Effect of Oleuropein on Anti-Obesity and Uncoupling Protein 1 Level in Brown Adipose Tissue in Mild Treadmill Walking Rats with Diet-Induced Obesity.

Oleuropein aglycone (OA), which is the absorbed form of oleuropein, is a major phenolic compound in extra virgin olive oil. We analyzed the anti-obesity effect of OA intake combined with mild treadmill walking (MTW, 4 m/min for 20 min/d, 5-6 d/wk, without electric shocks and slope) in rats under a high-fat diet (HF). Four-week-old male Sprague-Dawley rats (n=28) were equally divided into four groups: control (HF), 0.08% oleuropein-supplemented HF (HFO), HF with MTW (HF+W), and HFO with MTW (HFO+W) groups. After 28 d, the inguinal subcutaneous fat content and weight gain were significantly lower in the HFO+W group than in the control group. The HFO+W group also had significantly higher levels of urinary noradrenaline secretion, interscapular brown adipose tissue, uncoupling protein 1, brain transient receptor potential ankyrin subtype 1 (TRPA1), vanilloid subtype 1 (TRPV1), and brain-derived neurotrophic factor (BDNF) than the control group. Especially, the HFO+W group showed a synergistic effect on noradrenaline secretion. Therefore, OA combined with MTW may accelerate the enhancement of UCP1 and BDNF levels in rats with HF-induced obesity by increasing noradrenaline secretion after TRPA1 and TRPV1 activation.

Polyphenol Compound 18a Modulates UCP1-Dependent Thermogenesis to Counteract Obesity.

Recent studies increasingly suggest that targeting brown/beige adipose tissues to enhance energy expenditure offers a novel therapeutic approach for treating metabolic diseases. Brown/beige adipocytes exhibit elevated expression of uncoupling protein 1 (UCP1), which is a thermogenic protein that efficiently converts energy into heat, particularly in response to cold stimulation. Polyphenols possess potential anti-obesity properties, but their pharmacological effects are limited by their bioavailability and distribution within tissue. This study discovered 18a, a polyphenol compound with a favorable distribution within adipose tissues, which transcriptionally activates UCP1, thereby promoting thermogenesis and enhancing mitochondrial respiration in brown adipocytes. Furthermore, in vivo studies demonstrated that 18a prevents high-fat-diet-induced weight gain and improves insulin sensitivity. Our research provides strong mechanistic evidence that UCP1 is a complex mediator of 18a-induced thermogenesis, which is a critical process in obesity mitigation. Brown adipose thermogenesis is triggered by 18a via the AMPK-PGC-1α pathway. As a result, our research highlights a thermogenic controlled polyphenol compound 18a and clarifies its underlying mechanisms, thus offering a potential strategy for the thermogenic targeting of adipose tissue to reduce the incidence of obesity and its related metabolic problems.

Molecular Regulation of Thermogenic Mechanisms in Beige Adipocytes.

Adipose tissue is conventionally recognized as a metabolic organ responsible for storing energy. However, a proportion of adipose tissue also functions as a thermogenic organ, contributing to the inhibition of weight gain and prevention of metabolic diseases. In recent years, there has been significant progress in the study of thermogenic fats, particularly brown adipose tissue (BAT). Despite this progress, the mechanism underlying thermogenesis in beige adipose tissue remains highly controversial. It is widely acknowledged that beige adipose tissue has three additional thermogenic mechanisms in addition to the conventional UCP1-dependent thermogenesis: Ca2+ cycling thermogenesis, creatine substrate cycling thermogenesis, and triacylglycerol/fatty acid cycling thermogenesis. This paper delves into these three mechanisms and reviews the latest advancements in the molecular regulation of thermogenesis from the molecular genetic perspective. The objective of this review is to provide readers with a foundation of knowledge regarding the beige fats and a foundation for future research into the mechanisms of this process, which may lead to the development of new strategies for maintaining human health.

Biomarkers Screening and Mechanisms Analysis of the Restraint Stress-Induced Myocardial Injury in Hyperlipidemia ApoE-/- Mice.

