Sestrin2 knockout exacerbates high-fat diet induced metabolic disorders and complications in female mice.

BACKGROUND: Obesity and its associated complications raise significant public concern, revealing gender disparities in the susceptibility to metabolic disorders, with females often displaying greater resistance to obesity-related metabolic disorder than males. Sestrin2 is a crucial protein involved in metabolism and energy balance. This study seeks to explore whether Sesn2 knockout (KO) exacerbates high-fat diet (HFD) induced obesity in female mice. METHODS: Female mice with wild-type (WT) and Sesn2 KO were subjected to a 12-week regimen of normal diet or HFD. Using a Body Composition Analyzer, body composition was gauged. Biochemical assays encompassed glucose, lipid, and liver function measurements, alongside 24-hour urine albumin excretion. Echocardiographic evaluation assessed cardiac function. Histopathological analysis of key metabolic tissues (liver, kidney, and heart tissues) were conducted. Western blotting or qRT-PCR evaluated key proteins and genes linked to inflammation, mitochondrial, and lipid metabolism in adipose tissues. RESULTS: In comparison to mice fed a regular diet, those on a HFD exhibited significant increases in body weight and fat mass. Notably, Sesn2 KO further aggravated obesity, showcasing the most pronounced metabolic anomalies: elevated body weight, fat mass, impaired glucose tolerance, and insulin sensitivity, alongside heightened levels of free fatty acids and triglycerides. Additionally, KO-HFD mice displayed exacerbated multi-tissue impairments, including elevated hepatic enzymes, increased urinary albumin excretion, compromised cardiac function, and accumulation of lipids in the liver, kidney, and heart. Moreover, adipose tissue showcased altered lipid dynamics and function, characterized by enhanced triglyceride breakdown and modified adipokine levels. Browning was diminished, along with decreased Pgc1α and Sirt1 in KO-HFD mice. CONCLUSION: Sesn2 KO exacerbates HFD-induced obesity and metabolic disorders in female mice. These findings underscore Sestrin2's novel role as a regulator of obesity in female mice.

Ling-gui-zhu-gan granules reduces obesity and ameliorates metabolic disorders by inducing white adipose tissue browning in obese mice.

Background: Ling-gui-zhu-gan (LGZG) formula has been demonstrated to effectively ameliorate the clinical symptoms of patients with obesity or metabolic syndrome. This study aimed to explore both the effect and the underlying mechanisms of LGZG against obesity. Methods: Male C57BL/6N mice were randomized into four groups (n = 8): normal control (NC), obese (OB), metformin (Met), and LGZG. After 8 weeks of gavage administration, the pharmacological effects of LGZG on obesity and metabolism were investigated using biochemical parameters, histomorphological examination, and lipidomics techniques. Pivotal factors associated with white adipose tissue browning were evaluated using quantitative real-time polymerase chain reaction and western blotting. Results: The results revealed that LGZG reduced the levels of obesity markers, including body weights, body fat mass and food intake in obese mice. Further evaluations highlighted that LGZG restored glucose homeostasis and significantly improved insulin sensitivity in obese mice. Importantly, LGZG could adjust serum lipid profiles and regulate the lipidomic spectrum of intestinal contents, with noticeable shifts in the levels of certain lipids, particularly diacylglycerols and monoacylglycerols. Histopathological examinations of LGZG-treated mice also revealed more favorable adipose tissue structures than their obese counterparts. Furthermore, we found that LGZG upregulated the expression of several key thermogenesis-related factors, such as UCP1, PRDM16, PGC-1α, PPARα, PPARγ, CTBP1, and CTBP2 in white adipose tissues. Conclusion: Our findings position LGZG as a novel strategy for preventing obesity and improving metabolic health.

Development of a functional beige fat cell line uncovers independent subclasses of cells expressing UCP1 and the futile creatine cycle.

