Search Results (486)

The kallikrein–kinin system and its B1 and B2 receptors are key regulators in metabolic disorders such as obesity, diabetes, and insulin resistance. Obesity, a chronic and multifactorial condition often associated with comorbidities like type 2 diabetes and dyslipidemia, remains poorly understood at the metabolic level. The kinin B2 receptor (B2R) is involved in blood pressure regulation and glucose metabolism, promoting glucose uptake in skeletal muscle via bradykinin. Studies in B2R-KO mice demonstrate that the absence of this receptor predisposes animals to glucose intolerance under a high-fat diet and impairs adaptive thermogenesis, indicating a protective role for B2R in metabolic homeostasis and insulin sensitivity. In contrast, the kinin B1 receptor (B1R) is inducible under pathological conditions and is activated by kinin metabolites. Mouse models lacking B1R exhibit improved metabolic profiles, including protection against high-fat diet-induced obesity and insulin resistance, enhanced energy expenditure, and increased leptin sensitivity. B1R inactivation in adipocytes enhances insulin responsiveness and glucose tolerance, supporting its role in the development of insulin resistance. Moreover, B1R deficiency improves energy metabolism and thermogenic responses to adrenergic and cold stimuli, promoting the activation of brown adipose tissue and the browning of white adipose tissue. Collectively, these findings suggest that B1R and B2R represent promising therapeutic targets for the treatment of metabolic disorders. 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

The global obese population accounts for approximately 30% of the total population and continues to increase. White adipocytes, which accumulate in the body for energy storage, are associated with obesity. Mechanisms that activate browning of white adipocytes are an attractive therapeutic target for obesity and metabolic disorders. Exosomes are nano-sized biovesicles that play a role in cell-to-cell communication though the transfer of cargos such as microRNAs. Although milk exosomes contain many endogenous microRNA molecules, the role of microRNAs in milk exosomes is limited. Therefore, the aim of this study was to investigate the effects of milk exosomes on the browning of white adipocyte. Mouse pre-adipocytes (3T3-L1) and human adipose-derived stem cells (hADSCs) were differentiated and exposed to milk exosomes. Compared to control, milk exosomes promoted the expression of thermogenic genes and cellular mitochondrial energy metabolism in both 3T3-L1 cells and hADSCs. Additionally, milk exosomes were orally administered to mice fed a high-fat diet. As the intake of milk exosomes increased, the mice’s body weight decreased. Milk exosomes also increased the protein levels of thermogenic genes and mitochondrial-related genes in mouse adipose tissue. The overexpression of miR-11987, which is abundant in milk exosomes, in both 3T3-L1 cells and hADSCs led to the increased expression of thermogenic genes and mitochondrial activity. Our results support that bovine-specific miR-11987 in milk exosomes promotes the browning of white adipocytes. Therefore, milk exosome and milk exosomal miR-11987 could have significant clinical implications for obesity and metabolic syndrome. Full article

The conversion of carbohydrates into fatty acids is central for energy storage and the development and functioning of organs. Our previous study revealed that Hacd2 deficiency alleviates the fatty liver and diabetes induced by HFD. This study aimed to explore the roles of Hacd2 in organ development and metabolic homeostasis under an LFHCD, which still need to be more deeply explored. We found that the germline deletion of Hacd2 impairs long-chain fatty acid synthesis, which caused embryonic abnormalities after 7.5 days and led to embryonic lethality, as confirmed via photograph and hematoxylin-eosin staining. We next constructed Hacd2LKO mice and found that Hacd2LKO mice were largely normal when fed a chow diet, except for reduced inguinal white adipose tissue formation and glucose metabolism. Meanwhile, under an LFHCD, Hacd2 deletion markedly controlled body weight and white adipose tissue formation, leading to lower cholesterol and triglycerides in serum; however, it unexpectedly resulted in enlarged liver volume, hepatocyte swelling and nuclear abnormalities, and infiltration of inflammatory cells, including macrophages, neutrophils and dendritic cells. Furthermore, inhibition of Hacd2 also reduced triglyceride levels and the expression of related lipogenic genes during adipocyte differentiation, as confirmed via RNA interference analysis. These findings highlight the critical roles of Hacd2 in embryonic development and metabolic diseases, revealing its protective function in maintaining liver homeostasis under an LFHCD. Therefore, targeted interventions involving Hacd2 for metabolic diseases must take into account dietary changes and the functioning of the liver. Full article