OBJECTIVES: To explore the biomarkers and potential mechanisms of chronic restraint stress-induced myocardial injury in hyperlipidemia ApoE-/- mice. METHODS: The hyperlipidemia combined with the chronic stress model was established by restraining the ApoE-/- mice. Proteomics and bioinformatics techniques were used to describe the characteristic molecular changes and related regulatory mechanisms of chronic stress-induced myocardial injury in hyperlipidemia mice and to explore potential diagnostic biomarkers. RESULTS: Proteomic analysis showed that there were 43 significantly up-regulated and 58 significantly down-regulated differentially expressed proteins in hyperlipidemia combined with the restraint stress group compared with the hyperlipidemia group. Among them, GBP2, TAOK3, TFR1 and UCP1 were biomarkers with great diagnostic potential. KEGG pathway enrichment analysis indicated that ferroptosis was a significant pathway that accelerated the myocardial injury in hyperlipidemia combined with restraint stress-induced model. The mmu_circ_0001567/miR-7a/Tfr-1 and mmu_circ_0001042/miR-7a/Tfr-1 might be important circRNA-miRNA-mRNA regulatory networks related to ferroptosis in this model. CONCLUSIONS: Chronic restraint stress may aggravate myocardial injury in hyperlipidemia mice via ferroptosis. Four potential biomarkers are selected for myocardial injury diagnosis, providing a new direction for sudden cardiac death (SCD) caused by hyperlipidemia combined with the restraint stress.

Chronic Inorganic Nitrate Administration Increases the Expression of Genes Involved in the Browning of Gonadal Adipose Tissue in Ovariectomized Rats.

BACKGROUND AND OBJECTIVE: Nitrate, as nitric oxide (NO) donor, has been suggested as a nutrition-based treatment for decreasing the risk of menopause-related obesity. This study aimed to specify the effects of chronic inorganic nitrate administration on uncoupling protein-1 (UCP-1), peroxisome proliferator-activated-receptor-947; (PPAR-947;) coactivator-1945; (PGC-1945;), and PPAR-947; expression in gonadal adipose tissue (GAT) of ovariectomized (OVX) rats. METHODS: Female rats were assigned to 3 groups: Control, OVX, and OVX+nitrate (n=7/group), which consumed water containing inorganic nitrate (100 mg/L) for 9 months. At month 9, GAT was used for the measurement of NO metabolites (NOx), mRNA levels of NO synthases (endothelial (eNOS), inducible (iNOS), neuronal (nNOS)), and mRNA and protein levels of UCP-1, PGC-1945;, and PPAR-947;. RESULTS: OVX rats had lower NOx concentration (45%) and eNOS (38%) and nNOS (30%) expression in GAT that was restored to normal values following nitrate administration. OVX rats had significantly lower mRNA and protein levels of UCP-1 (83% and 30%), PGC-1945; (65% and 39%), and PPAR-947; (66% and 34.5%) in GAT. Chronic inorganic nitrate administration in OVXrats increased mRNA and protein levels of UCP-1 (128% and 34%), PGC-1945; (115% and 43%), and PPAR-947; (236% and 38%), respectively. CONCLUSION: In OVX rats, chronic nitrate administration increased gene and protein levels of UCP-1, PGC-1945;, and PPAR-947; in GAT, indicating the anti-obesity effects of nitrate are partially mediated by the white adipose tissue (WAT) browning. Moreover, the stimulatory effect of inorganic nitrate on the WAT browning in OVX rats was associated with blunting the OVXinduced NO deficiency in GAT.

Mitochondrial lipidomes are tissue specific - low cholesterol contents relate to UCP1 activity.

Lipid composition is conserved within sub-cellular compartments to maintain cell function. Lipidomic analyses of liver, muscle, white and brown adipose tissue (BAT) mitochondria revealed substantial differences in their glycerophospholipid (GPL) and free cholesterol (FC) contents. The GPL to FC ratio was 50-fold higher in brown than white adipose tissue mitochondria. Their purity was verified by comparison of proteomes with ER and mitochondria-associated membranes. A lipid signature containing PC and FC, calculated from the lipidomic profiles, allowed differentiation of mitochondria from BAT of mice housed at different temperatures. Elevating FC in BAT mitochondria prevented uncoupling protein (UCP) 1 function, whereas increasing GPL boosted it. Similarly, STARD3 overexpression facilitating mitochondrial FC import inhibited UCP1 function in primary brown adipocytes, whereas a knockdown promoted it. We conclude that the mitochondrial GPL/FC ratio is key for BAT function and propose that targeting it might be a promising strategy to promote UCP1 activity.

Two-stage evolution of mammalian adipose tissue thermogenesis.