Although uncoupling protein 1 (UCP1) is established as a major contributor to adipose thermogenesis, recent data have illustrated an important role for alternative pathways, particularly the futile creatine cycle (FCC). How these pathways co-exist in cells and tissues has not been explored. Beige cell adipogenesis occurs in vivo but has been difficult to model in vitro; here, we describe the development of a murine beige cell line that executes a robust respiratory response, including uncoupled respiration and the FCC. The key FCC enzyme, tissue-nonspecific alkaline phosphatase (TNAP), is localized almost exclusively to mitochondria in these cells. Surprisingly, single-cell cloning from this cell line shows that cells with the highest levels of UCP1 express little TNAP, and cells with the highest expression of TNAP express little UCP1. Immunofluorescence analysis of subcutaneous fat from cold-exposed mice confirms that the highest levels of these critical thermogenic components are expressed in distinct fat cell populations.

[Effect of polymethoxylated flavonoids on glucose and lipid metabolism in rat model of obesity induced by a high-fat diet].

This study established a rat model of obesity by using a high-fat diet(HFD) to explore the effect of polymethoxylated flavonoids on glucose and lipid metabolism in the model rats and decipher the role and mechanism of polymethoxylated flavonoids in mitigating obesity. Thirty normal SD rats were selected and randomized into normal, model, ezetimibe(0.1 mg·kg~(-1)), and polymethoxylated flavonoids(62.5 mg·kg~(-1) and 125 mg·kg~(-1)) groups based on the body weight. Except the normal group receiving a conventional diet, the other groups received a HFD. Rats were administrated with corresponding doses of drugs by gavage. During the administration period, the body weight of each group of rats was regularly weighed, and the serum lipid and glucose levels were measured by a fully automated biochemical analyzer. Islet homeostasis and serum levels of obesity factors were measured by ELISA. The 16S rRNA high-throughput sequencing was employed to study the gut microbiota. Hematoxylin-eosin staining was employed to observe the histomorphology of white fat, brown fat, and pancreas. After the wet weights of white fat and brown fat were measured, the organ index was calculated. Immunohistochemistry and Western blot were employed to determine the protein levels. The results showed that polymethoxylated flavonoids reduced the body weight and Lee's index and improved blood lipid levels of the model rats. Polymethoxylated flavonoids reduced blood glucose and insulin secretion, increased insulin responsiveness, and alleviated insulin resistance. In addition, polymethoxylated flavonoids regulated the serum levels of obesity factors and reduced the weights and indexes of white fat and brown fat, the diameter of white adipocytes, and the number of fat vacuoles in brown fat and pancreatic islet cells. The intervention with polymethoxylated flavonoids increased the diversity of gut microbiota in the model rats, increasing the beneficial bacteria associated with glucose and lipid metabolism and reduced the harmful bacteria at the genus level. In addition, polymethoxylated flavonoids up-regulated the protein levels of glucose transporter 4(GLUT4), phosphorylated AMP-activated protein kinase(p-AMPK), peroxisome proliferator-activated receptor gamma coactivator-1α(PGC-1α), and uncoupling protein 1(UCP1). In summary, polymethoxylated flavonoids may increase the body utilization of glucose and lipids by regulating the homeostasis of insulin, the serum levels of obesity factors, the diversity of gut microbiota, and the expression of mitochondrial metabolism-related proteins in brown adipocytes, thereby mitigating obesity in rats.

Integrated analysis of omics reveals the role of scapular fat in thermogenesis adaptation in sunite sheep.