Adiponectin (APN) is a secreted adipokine that plays a key role in modulating energy and bone metabolism, as well as regulating inflammatory responses. The overexpression of APN has been proposed as a potential therapeutic strategy for treating obesity and related disorders. Lipid nanoparticles (LNPs) are promising vectors for transporting messenger ribonucleic acid (mRNA) molecules. This study tested whether delivering a stabilized version of adiponectin mRNA (APN mRNA) using lipid nanoparticles could reduce fat formation and promote bone repair in vitro and in vivo. We demonstrated that transfection with APN-LNP upregulated the mRNA and protein expression of APN, while inhibiting adipogenesis in 3T3-L1 adipocytes. APN-LNP enhanced osteogenic gene expression in MC3T3-E1 cells in a dose-dependent manner. It also reduced matrix metalloproteinase 9 expression in receptor activator of nuclear factor-kappaB ligand (RANKL)-stimulated RAW264.7 cells, suggesting an anti-resorptive effect. In vivo, a femoral fracture model was established to explore the application of APN-LNP in promoting bone healing in diet-induced obese mice. Micro-computed tomography and histology analysis indicated that intravenous injection with APN-LNP promoted bone healing. Fasting blood glucose and body weight were decreased in the APN-LNP group. Moreover, APN-LNP increased bone sialoprotein and runt-related transcription factor 2 expression in contralateral femurs, as well as interleukin-10 expression in white adipose tissues. Thus, our study provides promising preclinical data on the potential use of APN-LNP for treating bone disorders in obesity. Full article

Background: Dietary consumption of insulinogenic amino acids (IAA) is known to contribute to the development of insulin resistance. It remains to be studied whether dietary IAA restriction improves glucose metabolism and insulin sensitivity and whether this improvement is related to alterations in glucose metabolism in peripheral tissues. The objective of this study was to examine the effect of IAA restriction on glucose metabolism in a piglet model. Methods: Following the acclimation period, thirty-two seven-day-old male piglets were randomly assigned into one of three groups for three weeks as follows (n = 10–11/group): (1) NR (control): basal diet without IAA restriction; (2) R50: basal diet with IAA restricted by 50%; (3) R75: basal diet with IAA restricted by 75%. IAA were alanine (Ala), arginine (Arg), isoleucine (Ile), leucine (Leu), lysine (Lys), threonine (Thr), phenylalanine (Phe), and valine (Val) as suggested by previous studies. Thermal images, body weight, and growth parameters were recorded weekly, oral glucose tolerance tests were performed on week 2 of the study, and blood and tissue samples were collected on week 3 after a meal test. Results: R75 improved glucose tolerance and, together with R50, reduced blood insulin concentration and homeostatic model assessment for insulin resistance (HOMA-IR) value, which is suggestive of improved insulin sensitivity following IAA restriction. R75 increased thermal radiation and decreased adipocyte number in white adipose tissue (WAT). R75 had a greater transcript of glucose transporter 1 (GLUT1), phosphofructokinase, liver type (PFKL), and pyruvate kinase, liver, and RBC (PKLR) in the liver and glucokinase (GCK) in WAT indicating a higher uptake of glucose in the liver and greater glycolysis in both liver and WAT. R75 increased the mRNA abundance of insulin receptor substrate 1 (IRS1) and protein kinase B (AKT1) in skeletal muscle suggestive of enhanced insulin signaling. Further, R75 had a higher mRNA of fibroblast growth factor 21 (FGF-21) in both the liver and hypothalamus and its upstream molecules such as activating transcription factor 4 (ATF4) and inhibin subunit beta E (INHBE) which may contribute to increased energy expenditure and improved glucose tolerance during IAA restriction. Conclusions: IAA restriction improves glucose tolerance and insulin sensitivity in piglets while not reducing body weight, likely through improved hepatic glycolysis and insulin signaling in skeletal muscle, and induced FGF-21 signaling in both the liver and hypothalamus. Full article