Brown adipose tissue (BAT) is a heater organ that expresses thermogenic uncoupling protein 1 (UCP1) to maintain high body temperatures during cold stress. BAT thermogenesis is considered an overarching mammalian trait, but its evolutionary origin is unknown. We show that adipose tissue of marsupials, which diverged from eutherian mammals ~150 million years ago, expresses a nonthermogenic UCP1 variant governed by a partial transcriptomic BAT signature similar to that found in eutherian beige adipose tissue. We found that the reconstructed UCP1 sequence of the common eutherian ancestor displayed typical thermogenic activity, whereas therian ancestor UCP1 is nonthermogenic. Thus, mammalian adipose tissue thermogenesis may have evolved in two distinct stages, with a prethermogenic stage in the common therian ancestor linking UCP1 expression to adipose tissue and thermal stress. We propose that in a second stage, UCP1 acquired its thermogenic function specifically in eutherians, such that the onset of mammalian BAT thermogenesis occurred only after the divergence from marsupials.

7-MEGA™ inhibits adipogenesis in 3T3-L1 adipocytes and suppresses obesity in high-fat-diet-induced obese C57BL/6 mice.

BACKGROUND: Overweight, often known as obesity, is the abnormal and excessive accumulation of fat that exposes the health of a person at risk by increasing the likelihood that they may experience many chronic conditions. Consequently, obesity has become a global health threat, presenting serious health issues, and attracting a lot of attention in the healthcare profession and the scientific community. METHOD: This study aims to explore the anti-adipogenic properties of 7-MEGA™ in an attempt to address obesity, using both in vitro and in vivo research. The effects of 7MEGA™ at three distinct concentrations were investigated in obese mice who were given a high-fat diet (HFD) and 3T3-L1 adipocytes. RESULTS: 7MEGA™ decreased the total fat mass, overall body weight, and the perirenal and subcutaneous white adipose tissue (PWAT and SWAT) contents in HFD mice. Additionally, 7MEGA™ showed promise in improving the metabolic health of individuals with obesity and regulate the levels of insulin hormone, pro-inflammatory cytokines and adipokines. Furthermore, Peroxisome proliferator-activated receptors (PPAR) α and γ, Uncoupling Protein 1 (UCP-1), Sterol Regulatory Element-Binding Protein 1 (SREBP-1), Fatty Acid-Binding Protein 4 (FABP4), Fatty Acid Synthase (FAS), Acetyl-CoA Carboxylase (ACC), Stearoyl-CoA Desaturase-1 (SCD-1) and CCAAT/Enhancer-Binding Protein (C/EBPα) were among the adipogenic regulators that 7MEGA™ could regulate. CONCLUSION: In summary, this study uncovered that 7MEGA™ demonstrates anti-adipogenic and anti-obesity effects, suggesting its potential in combating obesity.

Knockdown of Esr1 from DRD1-Rich Brain Regions Affects Adipose Tissue Metabolism: Potential Crosstalk between Nucleus Accumbens and Adipose Tissue.

Declining estrogen (E2) leads to physical inactivity and adipose tissue (AT) dysfunction. Mechanisms are not fully understood, but E2's effects on dopamine (DA) activity in the nucleus accumbens (NAc) brain region may mediate changes in mood and voluntary physical activity (PA). Our prior work revealed that loss of E2 robustly affected NAc DA-related gene expression, and the pattern correlated with sedentary behavior and visceral fat. The current study used a new transgenic mouse model (D1ERKO) to determine whether the abolishment of E2 receptor alpha (ERα) signaling within DA-rich brain regions affects PA and AT metabolism. Adult male and female wild-type (WT) and D1ERKO (KD) mice were assessed for body composition, energy intake (EE), spontaneous PA (SPA), and energy expenditure (EE); underwent glucose tolerance testing; and were assessed for blood biochemistry. Perigonadal white AT (PGAT), brown AT (BAT), and NAc brain regions were assessed for genes and proteins associated with DA, E2 signaling, and metabolism; AT sections were also assessed for uncoupling protein (UCP1). KD mice had greater lean mass and EE (genotype effects) and a visible change in BAT phenotype characterized by increased UCP1 staining and lipid depletion, an effect seen only among females. Female KD had higher NAc Oprm1 transcript levels and greater PGAT UCP1. This group tended to have improved glucose tolerance (p = 0.07). NAc suppression of Esr1 does not appear to affect PA, yet it may directly affect metabolism. This work may lead to novel targets to improve metabolic dysfunction following E2 loss, possibly by targeting the NAc.

