Brown-like Adipocytes Research Articles

Plant miR6262 Modulates the Expression of Metabolic and Thermogenic Genes in Human Hepatocytes and Adipocytes.

Edible plants have been linked to the mitigation of metabolic disturbances in liver and adipose tissue, including the decrease of lipogenesis and the enhancement of lipolysis and adipocyte browning. In this context, plant microRNAs could be key bioactive molecules underlying the cross-kingdom beneficial effects of plants. This study sought to explore the impact of plant-derived microRNAs on the modulation of adipocyte and hepatocyte genes involved in metabolism and thermogenesis. Plant miR6262 was selected as a candidate from miRBase for the predicted effect on the regulation of human metabolic genes. Functional validation was conducted after transfection with plant miRNA mimics in HepG2 hepatocytes exposed to free fatty acids to mimic liver steatosis and hMADs cells differentiated into brown-like adipocytes. miR6262 decreases the expression of the predicted target RXRA in the fatty acids-treated hepatocytes and in brown-like adipocytes and affects the expression profile of critical genes involved in metabolism and thermogenesis, including PPARA, G6PC, SREBF1 (hepatocytes) and CIDEA, CPT1M and PLIN1 (adipocytes). Nevertheless, plant miR6262 mimic transfections did not decrease hepatocyte lipid accumulation or stimulate adipocyte browning. these findings suggest that plant miR6262 could have a cross-kingdom regulation relevance through the modulation of human genes involved in lipid and glucose metabolism and thermogenesis in adipocytes and hepatocytes.

Cocoa extract induces browning of white adipocytes and improves glucose intolerance in mice fed a high-fat diet.

Cocoa extract (CE) offers several health benefits, such as anti-obesity and improved glucose intolerance. However, the mechanisms remain unclear. Adipose tissue includes white adipose tissue (WAT) and brown adipose tissue. Brown adipose tissue leads to body fat reduction by metabolizing lipids to heat via uncoupling protein 1 (UCP1). The conversion of white adipocytes into brown-like adipocytes (beige adipocytes) is called browning, and it contributes to the anti-obesity effect and improved glucose tolerance. This study aimed to evaluate the effect of CE on glucose tolerance in terms of browning. We found that dietary supplementation with CE improved glucose intolerance in mice fed a high-fat diet, and it increased the expression levels of Ucp1 and browning-associated gene in inguinal WAT. Furthermore, in primary adipocytes of mice, CE induced Ucp1 expression through β3-adrenergic receptor stimulation. These results suggest that dietary CE improves glucose intolerance by inducing browning in WAT.

Carnosic Acid (CA) Induces a Brown Fat-like Phenotype, Increases Mitochondrial Biogenesis, and Activates AMPK in 3T3-L1 Adipocytes.

Adipose tissue plays a crucial role in regulating metabolic homeostasis, and its dysfunction in obesity leads to insulin resistance and type 2 diabetes (T2D). White adipose tissue (WAT) primarily stores energy as lipids, while brown adipose tissue (BAT) regulates thermogenesis by dissipating energy as heat. The process of browning involves the transdifferentiation of WAT into brown-like or beige adipocytes, which exhibit a similar phenotype as BAT. The browning of WAT is an attractive approach against obesity and T2D, and the activation of the energy sensor AMP-activated protein kinase (AMPK) has been shown to play a role in browning. Carnosic acid (CA), a polyphenolic diterpene, found in many plants including rosemary, is reported to possess potent antioxidant, anti-inflammatory, and anti-hyperglycemic properties. The limited evidence available indicates that CA activates AMPK and may have anti-obesity and antidiabetic potential; however, the effects in adipocyte browning remain largely unexplored. This study aimed to examine the effects of CA on the markers of adipocyte browning. The treatment of 3T3L1 adipocytes with CA activated AMPK, reduced lipid accumulation, and increased the expression of browning protein markers (UCP-1, PGC-1α, PRDM16, and TFAM) and mitochondrial biogenesis. The use of compound C, an AMPK inhibitor, significantly attenuated the effects of CA, indicating AMPK involvement. These studies demonstrate that CA can activate AMPK and stimulate the browning of white adipocytes. Future animal and human studies are required to examine the effects of CA in vivo.

White adipocytes in subcutaneous fat depots require KLF15 for maintenance in preclinical models.

Healthy adipose tissue is essential for normal physiology. There are 2 broad types of adipose tissue depots: brown adipose tissue (BAT), which contains adipocytes poised to burn energy through thermogenesis, and white adipose tissue (WAT), which contains adipocytes that store lipids. However, within those types of adipose, adipocytes possess depot and cell-specific properties that have important implications. For example, the subcutaneous and visceral WAT confers divergent risk for metabolic disease. Further, within a depot, different adipocytes can have distinct properties; subcutaneous WAT can contain adipocytes with either white or brown-like (beige) adipocyte properties. However, the pathways that regulate and maintain this cell and depot-specificity are incompletely understood. Here, we found that the transcription factor KLF15 is required for maintaining white adipocyte properties selectively within the subcutaneous WAT. We revealed that deletion of Klf15 is sufficient to induce beige adipocyte properties and that KLF15's direct regulation of Adrb1 is a critical molecular mechanism for this process. We uncovered that this activity is cell autonomous but has systemic implications in mouse models and is conserved in primary human adipose cells. Our results elucidate a pathway for depot-specific maintenance of white adipocyte properties that could enable the development of therapies for obesity and associated diseases.