Prolonged breastfeeding (BF), as opposed to artificial infant formula feeding (FF), has been shown to prevent the development of obesity later in life. The aim of our narrative review is to investigate the missing molecular link between postnatal protein overfeeding—often referred to as the “early protein hypothesis”—and the subsequent transcriptional and epigenetic changes that accelerate the expansion of adipocyte stem cells (ASCs) in the adipose vascular niche during postnatal white adipose tissue (WAT) development. To achieve this, we conducted a search on the Web of Science, Google Scholar, and PubMed databases from 2000 to 2025 and reviewed 750 papers. Our findings revealed that the overactivation of mechanistic target of rapamycin complex 1 (mTORC1) and S6 kinase 1 (S6K1), which inhibits wingless (Wnt) signaling due to protein overfeeding, serves as the primary pathway promoting ASC commitment and increasing preadipocyte numbers. Moreover, excessive protein intake, combined with the upregulation of the fat mass and obesity-associated gene (FTO) and a deficiency of breast milk-derived microRNAs from lactation, disrupts the proper regulation of FTO and Wnt pathway components. This disruption enhances ASC expansion in WAT while inhibiting brown adipose tissue development. While BF has been shown to have protective effects against obesity, the postnatal transcriptional and epigenetic changes induced by excessive protein intake from FF may predispose infants to early and excessive ASC commitment in WAT, thereby increasing the risk of obesity later in life. Full article

Obesity is defined as abnormal or excessive accumulation of body fat and contributes to several metabolic disorders. White adipose tissue (WAT) releases energy as free fatty acids and glycerol from triglycerides through a process called lipolysis. People with obesity have impaired catecholamine-stimulated lipolysis, but comprehensive understanding of this lipolysis is still unclear. We previously showed that expression of WW domain-containing E3 ubiquitin ligase 1 (WWP1), a member of the HECT-type E3 family of ubiquitin ligases, was increased in WAT of obese mice. In this study, we generated Wwp1 knockout (KO) mice to evaluate the effect of WWP1 in WAT of obese mice. The mRNA levels of beta-3 adrenergic receptor (Adrb3), which were decreased with a high-fat diet, were increased by Wwp1 KO in WAT. Moreover, Wwp1 KO mice showed increased phosphorylated hormone-sensitive lipase levels in WAT. In contrast, noradrenaline and its metabolism were not altered in WAT of obese Wwp1 KO mice. These findings indicate that WWP1, which is increased in adipocytes because of obesity, is a candidate for suppressing lipolysis independently of noradrenaline metabolism. We anticipate that inhibition of WWP1 is a promising approach for a new treatment of obesity and type-2 diabetes using Adrb3 agonists. Full article

Adipocyte differentiation is a complex process in which pluripotent mesenchymal stem cells (MSCs) differentiate and develop into mature fat cells, also known as adipocytes. This process is controlled by various transcription factors, hormones, and signaling molecules that regulate the development of these cells. Recently, an increasing number of non-coding RNAs (ncRNAs), especially microRNAs (miRNAs), have been established to be involved in the regulation of many biological processes, including adipocyte differentiation, development, metabolism, and energy homeostasis of white and brown adipose tissue. Several in vitro and in vivo studies reported the significant role of ncRNAs in either promoting or inhibiting adipocyte differentiation into white or brown fat cells by targeting specific transcription factors and regulating the expression of key adipogenic genes. Identifying the function of ncRNAs and their subsequent targets contributes to our understanding of how these molecules can be used as potential biomarkers and tools for therapies against obesity, diabetes, and other diseases related to obesity. This could also contribute to advancements in tissue-engineering based treatments. In this review, we intended to present an up-to-date comprehensive literature overview of the role of ncRNAs, including miRNAs, long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), focusing particularly on miRNAs, in regulating the differentiation and development of cells into white and brown adipose tissue. In addition, we further discuss the potential use of these molecules as biomarkers for the development of novel therapeutic strategies for future personalized treatment options for patients. Full article