EGCG Suppresses Adipogenesis and Promotes Browning of 3T3-L1 Cells by Inhibiting Notch1 Expression.

BACKGROUND: With the changes in lifestyle and diet structure, the incidence of obesity has increased year by year, and obesity is one of the inducements of many chronic metabolic diseases. Epigallocatechin gallate (EGCG), which is the most abundant component of tea polyphenols, has been used for many years to improve obesity and its complications. Though it has been reported that EGCG can improve obesity through many molecular mechanisms, EGCG may have many mechanisms yet to be explored. In this study, we explored other possible mechanisms through molecular docking and in vitro experiments. METHODS: AutoDock Vina was selected for conducting the molecular docking analysis to elucidate the interaction between EGCG and Notch1, while molecular dynamics simulations were employed to validate this interaction. Then, the new regulation mechanism of EGCG on obesity was verified with in vitro experiments, including a Western blot experiment, immunofluorescence experiment, oil red O staining, and other experiments in 3T3-L1 adipocytes. RESULTS: The molecular docking results showed that EGCG could bind to Notch1 protein through hydrogen bonding. In vitro cell experiments demonstrated that EGCG can significantly reduce the sizes of lipid droplets of 3T3-L1 adipocytes and promote UCP-1 expression by inhibiting the expression of Notch1 in 3T3-L1 adipocytes, thus promoting mitochondrial biogenesis. CONCLUSIONS: In this study, molecular docking and in vitro cell experiments were used to explore the possible mechanism of EGCG to improve obesity by inhibiting Notch1.

Sphingomyelin is involved in regulating UCP1-mediated nonshivering thermogenesis.

Adipogenesis is one of the major mechanisms for adipose tissue expansion, during which spindle-shaped mesenchymal stem cells commit to the fate of adipocyte precursors and differentiate into round-shaped fat-laden adipocytes. Here, we investigated the lipidomic profile dynamics of ex vivo-differentiated brown and white adipocytes derived from the stromal vascular fractions of interscapular brown (iBAT) and inguinal white adipose tissues. We showed that sphingomyelin was specifically enriched in terminally differentiated brown adipocytes, but not white adipocytes. In line with this, freshly isolated adipocytes of iBAT showed higher sphingomyelin content than those of inguinal white adipose tissue. Upon cold exposure, sphingomyelin abundance in iBAT gradually decreased in parallel with reduced sphingomyelin synthase 1 protein levels. Cold-exposed animals treated with an inhibitor of sphingomyelin hydrolases failed to maintain core body temperature and showed reduced oxygen consumption and iBAT UCP1 levels. Conversely, blockade of sphingomyelin synthetic enzymes resulted in enhanced nonshivering thermogenesis, reflected by elevated body temperature and UCP1 levels. Taken together, our results uncovered a relation between sphingomyelin abundance and fine-tuning of UCP1-mediated nonshivering thermogenesis.

Angiotensin II participates in mitochondrial thermogenic functions via the activation of glycolysis in chemically induced human brown adipocytes.

Brown adipocytes are potential therapeutic targets for the prevention of obesity-associated metabolic diseases because they consume circulating glucose and fatty acids for heat production. Angiotensin II (Ang II) peptide is involved in the pathogenesis of obesity- and cold-induced hypertension; however, the mechanism underlying the direct effects of Ang II on human brown adipocytes remains unclear. Our transcriptome analysis of chemical compound-induced brown adipocytes (ciBAs) showed that the Ang II type 1 receptor (AGTR1), but not AGTR2 and MAS1 receptors, was expressed. The Ang II/AGTR1 axis downregulated the expression of mitochondrial uncoupling protein 1 (UCP1). The simultaneous treatment with ß-adrenergic receptor agonists and Ang II attenuated UCP1 expression, triglyceride lipolysis, and cAMP levels, although cAMP response element-binding protein (CREB) phosphorylation was enhanced by Ang II mainly through the protein kinase C pathway. Despite reduced lipolysis, both coupled and uncoupled mitochondrial respiration was enhanced in Ang II-treated ciBAs. Instead, glycolysis and glucose uptake were robustly activated upon treatment with Ang II without a comprehensive transcriptional change in glucose metabolic genes. Elevated mitochondrial energy status induced by Ang II was likely associated with UCP1 repression. Our findings suggest that the Ang II/AGTR1 axis participates in mitochondrial thermogenic functions via glycolysis.

