Brown Adipose Tissue Research Articles

Dark seasons enhance brain and brown adipose tissue interactions related to mu-opioid receptor signaling.

Prior studies reveal seasonal variations of mu-opioid receptor (MOR) signaling in both the brain and the brown adipose tissue (BAT). However, the potential seasonality effect on brain-BAT interactions, related to this signaling pathway, remains unknown. Understanding this dynamic seasonal rhythm may provide novel insights into seasonal affective changes and related psychiatric disorders. Nine adult rats (6 males and 3 females) were housed under standard conditions with photoperiodic cycles simulating local seasonal changes. The rats underwent repeated [11C]carfentanil PET imaging to assess MOR availability in the brain and BAT. Partial Least Squares Regression (PLSR) analysis was applied to evaluate the predictability of brain MOR availability on corresponding BAT measures. Latent variables in the PLSR models were eventually categorized by photoperiod. PLSR models indicated that brain MOR availability considerably accounted for the variance of MOR levels in the BAT (22.82%), comparable to age (23%). Models applying different brain regional measures (striatum, neocortex and thalamus) produced consistent latent variables across models. A shorter photoperiod was associated with increased latent variable (beta = -4.32, 95% CI [-5.30, -3.35]). These findings suggest that shorter photoperiods enhance, while longer photoperiods reduce, the predictability of brain MOR levels on BAT MOR signaling. These data imply that darker seasons may amplify the interaction between brain activity and peripheral physiology associated with MOR signaling. The adaptability of brain-BAT interactions under stress stimuli offers a new avenue for exploring systems biology.

Effect of Different Fatty Acid Types on Mitochondrial Dysfunction Associated With Brown and Beige Adipose Tissue.

Adipose tissue serves as a dynamic endocrine organ that is pivotal in metabolic regulation. Augmenting mitochondrial activity within this tissue holds promise in combating obesity. Mitochondrial function is intricately modulated by diverse fatty acid compositions. This comprehensive review aimed to elucidate the molecular mechanisms underlying mitochondrial dysfunction induced by various fatty acid profiles. While saturated fatty acids (SFAs) pose a threat to mitochondrial integrity, polyunsaturated fatty acids (PUFAs), notably n-3, mitigate SFA-induced damage, concurrently regulating thermogenic gene expression. With regard to monounsaturated fatty acids (MUFAs), their impact on mitochondrial function in adipose tissue remains relatively unexplored. Although human studies are imperative for comprehensive insights, prioritizing the consumption of n-3 fatty acids and MUFAs has emerged as a strategic approach, potentially enhancing mitochondrial biogenesis and metabolic pathways. This synthesis underscores the critical need for further investigation of the differential effects of fatty acid types on adipose tissue mitochondria, offering potential avenues for obesity intervention.

Development of an adipocyte differentiation protocol using 3T3-L1 cells for the investigation of the browning process: identification of the PPAR-γ agonist rosiglitazone as a browning reference drug

BackgroundObesity is a metabolic disease that is characterized by an excessive accumulation of adipose tissue (AT) and is often associated with other pathologies. AT is a lipid storage organ with endocrine functions that presents two main phenotypes: white adipose tissue (WAT) and brown adipose tissue (BAT). Preadipocytes or mature white adipocyte cells can differentiate in a middle phenotype with morpho/functional characteristics between WAT and BAT, known as brown-like or beige adipose tissue (BeAT), through the browning process. Considering the interest in stimulating the browning process in metabolic disorders and the lack of clarity, evenness, and reproducibility of the preclinical models, the detailed description of an adipocyte differentiation protocol and the “de novo” development of a beige adipocyte phenotype has been described. Furthermore, the most described stimuli in inducing the browning process, such as PPAR-γ agonists (using rosiglitazone, RGZ) and β-adrenergic stimulators (using isoproterenol, ISO), were evaluated in order to describe their involvement in the browning process and identify a reference compound for the induction of the “de novo” browning.MethodsImmortalized murine embryonic fibroblasts (3T3-L1) cells were differentiated for up to 17 days using a differentiation medium (DM) and a maintenance medium (MM) with or without RGZ or ISO to obtain both the mature white and the beige adipocyte phenotype. The differentiation was evaluated by the Oil Red O (ORO) staining assay, citrate synthase activity, and mitochondrial uncoupling protein 1 (UCP-1) immunodetection and expression performed on different days (T0, T3, T10, and T17) after the induction of differentiation.ResultsThe results indicated that RGZ induced morphology and ORO-positive lipid deposits and increased the activity of citrate synthase enzyme and UCP-1 levels overlapping with a beige adipocyte phenotype after 17 days. ISO did not display a significant effect in these experimental conditions.ConclusionOverall, this work describes in depth the different phases of the adipocyte differentiation process by offering a detailed and reproducible “de novo” browning differentiation model. Furthermore, the efficacy of the stimulation of the PPAR-γ pathway in obtaining a beige adipocyte phenotype demonstrates that RGZ can induce the browning process and elects it as a perfect reference compound for experimental procedures in this field.