The Regulator of G Protein Signaling 14 (RGS14) knockout (KO) mouse is a model of healthful longevity, i.e., its lifespan is prolonged and demonstrates enhanced exercise performance and protection against heart disease and hypertension. In this investigation, we found the RGS14 KO mouse is also protected against obesity and glucose intolerance by promoting a low white adipose tissue (WAT) phenotype with increased brown adipose tissue (BAT). This was confirmed by lower body weight, lower white adipocyte size, increased metabolism and improved glucose tolerance and insulin sensitivity. Upon examination of the white adipose tissue, RGS14 KO exhibited increased expression of “beiging” genes as well as significant increase in Uncoupling protein-1 (UCP-1) expression. The mechanism behind this protection was due to its unique brown adipose tissue. This was determined by BAT transplantation, which led to a reversal of phenotype, such that RGS14 BAT recipients developed protection similar to intact RGS14 KO mice, and the RGS14 KO BAT donors lost their protection. Thus, two novel mechanisms mediating obesity and glucose intolerance were found, i.e., inhibition of RGS14 and its BAT. Full article

Obesity is characterized by an excessive imbalance in energy metabolism and is associated with metabolic syndrome. Mammals have two types of adipose tissue: white adipose tissue (WAT) and brown adipose tissue (BAT). These are key factors in regulating the energy balance. Strategies aimed at reducing obesity should encompass not only the prevention of lipid accumulation but also the stimulation of browning in both WAT and BAT, with the aim of enhancing energy expenditure. In this study, the mechanism by which Lactobacillus brevis-fermented gamma-aminobutyric acid (LB-GABA) prevents obesity was investigated, as well as whether it induces lipolysis and browning in WAT using 3T3-L1 adipocytes. The expression of proteins involved in signaling pathways regulating lipid accumulation and degradation, as well as browning, was measured using Western blotting analysis. We demonstrated that LB-GABA significantly inhibited lipid accumulation by suppressing adipogenesis and lipogenesis. In addition, the microscopic analysis of WAT demonstrated that LB-GABA reduced the adipocyte size and the number of lipid droplets. Moreover, Western blot analysis revealed that GABA increased lipolysis and activated the protein kinase A (PKA) signaling pathway, which promotes uncoupling protein 1 (UCP1)-mediated WAT browning. In conclusion, these results suggest that LB-GABA activates energy expenditure through lipid metabolism regulation and exerts anti-obesity effects. Full article

Adipose tissue is present in aortic valves (AVs). Valve interstitial cells (VICs) could differentiate into adipogenic lineages. We here characterize whether the presence of adipose tissue in the AV influences inflammation and extracellular matrix (ECM) composition in patients with aortic regurgitation (AR). A total of 144 AVs were analyzed by histological and molecular techniques. We performed discovery studies using Olink Proteomics^® technology in 40 AVs (N = 16 without and N = 24 with adipose tissue). In vitro, human white adipocytes (HWAs) or VICs were cultured with adipogenic media and co-cultured with control VICs. Of Avs, 67% presented white-like adipocytes within the spongiosa. Discovery studies revealed increased levels of inflammatory and ECM molecules in AVs containing adipocytes. Interestingly, the presence of adipocytes was associated with greater AV thickness, higher inflammation, and ECM remodeling, which was characterized by increased proinflammatory molecules, collagen, fibronectin, proteoglycans, and metalloproteinases. AV thickness positively correlated with markers of adipose tissue, inflammation, and ECM. In vitro, adipocyte-like VICs expressed higher levels of adipocyte markers, increased cytokines, fibronectin, decorin, and MMP-13. Analyses of supernatants from co-cultured control VICs with HWA or adipocyte-like VICs showed higher expression of inflammatory mediators, collagen type I, proteoglycans, and metalloproteinases. AVs presenting adipocytes were thicker and exhibited changes characterized by increased inflammation accompanied by aberrant expression of collagen, proteoglycans, and metalloproteinases. VICs could differentiate into adipogenic pathway, affect neighbor VICs, and contribute to inflammation, collagen and proteoglycan accumulation, as well as to metalloproteinases secretion. In summary, the presence of adipose tissue in AV could modify its composition, favoring inflammation and remodeling with an impact on AV thickness. Full article