UCP1-dependent brown adipose activation accelerates cardiac metabolic remodeling and reduces initial hypertrophic and fibrotic responses to pathological stress.

Brown adipose tissue (BAT) is correlated to cardiovascular health in rodents and humans, but the physiological role of BAT in the initial cardiac remodeling at the onset of stress is unknown. Activation of BAT via 48 h cold (16°C) in mice following transverse aortic constriction (TAC) reduced cardiac gene expression for LCFA uptake and oxidation in male mice and accelerated the onset of cardiac metabolic remodeling, with an early isoform shift of carnitine palmitoyltransferase 1 (CPT1) toward increased CPT1a, reduced entry of long chain fatty acid (LCFA) into oxidative metabolism (0.59 ± 0.02 vs. 0.72 ± 0.02 in RT TAC hearts, p < .05) and increased carbohydrate oxidation with altered glucose transporter content. BAT activation with TAC reduced early hypertrophic expression of ß-MHC by 61% versus RT-TAC and reduced pro-fibrotic TGF-ß1 and COL3α1 expression. While cardiac natriuretic peptide expression was yet to increase at only 3 days TAC, Nppa and Nppb expression were elevated in Cold TAC versus RT TAC hearts 2.7- and 2.4-fold, respectively. Eliminating BAT thermogenic activation with UCP1 KO mice eliminated differences between Cold TAC and RT TAC hearts, confirming effects of BAT activation rather than autonomous cardiac responses to cold. Female responses to BAT activation were blunted, with limited UCP1 changes with cold, partly due to already activated BAT in females at RT compared to thermoneutrality. These data reveal a previously unknown physiological mechanism of UCP1-dependent BAT activation in attenuating early cardiac hypertrophic and profibrotic signaling and accelerating remodeled metabolic activity in the heart at the onset of cardiac stress.

Mitochondrial UCP1: Potential thermogenic mechanistic switch for the treatment of obesity and neurodegenerative diseases using natural and epigenetic drug candidates.

BACKGROUND: Brown fat is known to provide non-shivering thermogenesis through mitochondrial uncoupling mediated by uncoupling protein 1 (UCP1). Non-shivering is not dependent on UCP2, UCP4, and BMCP1/UCP5 genes, which are distinct from UCP1 in a way that they are not constitutive uncouplers. Although they are susceptible to free fatty acid and free radical activation, their functioning has a significant impact on the performance of neurons. METHODOLOGY: Using subject-specific keywords (Adipose tissue; Adipocytes; Mitochondria; Obesity; Thermogenesis; UCP's in Neurodegeneration; Alzheimer's disease; Parkinson's disease), research articles and reviews were retrieved from Web of Science, ScienceDirect, Google Scholar, and PubMed. This article includespublications published between 2018 and 2023. The drugs that upregulate UCP1 are included in the study while the drugs that do not impact UCP1 are were not included. RESULTS: Neuronal UCPs have a direct impact on synaptic plasticity, neurodegenerative processes, and neurotransmission, by modulating calcium flux, mitochondrial biogenesis, local temperature, and free radical generation. Numerous significant advances in the study of neuronal UCPs and neuroprotection are still to be made. Identification of the tissue-dependent effects of UCPs is essential first. Pharmacologically targeting neuronal UCPs is a key strategy for preventing both neurodegenerative diseases and physiological aging. Given that UCP2 has activities that are tissue-specific, it will be essential to develop treatments without harmful side effects. The triggering of UCPs by CoQ, an essential cofactor, produces nigral mitochondrial uncoupling, reduces MPTP-induced toxicity, and may even decrease the course of Parkinson's disease, according to early indications. CONCLUSION: Herein, we explore the potential of UCP1 as a therapeutic target for treating obesity, neurodegenerative diseases as well as a potential activator of both synthetic and natural drugs. A deeper knowledge of synaptic signaling and neurodegeneration may pave the way to new discoveries regarding the functioning and controlling of these genes.

The function of brown adipose tissue at different sites of the body in Brandt's voles during cold acclimation.