Curcumin mitigates obesity-driven dysbiosis and liver steatosis while promoting browning and thermogenesis in white adipose tissue of high-fat diet-fed mice.

Curcumin mitigates obesity-driven dysbiosis and liver steatosis while promoting browning and thermogenesis in white adipose tissue of high-fat diet-fed mice.

Mipep deficiency in adipocytes impairs mitochondrial protein maturation and leads to systemic inflammation and metabolic dysfunctions

Most mitochondrial proteins encoded in the nuclear genome are synthesized in the cytoplasm. These proteins subsequently undergo maturation through the cleavage of a signal sequence at the N-terminus by one or two mitochondrial signal peptidases, which is essential for their function within mitochondria. The present study demonstrates that adipocyte-specific knockout of one mitochondrial signal peptidase, mitochondrial intermediate peptidase (MIPEP), resulted in disordered mitochondrial proteostasis of MIPEP substrate proteins and their defective maturation. MIPEP deficiency in white and brown adipocytes suppressed the expression of adipocyte differentiation, lipid metabolism, and mitochondrial biogenesis genes. These alterations led to lipoatrophy in white adipose tissue and the whitening of brown adipose tissue. Additionally, it induced an atypical mitochondrial unfolded protein response and local inflammation in white and brown adipose tissue. Furthermore, it induced fatty liver and splenomegaly and caused systemic impairments in glucose metabolism and inflammation. These findings indicate that maturation defects of certain mitochondrial proteins and subsequent proteostasis disorders in white and brown adipocytes cause chronic and systemic inflammatory and metabolic dysfunctions.

Mirabegron induces selective changes in the faecal microbiota of HFHFr rats without altering bile acid composition

IntroductionMetabolic dysfunction-associated steatotic liver (MASL), the initial, asymptomatic stage of the metabolic dysfunction-associated steatotic liver disease, is directly involved in the progression to steatohepatitis. Healthy lifestyle and dietary measures are currently the only treatments for MASL. Given the high prevalence of MASL in the human population, candidate drugs for its prevention or treatment should have an acceptable safety profile. Repurposing drugs already in clinical use could help to identify effective and safe drug treatments for MASL. We have characterized a high-fat, high-fructose rat dietary model of simple hepatic steatosis to evaluate the potential anti-steatotic effect of mirabegron, which is already in clinical use for the treatment of overactive bladder. We have previously reported that mirabegron administration was unable to reduce liver triglyceride content in our rat model.MethodsIn the present work, we analyse stored liver, adipose tissue (perigonadal and brown), serum and faecal samples from our previous study and present new biochemical, faecal metabolomic and microbiome data.Results and discussionWe show that oral administration of mirabegron significantly increases the expression of uncoupling protein 1 in brown adipose tissue and β3-Adrenergic receptor protein in perigonadal white adipose and liver tissues. Furthermore, mirabegron treatment changes the relative abundance of several genus and families of rat faecal microbiota, albeit without restoring the global biodiversity and evenness indexes observed in control rats, as well as faecal bile acids composition. These changes are probably due to a direct effect of mirabegron on the gut microbiome, rather than being mediated by changes in bile acid induced by drug treatment.