Inhabiting some of the world's most inhospitable climatic regions, the Sunite Mongolian sheep generates average temperatures as low as 4.3 °C and a minimum temperature of -38.8 °C; in these environments, they make essential cold adaptations. In this regard, scapular fat tissues from Mongolian sheep were collected both in winter and summer for transcriptomic and proteomic analyses to identify genes related to adaptive thermogenesis. In the transcriptome analysis, 588 differentially expressed genes were identified to participate in smooth muscle activity and fat metabolism, as well as in nutrient regulation. There were 343 upregulated and 245 downregulated genes. GO and KEGG pathway analyses on these genes revealed their participation in regulating smooth muscle activity, metabolism of fats, and nutrients. Proteomic analysis showed the differential expression of 925 proteins: among them, there are 432 up- and 493 down-expressed proteins. These proteins are mainly involved in oxidative phosphorylation, respiratory chain complex assembly, and ATP production by electron transport. Furthermore, using both sets at a more detailed level of analysis revealed over-representation in gene ontology categories related to hormone signaling, metabolism of lipids, the pentose phosphate pathway, the TCA cycle, and especially the process of oxidative phosphorylation. The identified essential genes and proteins were further validated by quantitative real-time polymerase chain reaction and Western blotting, respectively; key metabolic network constriction was constructed. The present study emphasized the critical role of lipid turnover in scapular fat for thermogenic adaptation in Sunite sheep.

Myeloid-derived suppressor cells in the tumor microenvironment reduce uncoupling protein 1 expression to boost immunosuppressive activity.

Uncoupling protein 1 (UCP1) is located at the inner membrane of mitochondria and mediates nonshivering thermogenesis. Its abnormal expression is associated with metabolic diseases, cancer, and acute kidney injury. Myeloid-derived suppressor cells (MDSCs) with immunosuppressive activity accumulate in the tumor microenvironment (TME). Here, decreased UCP1 expression in MDSCs was observed in the peripheral blood of patients with colorectal cancer and transplanted mouse tumors. Aggravated tumor progression was observed in UCP1-knockout mice and conditional knockout mice (UCP1fl/fl-S100A8cre). The number of G-MDSCs and M-MDSCs increased in the transplanted tumor tissues from UCP1-deficient mice compared with those from wild-type mice. The tumor-promoting effect disappeared when the tumor-bearing mice were depleted of MDSCs by the α-DR5 administration. Adoptive transfer of tumor-derived MDSCs sharply promoted the tumor growth in vivo. Furthermore, these tumor-derived MDSCs enhanced the proliferation, reduced death, inhibited IFN-γ production of CD4+ and CD8+T cells, and induced Treg cells ex vivo. In conclusion, MDSCs in the TME alter the metabolic pattern by decreasing UCP1 expression to enhance immunosuppressive activity for tumor escape.

Engineering an energy-dissipating hybrid tissue in vivo for obesity treatment.

Obesity is a global health challenge with limited therapeutic solutions. Here, we demonstrate the engineering of an energy-dissipating hybrid tissue (EDHT) in the body for weight control. EDHT is constructed by implanting a synthetic gel matrix comprising immunomodulatory signals and functional cells into the recipient mouse. The immunomodulatory signals induce the host stromal cells to create an immunosuppressive niche that protects the functional cells, which are overexpressing the uncoupling protein 1 (UCP1), from immune rejection. Consequently, these endogenous and exogenous cells co-develop a hybrid tissue that sustainedly produces UCP1 to accelerate the host's energy expenditure. Systematic experiments in high-fat diet (HFD) and transgenic (ob/ob) mice show that EDHT efficiently reduces body weight and relieves obesity-associated pathological conditions. Importantly, an 18-month observation for safety assessment excludes cell leakage from EDHT and reports no adverse physiological responses. Overall, EDHT demonstrates convincing efficacy and safety in controlling body weight.

Versican maintains the homeostasis of adipose tissues and regulates energy metabolism.

Versican is a large chondroitin sulfate proteoglycan in the extracellular matrix. It plays a pivotal role in the formation of the provisional matrix. S100a4, previously known as fibroblast-specific protein, functions as a calcium channel-binding protein. To investigate the role of versican expressed in fibroblasts, we generated conditional knockout mice in which versican expression is deleted in cells expressing S100a4. We found that S100a4 is expressed in adipose tissues, and these mice exhibit obesity under a normal diet, which becomes apparent as early as five months. The white adipose tissues of these mice exhibited decreased expression levels of S100a4 and versican and hypertrophy of adipocytes. qRT-PCR showed a reduced level of UCP1 in their white adipose tissues, indicating that the basic energy metabolism is diminished. These results suggest that versican in adipose tissues maintains the homeostasis of adipose tissues and regulates energy metabolism.