Ambient temperatures have great impacts on thermoregulation of small mammals. Brown adipose tissue (BAT), an obligative thermogenic tissue for small mammals, is localized not only in the interscapular depot (iBAT), but also in supraclavicular, infra/subscapular, cervical, paravertebral, and periaortic depots. The iBAT is known for its cold-induced thermogenesis, however, less has been paid attention to the function of BAT at other sites. Here, we investigated the function of BAT at different sites of the body during cold acclimation in a small rodent species. As expected, Brandt's voles (Lasiopodomys brandtii) consumed more food and reduced the body mass gain when they were exposed to cold. The voles increased resting metabolic rate and maintained a relatively lower body temperature in the cold (36.5 ± 0.27 °C) compared to those in the warm condition (37.1 ± 0.36 °C). During cold acclimation, the uncoupling protein 1 (UCP1) increased in aBAT (axillary), cBAT (anterior cervical), iBAT (interscapular), nBAT (supraclavicular), and sBAT (suprascapular). The levels of proliferating cell nuclear antigen (PCNA), a marker for cell proliferation, were higher in cBAT and iBAT in the cold than in the warm group. The pAMPK/AMPK and pCREB/CREB were increased in cBAT and iBAT during cold acclimation, respectively. These data indicate that these different sites of BAT play the cold-induced thermogenic function for small mammals.

The histone methyltransferase SUV420H2 regulates brown and beige adipocyte thermogenesis.

Activation of brown adipose tissue (BAT) thermogenesis increases energy expenditure and alleviates obesity. Here we discover that histone methyltransferase suppressor of variegation 4-20 homolog 2 (Suv420h2) expression parallels that of Ucp1 in brown and beige adipocytes and that Suv420h2 knockdown significantly reduces - whereas Suv420h2 overexpression significantly increases - Ucp1 levels in brown adipocytes. Suv420h2 knockout (H2KO) mice exhibit impaired cold-induced thermogenesis and are prone to diet-induced obesity. In contrast, mice with specific overexpression of Suv420h2 in adipocytes display enhanced cold-induced thermogenesis and are resistant to diet-induced obesity. Further study shows that Suv420h2 catalyzes H4K20 trimethylation at eukaryotic translation initiation factor 4E-binding protein 1 (4e-bp1) promoter, leading to downregulated expression of 4e-bp1, a negative regulator of the translation initiation complex. This in turn upregulates PGC1α protein levels, and this upregulation is associated with increased expression of thermogenic program. We conclude that Suv420h2 is a key regulator of brown/beige adipocyte development and thermogenesis.

SLC25A28 Overexpression Promotes Adipogenesis by Reducing ATGL.

Adipose tissue dysfunction is seen among obese and type 2 diabetic individuals. Adipocyte proliferation and hypertrophy are the root causes of adipose tissue expansion. Solute carrier family 25 member 28 (SLC25A28) is an iron transporter in the inner mitochondrial membrane. This study is aimed at validating the involvement of SLC25A28 in adipose accumulation by tail vein injection of adenovirus (Ad)-SLC25A28 and Ad-green fluorescent protein viral particles into C57BL/6J mice. After 16 weeks, the body weight of the mice was measured. Subsequently, morphological analysis was performed to establish a high-fat diet (HFD)-induced model. SLC25A28 overexpression accelerated lipid accumulation in white and brown adipose tissue (BAT), enhanced body weight, reduced serum triglyceride (TG), and impaired serum glucose tolerance. The protein expression level of lipogenesis, lipolysis, and serum adipose secretion hormone was evaluated by western blotting. The results showed that adipose TG lipase (ATGL) protein expression was reduced significantly in white and BAT after overexpression SLC25A28 compared to the control group. Moreover, SLC25A28 overexpression inhibited the BAT formation by downregulating UCP-1 and the mitochondrial biosynthesis marker PGC-1α. Serum adiponectin protein expression was unregulated, which was consistent with the expression in inguinal white adipose tissue (iWAT). Remarkably, serum fibroblast growth factor (FGF21) protein expression was negatively related to the expansion of adipose tissue after administrated by Ad-SLC25A28. Data from the current study indicate that SLC25A28 overexpression promotes diet-induced obesity and accelerates lipid accumulation by regulating hormone secretion and inhibiting lipolysis in adipose tissue.

Oral supplementation with resveratrol improves hormonal profile and increases expression of genes associated with thermogenesis in oophorectomy mice.