Plasma CCL3 predicts adverse heart failure outcomes in patients with arrhythmogenic cardiomyopathy

BackgroundFibro-fatty replacement of the myocardium plays a key role in the pathogenesis of arrhythmogenic cardiomyopathy (ACM) and may be associated with progressive heart failure (HF). We aimed to investigate the characteristic of the fibro-fatty tissues of ACM patients and the plasma chemokines levels according to HF burden.MethodsThe expression level of markers for brown, beige, and white fat of fibro-fatty tissues was determined using a quantitative real-time polymerase chain reaction. Lipidomics analysis of fibro-fatty tissues (n = 10 for normal control [NC]; n = 24 for ACM patients) was conducted using LC–MS. Single-cell RNA sequencing (n = 2 for NC; n = 6 for ACM patients) was used to compare the immune environment in the myocardium. Immunostaining and enzyme-linked immunosorbent assay were used to examine the expression of CCL3 in the myocardium and plasma samples, respectively.ResultsThe expression level of beige (TBX1 and TMEM26) and brown (TNFRSF9) fat markers were higher in the fibro-fatty tissues of ACM patients compared to NC. The fibro-fatty tissues revealed a significant increased level of saturated triglycerides (TGs) in ACM patients compared with NC. Single-cell RNA sequencing revealed the obvious accumulation of proinflammatory macrophages and a high expression level of proinflammatory markers in the myocardium of ACM patients compared to NC. The expression of CCL3 in the fibro-fatty tissues was positively correlated with HF progression in patients with ACM. Plasma CCL3 levels were significantly higher in patients with ACM compared to healthy volunteer. A total of 102 patients with ACM have been followed for a median of 7.8 years, indicating that plasma CCL3 levels could successfully predict the incidence of HF and heart transplantation (HTx)/death in patients with ACM (hazard ratio = 3.122 [95% confidence interval, 1.556–6.264]). The ROC curve analysis revealed the AUC value reached 0.814 for HF and 0.756 for HTx/death.ConclusionsThe increased level of saturated TGs and CCL3 in the fibro-fatty tissues might promote HF progression in ACM patients. Plasma CCL3 levels are useful for predicting HF-related adverse events in patients with ACM, but requiring further validation in larger and independent cohorts.Graphical

Effects of Maternal Blood β-Hydroxybutyrate on Brown Adipose Tissue Functions and Thermogenic and Metabolic Health in Neonatal Calves.

Effects of Maternal Blood β-Hydroxybutyrate on Brown Adipose Tissue Functions and Thermogenic and Metabolic Health in Neonatal Calves.

Bone Modelling and Remodelling in Cold Environment

People engaged in various activities in cold environments—such as those living in cold climates, polar workers, cold storage workers, and athletes engaged in winter sports—are frequently affected by cold environments. Therefore, it is of great significance to explore the modelling and remodelling of bones in cold environments. Cold environments can shorten the length of bones, thin the thickness of bones, decrease bone mineral density (BMD), change the biomechanical properties of bones, and lead to bone loss. In addition, cold directly affects the bone microenvironment. Exposure to cold causes spindle-like and fibroblast-like changes in bone marrow mesenchymal stem cells (BMSCs) and decreases their proliferation, and cold exposure promotes the osteogenic differentiation of BMSCs partly through the p38 MAPK pathway. Cold also alters the dendritic differentiation of OBs by reducing the transmembrane glycoprotein E11/podoplanin and damages endothelial cells (ECs) by elevating levels of VEGF, resulting in a reduced blood supply and thus fewer OBs. In addition, cold promotes lipolysis of marrow adipose tissue (MAT), but in combination with exercise, it can promote the differentiation of BMSCs into MAT. Cold environments interfere with angiogenesis and inhibit bone growth by affecting factors such as platelet-derived growth factor type BB (PDGF-BB), slit guidance ligand 3 (SLIT3), Notch, and VEGF. In addition, cold environments may promote bone resorption by activating sympathetic nerves to activate β-adrenergic receptors and regulating leptin secretion, and regulate bone metabolism by activating the p38 MAPK signalling pathway and increasing the synthesis of brown fat, which ultimately inhibit bone formation and enhance bone resorption. In this paper, we describe the effects of cold environments on bones in the locomotor system in terms of bone structure, bone mass, biomechanical properties, and various skeletal cells, bone blood vessels, and bone fat systems in the bone microenvironment.