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.

CTRP9 Promotes Brown Adipose Tissue Lipolysis in Mice Fed a High-Fat Diet.

BACKGROUND: This study aimed to elucidate the molecular mechanism through which C1q/tumor necrosis factor (TNF)-related protein 9 (CTRP9) acts in the formation and differentiation of brown adipose tissue (BAT). METHODS: Adenovirus particles encoding CTRP9 and green fluorescent protein were inoculated into the scapula of C57BL/6J mice and fed a high-fat diet for 8 weeks; the body weight, lipid droplet morphology, glucose tolerance, insulin tolerance, and protein expression levels were analyzed. In addition, CTRP9 adenovirus was transfected into brown preadipocytes, and differentiation was induced to identify the effect of CTRP9 overexpression on adipocyte differentiation. RESULTS: CTRP9 overexpression significantly increased the weight gain of mice. Additionally, the CTRP9 overexpression group exhibited significantly increased adipose tissue weight and glucose clearance rates and decreased insulin sensitivity and serum triglyceride levels compared to the control group. Furthermore, CTRP9 overexpression significantly upregulated the adipose triglyceride lipase (ATGL) and perilipin 1 protein expression levels in BAT. The cell experiment results confirmed that CTRP9 overexpression significantly inhibited the adipogenesis of brown adipocytes as evidenced by the downregulation of uncoupling protein 1, beta-3 adrenergic receptor, ATGL, and hormone-sensitive lipase mRNA levels and the significant suppression of uncoupling protein 1, ATGL, and perilipin 1 protein levels in brown adipocytes. CONCLUSIONS: The finding of this study demonstrated that CTRP9 promotes lipolysis by upregulating ATGL expression in vivo and inhibits the differentiation of brown preadipocytes in vitro.

UCP1 expression in human brown adipose tissue is inversely associated with cardiometabolic risk factors.

OBJECTIVE: Brown adipose tissue (BAT) is a therapeutic target for obesity. 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) is commonly used to quantify human BAT mass and activity. Detectable 18F-FDG uptake by BAT is associated with reduced prevalence of cardiometabolic disease. However, 18F-FDG uptake may not always be a reliable marker of BAT thermogenesis, for example, insulin resistance may reduce glucose uptake. Uncoupling protein 1 (UCP1) is the key thermogenic protein in BAT. Therefore, we hypothesised that UCP1 expression may be altered in individuals with cardiometabolic risk factors. METHODS: We quantified UCP1 expression as an alternative marker of thermogenic capacity in BAT and white adipose tissue (WAT) samples (n = 53) and in differentiated brown and white pre-adipocytes (n = 85). RESULTS: UCP1 expression in BAT, but not in WAT or brown/white differentiated pre-adipocytes, was reduced with increasing age, obesity, and adverse cardiometabolic risk factors such as fasting glucose, insulin, and blood pressure. However, UCP1 expression in BAT was preserved in obese subjects of <40 years of age. To determine if BAT activity was also preserved in vivo, we undertook a case-control study, performing 18F-FDG scanning during mild cold exposure in young (mean age ∼22 years) normal weight and obese volunteers. 18F-FDG uptake by BAT and BAT volume were similar between groups, despite increased insulin resistance. CONCLUSION: 18F-FDG uptake by BAT and UCP1 expression are preserved in young obese adults. Older subjects retain precursor cells with the capacity to form new thermogenic adipocytes. These data highlight the therapeutic potential of BAT mass expansion and activation in obesity.

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.

Short-term cold exposure induces persistent epigenomic memory in brown fat.

