules for protein construction. Previous in vitro studies in human and murine cancer cells, along with in vivo studies in mice, have shown that an excess of essential amino acids (EAAs) exerts an inhibitory effect on tumor proliferation by promoting apoptosis and autophagy. In this study, both in vitro and in vivo, we evaluated whether a mixture based on EAA can influence the development of human colon cancer (HCT116). To this end, in vitro, we assessed the proliferation of HCT116 cells treated with a special mix of EAA. In vivo, immunosuppressed athymic nude mice, injected with HCT116 cells subcutaneously (s.c.) or intraperitoneally (i.p.), were given a modified EAAs-rich diet (EAARD) compared to the standard laboratory diet (StD). In vitro data showed that the EAA mix impairs cancer growth by inducing apoptosis and autophagy. In vivo, the results demonstrated that EAARD-fed mice developed s.c. tumors significantly smaller than those of StD-fed mice (total mass 3.24 vs. 6.09 g, respectively). Mice injected i.p. and fed with EAARD showed a smaller and more limited number of intra-peritoneal tumors than StD-fed mice (total mass 0.79 vs. 4.77 g, respectively). EAAs prevents the growth of HCT116 cells by inducing autophagy and apoptosis, increasing endoplasmic reticulum stress, and inhibiting inflammation and neo-vascularization. In addition, the EAARD-fed mice, maintained muscle mass and white and brown adipose tissues. A diet with an excess of EAAs affects the survival and proliferative capacity of human colon cancer cells, maintaining anabolic stimuli in muscular cells. Full article

Forskolin (FSK) induces the browning of white adipose tissue (WAT) through the activation of adenylate cyclase (AC) and cyclic adenosine monophosphate (cAMP) generation. When administered intravenously or orally, FSK undergoes significant metabolism and accumulation in the liver and other tissues, resulting in high side effects and low anti-obesity effects due to trivial amounts reaching WAT. This study examines the potential anti-obesity and metabolic effects of the inguinal WAT (IWAT) delivery of FSK in high-fat diet-induced C57BL/6J obese mice. Mice received one of the following treatments twice weekly for 4 weeks: 1. Control into both IWAT depots (Con^both); 2. FSK 15 mg/kg body weight (BW)/injection into both inguinal WAT (IWAT) depots (FSK15^both); 3. FSK 7.5 mg/kg BW/injection into both IWAT depots (FSK7.5^both); and 4. FSK 7.5 mg/kg BW/injection into the left IWAT depot (FSK7.5^left). Both the FSK15^both and FSK7.5^both treatments improved metabolic parameters by lowering blood glucose, enhancing glucose tolerance, and reducing serum insulin and cholesterol. The FSK15^both treatment had a greater impact on IWAT, resulting in smaller adipocytes and increased expression of Ucp1 and Tmem26 mRNA levels. All FSK treatments also reduced inflammatory and lipogenic markers in the liver, indicating improved hepatic metabolism. These findings suggest that local delivery of FSK into subcutaneous WAT is a potential strategy for combating obesity and improving metabolic health. However, further studies are needed to confirm the statistical and biological significance of these effects. Full article

Adipose tissue is a dynamic and heterogeneous organ with distinct depots that play divergent roles in metabolic regulation. This review highlights the functional differences between brown, subcutaneous, and visceral adipose tissue, and their contributions to obesity-related insulin resistance. We explore how chronic low-grade inflammation, mitochondrial dysfunction, and fibrosis evolve within specific fat depots and how these changes disrupt systemic energy homeostasis. Visceral white adipose tissue (vWAT) emerges as a critical site of inflammation and metabolic inflexibility, while subcutaneous white adipose tissue (sWAT) may retain protective features in early obesity. The endocrine roles of adipokines and batokines are also discussed, emphasizing depot-specific signaling and systemic effects. Furthermore, we examine emerging therapeutic strategies aimed at modulating immune responses, enhancing mitochondrial function, and reprogramming adipose progenitor cells (APCs) to restore healthy tissue remodeling. A deeper understanding of adipose-depot-specific biology and progenitor cell dynamics offers promising avenues for personalized interventions in metabolic diseases. Full article

Overweight patients with cardiovascular disease (CVD) tend to survive longer than normal-weight patients, a phenomenon known as the “obesity paradox”. The phenotypic characteristics of adipose distribution in these patients (who survive longer) often reveal a larger proportion of subcutaneous white adipose tissue (scWAT), suggesting that the presence of scWAT is negatively associated with all-cause mortality and that scWAT appears to provide protective benefits in patients facing unhealthy states. Exercise-mediated browning is a crucial aspect of the benign remodeling process of adipose tissue (AT). Reduced accumulation, reduced inflammation, and associated adipokine secretion are directly related to the reduction in CVD mortality. This paper summarized the pathogenetic factors associated with AT accumulation in patients with CVD and analyzed the possible role and pathway of exercise-mediated adipose browning in reducing the risk of CVD and CVD-related mortality. It is suggested that exercise-mediated browning may provide a new perspective on the “obesity paradox”; that is, overweight CVD patients who have more scWAT may gain greater cardiovascular health benefits through exercise. Full article

Obesity has become a major public health threat, as it can cause various complications such as diabetes, cardiovascular disease, sleep apnea, cancer, and osteoarthritis. The primary anti-obesity therapies include dietary control, physical exercise, surgical interventions, and drug therapy; however, these treatments often have poor therapeutic efficacy, significant side effects, and unavoidable weight rebound. As a revolutionized transdermal drug delivery system, microneedles (MNs) have been increasingly used to deliver anti-obesity therapeutics to subcutaneous adipose tissue or targeted absorption sites, significantly enhancing anti-obese effects. Nevertheless, there is still a lack of a review to comprehensively summarize the latest progress of MN-mediated treatment of obesity. This review provides an overview of the application of MN technology in obesity, focusing on the delivery of various therapeutics to promote the browning of white adipose tissue (WAT), suppress adipogenesis, and improve metabolic function. In addition, this review presents detailed examples of the integration of MN technology with iontophoresis (INT) or photothermal therapy (PTT) to promote drug penetration into deeper dermis and exert synergistic anti-obese effects. Furthermore, the challenges and prospects of MN technology used for obesity treatment are also discussed, which helps to guide the design and optimization of MNs. Overall, this review provides insight into the development and clinical translation of MN technology for the treatment of obesity. Full article

Adipose tissue of obese people secretes a number of adipokines, including adiponectin and resistin, which have an antagonistic effect on the human metabolism, influencing the pathogenesis of many diseases based on low-grade inflammation. Body composition analysis using bioelectrical impedance analysis (BIA) was performed in 84 adults with obesity, i.e., body mass index (BMI) greater than or equal to 30 kg/m². Serum was collected to analyze the concentration of adiponectin (ApN) and resistin. The subjects additionally completed a food frequency questionnaire FFQ-6 and a three-day food diary. Adiponectin-resistin index (AR index) was calculated. The results show a positive correlation between resistin levels and BMI and subcutaneous fat content. AR index value was also positively associated with the amount of adipose tissue and body mass. Adiponectin level in the serum of the studied individuals decreased with the content of lean tissue. Adiponectin level also decreased with the amount of carbohydrates, amount of starch, and glycemic load of the diet. Resistin decreased in patients who frequently consumed white pasta and red meat, while AR index was positively associated with the amount of white rice and saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs) consumed but negatively associated with the frequent consumption of carbohydrates, including starch. Physical activity was negatively correlated with adiponectin levels and AR index. We concluded that body composition significantly influenced serum resistin and adiponectin concentrations the AR index. Dietary components also had a significant effect. Full article