Acyl CoA-binding protein in brown adipose tissue acts as a negative regulator of adaptive thermogenesis.

Acyl CoA-binding protein in brown adipose tissue acts as a negative regulator of adaptive thermogenesis.

BAP1 suppresses white adipose tissue browning and thermogenesis through deubiquitinating KDM1B.

Obesity is a growing global health threat, and inducing browning of white adipose tissue (WAT) to increase energy expenditure has become an attractive strategy for treating obesity and related metabolic complications. BRCA1-associated protein 1 (BAP1), a ubiquitin C-terminal hydrolase (UCH) domain-containing deubiquitinase (DUB) expressed broadly across tissues, has previously been shown to play an important role in liver carbohydrate and lipid metabolism. However, its role in the browning of inguinal white adipose tissue (iWAT) has not been studied. Our study initially found that BAP1 expression was downregulated in cold-induced mouse iWAT but upregulated in obese conditions. Furthermore, overexpression of BAP1 in the inguinal fat tissue suppressed iWAT browning and thermogenesis. Mechanistically, we found that BAP1 interacts with KDM1B and stabilizes it through deubiquitination. Subsequently, KDM1B demethylates H3K4me1/2 modifications in proximity to thermogenesis-related genes, thereby inhibiting the expression of genes essential for browning. In summary, our study shows that BAP1 negatively regulates iWAT browning via a mechanism mediated by KDM1B.

Suppression of hypothalamic oestrogenic signal sustains hyperprolactinemia and metabolic adaptation in lactating mice.

17β-oestradiol (E2) inhibits overeating and promotes brown adipose tissue (BAT) thermogenesis, whereas prolactin (PRL) does the opposite. During lactation, the simultaneous decline in E2 and surge in PRL contribute to maternal metabolic adaptations, including hyperphagia and suppressed BAT thermogenesis. However, the underlying neuroendocrine mechanisms remain unclear. Here, we find that oestrogen receptor alpha (ERα)-expressing neurons in the medial basal hypothalamus (MBH), specifically the arcuate nucleus of the hypothalamus and the ventrolateral subdivision of the ventromedial hypothalamus (vlVMH), are suppressed during lactation. Deletion of ERα from MBH neurons in virgin female mice induces metabolic phenotypes characteristic of lactation, including hyperprolactinemia, hyperphagia and suppressed BAT thermogenesis. By contrast, activation of ERαvlVMH neurons in lactating mice attenuates these phenotypes. Overall, our study reveals an inhibitory effect of E2-ERαvlVMH signalling on PRL production, which is suppressed during lactation to sustain hyperprolactinemia and metabolic adaptations.

From Fat Providers to Cancer Therapy: Adipocytes as Unexpected Allies.

Adipocytes from white adipose tissue support cancer progression by supplying fatty acids to tumor cells while cold-activated brown adipose tissue has been shown to inhibit tumor growth by disrupting cancer cell metabolism. In a groundbreaking study published in Nature Biotechnology, Nguyen and colleagues developed Adipose-Modified Therapy (AMT), a strategy that genetically reprograms white adipocytes to outcompete tumors for key nutrients. Using CRISPR activation technology, researchers enhanced adipocyte glucose and fatty acid consumption, by inducing a stable browning phenotype. In vitro, browned adipocytes reduced glycolysis and fatty acid oxidation in cancer cells, inhibiting their proliferation. Implantation of engineered adipose organoids adjacent to tumors suppressed tumor growth, reduced angiogenesis, and altered metabolic gene expression in xenograft models. AMT also prevented tumor development in genetic mouse models of cancer, suggesting a role in cancer prevention. Finally, modified human mammary adipocytes inhibited the growth of patient-derived breast cancer organoids. This therapy, based on autologous fat transplantation, could offer a reversible and patient-specific approach. Challenges remain, including metabolic plasticity in cancer cells and the fragility of mature adipocytes in cell culture. AMT represents a paradigm shift in cancer therapy, leveraging adipocytes as metabolic competitors rather than tumor facilitators, opening new avenues for metabolism-targeted cancer treatments.