Perirenal adipose tissue (PRAT) exhibits particular morphological features, with its activity being mainly related to thermogenesis. However, an expanded PRAT area seems to play a significant role in cardiovascular diseases, diabetes mellitus, and chronic kidney disease pathogenesis. Numerous studies have demonstrated that PRAT may support cancer progression and invasion, mainly in obese patients. The mechanism underlying these processes is of dysregulation of PRAT’s secretion of adipokines and pro-inflammatory cytokines, such as leptin, adiponectin, chemerin, apelin, omentin-1, vistatin, nesfatin-1, and other pro-inflammatory cytokines, modulated by tumor cells. Cancer cells may also induce a metabolic reprogramming of perirenal adipocytes, leading to increased lipids and lactate transfer to the tumor microenvironment, contributing to cancer growth in a hypoxic milieu. In addition, the PRAT browning process has been specifically detected in renal cell carcinoma (RCC), being characterized by upregulated expression of brown/beige adipocytes markers (UCP1, PPAR-ɣ, c/EBPα, and PGC1α) and downregulated white fat cells markers, such as LEPTIN, SHOX2, HOXC8, and HOXC9. Considering its multifaceted role in cancer, modulation of PRAT’s role in tumor progression may open new directions for oncologic therapy improvement. Considering the increasing evidence of the relationship between PRAT and tumor cells, our review aims to provide a comprehensive analysis of the perirenal adipocytes’ impact on tumor progression and metastasis. Full article

In mammals, exposure to low temperatures induces white adipose tissue (WAT) browning and alters lipid metabolism to promote thermogenesis, thereby maintaining body temperature. However, this response varies across different adipose depots. In this study, Hezuo pigs were exposed to either room temperature (23 ± 2 °C) or low temperature (−15 ± 2 °C) for periods of 12 h, 24 h, 48 h, 5 d, 10 d, and 15 d. Inguinal fat (IF) and perirenal fat (PF) were collected and analyzed using hematoxylin and eosin (HE) staining, transmission electron microscopy, RT-qPCR, and RNA-seq. Following cryoexposure, our results demonstrated a significant increase in adipocyte number and a corresponding decrease in cross-sectional area in both IF and PF groups from 24 h to 10 d. While adipocyte numbers were elevated at 12 h and 15 d, these changes were not statistically significant. Moreover, lipid droplets and mitochondria were more abundant, and the mRNA expression levels of thermogenic genes UCP3 and PGC-1α were significantly higher compared to the control group during the 24 h-10 d cold exposure period. No significant changes were observed in the other groups. RNA-seq data indicated that the lipid metabolism of IF and PF peaked on day 5 of low-temperature treatment. In IF tissue, lipid metabolism is mainly regulated by genes such as FABP4, WNT10B, PCK1, PLIN1, LEPR, and ADIPOQ. These genes are involved in the classical lipid metabolism pathway and provide energy for cold adaptation. In contrast, in PF tissue, genes like ATP5F1A, ATP5PO, SDHB, NDUFS8, SDHA, and COX5A play roles within the neurodegenerative disease pathway, and PF tissue has a positive impact on the process related to degenerative diseases. Further investigation is needed to clarify the functions of these candidate genes in lipid metabolism in Hezuo pigs and to explore the genetic mechanisms underlying the cold-resistance traits in local pig populations. Full article

Thyroid hormones (THs) are important modulators of many metabolic processes, being strictly associated with the control of energy balance, mainly through activities on the brain, white and brown adipose tissue, skeletal muscle, liver, and pancreas. In this review, the principal mechanisms of TH regulation on metabolic processes will be discussed and THs’ relevance in metabolic disease progression will be evaluated, especially in the cardiovascular context and correlated diseases. Moreover, we will discuss THs’ regulatory role on metabolic events in white and brown adipose tissue, with a special focus on the process of “browning”, which consists of the gradual acquisition by white adipocytes of the physical and functional characteristics of brown adipocytes. The advancements in research on molecular mechanisms and proposed physiopathological relevance of this process will be discussed. Full article