Deficiency of the epigenome modulator histone deacetylase 3 (HDAC3) in brown adipose tissue (BAT) impairs the ability of mice to survive in near-freezing temperatures. Here, we report that short-term exposure to mild cold temperature (STEMCT: 15°C for 24 h) averted lethal hypothermia of mice lacking HDAC3 in BAT (HDAC3 BAT KO) exposed to 4°C. STEMCT restored the induction of the thermogenic coactivator PGC-1α along with UCP1 at 22°C, which is greatly impaired in HDAC3-deficient BAT, and deletion of either UCP1 or PGC-1α prevented the protective effect of STEMCT. Remarkably, this protection lasted for up to 7 days. Transcriptional activator C/EBPß was induced by short-term cold exposure in mouse and human BAT and, uniquely, remained high for 7 days following STEMCT. Adeno-associated virus-mediated knockdown of BAT C/EBPß in HDAC3 BAT KO mice erased the persistent memory of STEMCT, revealing the existence of a C/EBPß-dependent and HDAC3-independent cold-adaptive epigenomic memory.

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.

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.

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.

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.

Effects of N-acetylcysteine on the expressions of UCP1 and factors related to thyroid function in visceral adipose tissue of obese adults: a randomized, double-blind clinical trial.

BACKGROUND: Evidences have shown that obesity is influenced by various factors, including various hormones such as thyroid hormones and the body's metabolism rate. It seems that practical solutions such as weight loss diets and common drugs can affect these potential disorders. In this study, we investigate one of these common drugs, N-Acetylcysteine (NAC), on expressions of UCP1 and factors related to thyroid function in adults with obesity. METHODS AND ANALYSIS: The current investigation was carried out as a randomized clinical trial (RCT) including 43 adults with obesity who were potential candidates for bariatric surgery. These individuals were randomly divided into two groups: 600 mg of NAC (n = 22) or placebo (n = 21) for a duration of 8 weeks. Visceral adipose tissue was utilized in the context of bariatric surgery to investigate the gene expression of UCP1 and thyroid function. Polymerase chain reaction (PCR) was performed in duplicate for UCP1, DIO2, DIO3, THRα and ß, and 18s RNA (as an internal control) using the provided instructions to investigate the expression of the respective genes. RESULTS: Our findings revealed that after 8 weeks compared to placebo, NAC caused a significant decrease in the expression of the DIO3 gene as one of the genes related to thyroid function and metabolism. However, regarding other related genes, no statistically significant was found (despite the increase in UCP1, DIO2, and THRα expression and decrease in THRß expression). In addition, after adjustment of possible confounders, no significant effect was observed on anthropometric factors and serum levels of thyroid hormones. CONCLUSION: The results of this study indicate that, following an 8-week period, NAC effectively decreases the expression of the DIO3 gene in the visceral fat tissue, in comparison to the placebo.

Adipose Tissue Dynamics, Thermogenesis, and Interorgan Connections for Preventing Obesity and Metabolic Disorders.

Adipose tissues, such as white, brown, and beige tissues, play pivotal roles in maintaining energy balance and metabolic health. Whereas white adipocytes store energy, brown and beige adipocytes exhibit high energy expenditure owing to their distinct mitochondrial density and UCP1 expression. Dysfunction in these tissues contributes to metabolic disorders such as type 2 diabetes and cardiovascular diseases. Adipose tissue expansion through cell enlargement or increased cell numbers caused by excess energy storage in white adipocytes substantially influences metabolic health. In obesity, hypertrophic adipocytes trigger inflammation, fibrosis, and hypoxia, whereas smaller adipocytes exert favorable metabolic effects, contributing to insulin sensitivity. Brown and beige adipocytes consume energy for thermogenesis to maintain body temperature, contributing to metabolic homeostasis. The intricate interactions between brown adipose tissues and various organs, such as the liver and heart, highlight the systemic implications of adipose tissue functions. Understanding the complex underlying mechanisms may lead to the development of innovative therapies targeting metabolic disorders by modulating the functions of brown adipose tissue and its interactions with other physiological systems. In this review, we discuss insights into the mechanisms underlying the dysregulation of metabolism owing to abnormalities in adipose tissue remodeling. We focus on the endocrine functions of thermogenic brown and beige adipocytes and explore the interorgan interactions that influence whole-body metabolism.