TRIM22 governs tumorigenesis and protects against endometrial cancer-associated cachexia by inhibiting inflammatory response and adipose thermogenic activity

BackgroundEndometrial cancer (EC) is one of the most common cancers in women, with a short overall survival and poor prognosis. Besides the biologically aggressive EC properties, Cancer-associated cachexia is the main factor. However, the detailed mechanism underlying EC-related cachexia and its harmful effects on EC progression and patient prognosis remains unclear.MethodsFor clinical specimen and the vitro experiment, we detected TRIM22 expression level, EC patients’ survival time, EC cell functional change, and adipose thermogenic changes to identify the function of TRIM22 in EC progression, EC-associated cachexia, and their molecular mechanisms. Then, for the vivo experiment, we exploited the xenografts in mice to identify the function of TRIM22 again, and to screen the drug therapeutic schedule.ResultsHerein, we demonstrated that TRIM22 inhibited EC cell growth, invasion, and migration. Interleukin (IL)-6 mediated brown adipose tissue activation and white adipose tissue browning which induced EC-related cachexia. TRIM22 suppressed the EC cells’ secretion of IL-6, and IL-6 mediated EC-related cachexia. Mechanistically, TRIM22 inhibited EC progression by suppressing the nucleotide-binding oligomerization domain 2(NOD2)/nuclear factor-kappaB (NF-κB) signaling pathway, with the purpose of impeding the production of IL-6. Moreover, we revealed that TRIM22 inhibited EC-associated cachexia by suppressing the IL-6/IL-6 receptor (IL-6R) signaling pathway. Therapeutically, we demonstrated that combination treatment with a TRIM22 inducer (progesterone) and a thermogenic inhibitor (IL-6R antibody) synergistically augmented the antitumor efficacy of carbotaxol (carboplatin and paclitaxel), in vivo.ConclusionOur data reveals that TRIM22-EC-IL-6-cachexia cross-communication has important clinical relevance and that the use of combined therapy holds great promise for enhancing the efficacy of anti-ECs. (Fig. graphical abstract)Graphical abstract

Pre-fertilization-origin preservation of brown fat-mediated energy expenditure in humans.

Environmental thermal stress substantially affects cellular plasticity of thermogenic adipocytes and energy balance through transcriptional and epigenetic mechanisms in rodents. However, roles of cold-adaptive epigenetic regulation of brown adipose tissue (BAT) in systemic energy metabolism in humans remained poorly understood. Here we report that individuals whose mothers conceived during cold seasons exhibit higher BAT activity, adaptive thermogenesis, increased daily total energy expenditure and lower body mass index and visceral fat accumulation. Structural equation modelling indicated that conception during the cold season protects against age-associated increase in body mass index through BAT activation in offspring. Meteorological analysis revealed that lower outdoor temperatures and greater fluctuations in daily temperatures during the fertilization period are key determinants of BAT activity. These findings suggest that BAT metabolic fate and susceptibility of metabolic diseases are preprogrammed by the epigenetic inheritance of cold exposure before the fertilization in humans.

Sonographic Measurement of Adipose Tissue; Potential Biomarkers of Brown Fat

Sonographic Measurement of Adipose Tissue; Potential Biomarkers of Brown Fat

16/8 intermittent fasting in mice protects from diet‐induced obesity by increasing leptin sensitivity and postprandial thermogenesis