Menopause causes important bodily and metabolic changes, which favor the increased occurrence of cardiovascular diseases, obesity, diabetes, and osteoporosis. Resveratrol exerts proven effects on body metabolism, improving glucose and lipid homeostasis and reducing inflammation and oxidative stress in various organs and tissues. Accordingly, this study evaluates the effects of resveratrol supplementation on the expression of markers associated with thermogenesis in brown adipose tissue, and on the body, metabolic and hormonal parameters of female mice submitted to bilateral oophorectomy. Eighteen female mice were randomized into three groups: G1: control (CONTROL), G2: oophorectomy (OOF), and G3: oophorectomy + resveratrol (OOF + RSV); the animals were kept under treatment for twelve weeks, being fed a standard diet and treated with resveratrol via gavage. Body, biochemical, hormonal, and histological parameters were measured; in addition to the expression of markers associated with thermogenesis in brown adipose tissue. The results showed that animals supplemented with resveratrol showed reduced body weight and visceral adiposity, in addition to glucose, total cholesterol, and triglyceride levels; decreased serum FSH levels and increased estrogen levels were observed compared to the OOF group and mRNA expression of PRDM16, UCP1, and SIRT3 in brown adipose tissue. The findings of this study suggest the important role of resveratrol in terms of improving body, metabolic, and hormonal parameters, as well as modulating markers associated with thermogenesis in brown adipose tissue of female mice submitted to oophorectomy.

Butein derivatives prevent obesity and improve insulin resistance through the induction of energy expenditure in high-fat diet-fed obese mice.

Obesity is a global public health problem and is related with fatal diseases such as cancer and cardiovascular and metabolic diseases. Medical and lifestyle-related strategies to combat obesity have their limitations. White adipose tissue (WAT) browning is a promising strategy for increasing energy expenditure in individuals with obesity. Uncoupling protein 1 (UCP1) drives WAT browning. We previously screened natural products that enable induction of Ucp1 and demonstrated that these natural products induced WAT browning and increased energy expenditure in mice with diet-induced obesity. In this study, we aimed to extensively optimise the structure of compound 1, previously shown to promote WAT browning. Compound 3 s exhibited a significantly higher ability to induce Ucp1 in white and brown adipocytes than did compound 1. A daily injection of compound 3 s at 5 mg/kg prevented weight gain by 13.6 % in high-fat diet-fed mice without any toxicological observation. In addition, compound 3 s significantly improved glucose homeostasis, decreased serum triacylglycerol levels, and reduced total cholesterol and LDL cholesterol levels, without altering dietary intake or physical activity. Pharmaceutical properties such as solubility, lipophilicity, and membrane permeability as well as metabolic stability, half-life (T1/2), and blood exposure ratio of i.p to i.v were significantly improved in compound 3 s when compared with those in compound 1. Regarding the mode of action of WAT browning, the induction of Ucp1 and Prdm4 by compounds 1 and 3 s was dependent on Akt1 in mouse embryonic fibroblasts. Therefore, this study suggests the potential of compound 3 s as a therapeutic agent for individuals with obesity and related metabolic diseases, which acts through the induction of WAT browning as well as brown adipose tissue activation.

Lactobacillus casei-fermented Amomum xanthioides ameliorates metabolic dysfunction in high-fat diet-induced obese mice.

Amomum xanthioides (AX) has been used as an edible herbal medicine to treat digestive system disorders in Asia. Additionally, Lactobacillus casei is a well-known probiotic commonly used in fermentation processes as a starter. The current study aimed to investigate the potential of Lactobacillus casei-fermented Amomum xanthioides (LAX) in alleviating metabolic disorders induced by high-fat diet (HFD) in a mouse model. LAX significantly reduced the body and fat weight, outperforming AX, yet without suppressing appetite. LAX also markedly ameliorated excessive lipid accumulation and reduced inflammatory cytokine (IL-6) levels in serum superior to AX in association with UCP1 activation and adiponectin elevation. Furthermore, LAX noticeably improved the levels of fasting blood glucose, serum insulin, and HOMA-IR through positive regulation of glucose transporters (GLUT2, GLUT4), and insulin receptor gene expression. In conclusion, the fermentation of AX demonstrates a pronounced mitigation of overnutrition-induced metabolic dysfunction, including hyperlipidemia, hyperglycemia, hyperinsulinemia, and obesity, compared to non-fermented AX. Consequently, we proposed that the fermentation of AX holds promise as a potential candidate for effectively ameliorating metabolic disorders.