AbstractAimsTo evaluate the molecular mechanisms involved in intermittent fasting 16/8 (16/8 IF), a widespread dietary practice adopted worldwide that consists of 16 h of fasting and 8 h of feeding.MethodsObese mice were fasted daily from 6 am to 10 pm. Food intake, body weight, and energy expenditure were measured. Molecular mechanisms were investigated using ELISA, western blot, and qPCR of white and brown adipose tissues. Glucose homeostasis was also evaluated. Ucp1 knockout and ob/ob mice were utilized.ResultsThe 16/8 IF regimen improved glucose homeostasis and reduced body weight, food intake, and overall adiposity. Postprandial VO2, heat production, brown adipose tissue (BAT) temperature, and ketone bodies increased with 16/8 IF. Postprandial thermogenesis induced by 16/8 IF was abolished in mice after BAT denervation or Ucp1 deletion. Serum leptin levels were elevated, and most metabolic effects of 16/8 IF were absent in leptin‐deficient ob/ob mice. Additionally, leptin sensitivity increased in mice exposed to 16/8 IF.ConclusionThe 16/8 IF regimen can improve metabolism, with findings underscoring the role of enhanced leptin action in inhibiting food intake and promoting postprandial thermogenesis during 16/8 IF.

The Futile Creatine Cycle powers UCP1-independent thermogenesis in classical BAT

Classical brown adipose tissue (BAT) is traditionally viewed as relying exclusively on uncoupling protein 1 (UCP1) for thermogenesis via inducible proton leak. However, the physiological significance of UCP1-independent mechanisms linking substrate oxidation to ATP turnover in classical BAT has remained unclear. Here, we identify the Futile Creatine Cycle (FCC), a mitochondrial-localized energy-wasting pathway involving creatine phosphorylation by creatine kinase b (CKB) and phosphocreatine hydrolysis by tissue-nonspecific alkaline phosphatase (TNAP), as a key UCP1-independent thermogenic mechanism in classical BAT. Reintroducing mitochondrial-targeted CKB exclusively into interscapular brown adipocytes in vivo restores thermogenesis and cold tolerance in mice lacking native UCP1 and CKB, in a TNAP-dependent manner. Furthermore, mice with inducible adipocyte-specific co-deletion of TNAP and UCP1 exhibit severe cold-intolerance. These findings challenge the view that BAT thermogenesis depends solely on UCP1 because of insufficient ATP synthase activity and establishes the FCC as a physiologically relevant thermogenic pathway in classical BAT.

Unraveling the gut microbiota’s role in obesity: key metabolites, microbial species, and therapeutic insights

ABSTRACT Obesity, characterized by excessive fat accumulation, stems from an imbalance between energy intake and expenditure, with the gut microbiota playing a crucial role. This review highlights how gut microbiota influences metabolic pathways, inflammation, and adipose tissue regulation in obesity. Specific bacteria and metabolites, such as lipopolysaccharides (LPS) and short-chain fatty acids (SCFAs), modulate gut permeability, inflammation, and energy harvest, impacting obesity development. Certain gut bacteria, including Clostridium XIVb , Dorea spp., Enterobacter cloacae , and Collinsella aerofaciens , promote obesity by increasing energy harvest, gut permeability, and inflammatory response through LPS translocation into the bloodstream. Conversely, beneficial bacteria like Akkermansia muciniphila , Lactobacillus spp., and Bifidobacterium spp. enhance gut barrier integrity, regulate SCFA production, and modulate fasting-induced adipose factor, which collectively support metabolic health by reducing fat storage and inflammation. Metabolites such as SCFAs (acetate, propionate, and butyrate) interact with G-protein coupled receptors to regulate lipid metabolism and promote the browning of white adipose tissue (WAT), thus enhancing thermogenesis and energy expenditure. However, LPS contributes to insulin resistance and fat accumulation, highlighting the dual roles of these microbial metabolites in both supporting and disrupting metabolic function. Therapeutic interventions targeting gut microbiota, such as promoting WAT browning and activating brown adipose tissue (BAT), hold promise for obesity management. However, personalized approaches are necessary due to individual microbiome variability. Further research is essential to translate these insights into microbiota-based clinical therapies.

Publisher Correction: Cold-induced expression of a truncated adenylyl cyclase 3 acts as rheostat to brown fat function

Publisher Correction: Cold-induced expression of a truncated adenylyl cyclase 3 acts as rheostat to brown fat function