Interleukin-10 deficiency induces thoracic perivascular adipose tissue whitening and vascular remodeling.

Perivascular adipose tissue (PVAT) is an adipose layer, surrounding blood vessels, with a local modulatory role. Interleukin-10 (IL-10) has been shown to modulate vascular tissue. This study aimed to characterize the endogenous role of IL-10 in vascular remodeling, and PVAT phenotyping. Thoracic aortic segments from control (C57BL/6J) and IL-10 knockout (IL-10-/-) male mice were used. Analyzes of aorta/PVAT morphometry, and elastin, collagen and reticulin deposition were performed. Tissue uncoupling protein 1 (UCP1) was accessed by Western blotting. Endogenous absence of IL-10 reduced total PVAT area (p = 0.0310), and wall/lumen ratio (p = 0.0024), whereas increased vascular area and thickness (p < 0.0001). Total collagen deposition was augmented in IL-10-/-, but under polarized light, the reduction of collagen-I (p = 0.0075) and the increase of collagen-III (p = 0.0055) was found, simultaneously with reduced elastic fibers deposition (p = 0.0282) and increased deposition of reticular fibers (p < 0.0001). Adipocyte area was augmented in the IL-10 absence (p = 0.0225), and UCP1 expression was reduced (p = 0.0420). Moreover, relative frequency of white adipose cells and connective tissue was augmented in IL-10-/- (p < 0.0001), added to a reduction in brown adipose cells (p < 0.0001). Altogether, these data characterize aorta PVAT from IL-10-/- as a white-like adipocyte phenotype. Endogenous IL-10 prevents vascular remodeling and favors a brown-like adipocyte phenotype, suggesting a modulatory role for IL-10 in PVAT plasticity.

Deep learning enables the quantification of browning capacity of human adipose samples

BackgroundThe recruitment of thermogenic adipocytes in human fat depots markedly improves metabolic disorders such as type 2 diabetes mellitus (T2DM). However, identification and quantification of thermogenic cells in human fats, especially in metabolic disorders patients, remains a major challenge. Here, we aim to provide a stringent validation of human thermogenic adipocyte signature genes, and construct transcriptome-based models to quantify the browning degree of human fats.MethodsEvidence from RNA-seq, microarray analyses and experimental approaches were integrated to isolate robust human brown-like fat signature genes. Meta-analysis was employed to validate the performance of known human brown-like fat marker genes. Autoencoder was used to reveal the browning levels of human adipose samples for supervised machine learning. Ensemble machine learning was applied to devised molecular metrics for quantifying browning degree of human fats. Obesity and T2DM datasets were used to validate the performance of the molecular metrics in adipose-related metabolic disorders.ResultsHuman brown-like adipocytes were heterogeneous populations which showed distinct transcriptional patterns and biological features. Only DHRS11, REEP6 and STX11 were robust signature genes that were consistently up-regulated in different human brown-like fats, especially in creatine-induced UCP1-independent adipocytes. The molecular metrices based on the expression patterns of the three signature genes, named human browning capacity index (HBI) and absolute HBI (absHBI), were superior to 26 traditional human brown-like fat marker genes and previously reported browning classifier in prediction of browning levels of human adipocytes and adipose tissues as well as primary cell cultures upon various physiological and pharmacological stimuli. Notably, these molecular metrics also reflected the insulin sensitivity and glucose-lipid metabolic activity of human adipose samples from obesity and T2DM patients.ConclusionsIn summary, this study provides promising signatures and computational tools for evaluating browning levels of human adipose samples in response to physiological and medical intervention. The metrices construction pipeline provides an alternative approach for training machine learning models using unlabeled samples.

Mitophagy Responds to the Environmental Temperature and Regulates Mitochondrial Mass in Adipose Tissues.

There are at least two types of adipose tissues in the body, defined as brown adipose tissues (BATs) and white adipose tissues (WATs). These tissues comprise brown and white adipocytes, respectively. The adipocytes are commonly endowed with mitochondria, but they have diverse characteristics and roles. Brown adipocytes have abundant mitochondria that contribute to the β-oxidation of fatty acids to produce chemical energy and the production of heat via uncoupling of the mitochondrial membrane potential from ATP synthesis. Alternatively, white adipocytes have fewer mitochondria that contribute to the generation of free fatty acids via lipogenesis by providing key intermediates. Besides the described types of adipocytes, brown-like adipocytes, termed beige adipocytes, are developed in WAT depots during cold exposure. Beige adipocytes also contribute to thermogenesis. Notably, beige adipocytes may transform into white-like adipocytes after the withdrawal of cold exposure. This process is marked by the elimination of mitochondria through the activation of mitochondria autophagy (mitophagy). This review aims to describe the mitophagy that occurs during the beige-to-white transition and discuss recent insights into the molecular mechanisms of this transformation. Additionally, we describe the mitophagy monitoring strategy in adipose tissues using three independent reporter systems and discuss the availabilities and limitations of the method.

Cold-inducible lncRNA266 promotes browning and the thermogenic program in white adipose tissue.

Cold-induced nonshivering thermogenesis has contributed to the improvement of several metabolic syndromes caused by obesity. Several long noncoding RNAs (lncRNAs) have been shown to play a role in brown fat biogenesis and thermogenesis. Here we show that the lncRNA lnc266 is induced by cold exposure in inguinal white adipose tissue (iWAT). In vitro functional studies reveal that lnc266 promotes brown adipocyte differentiation and thermogenic gene expression. At room temperature, lnc266 has no effects on white fat browning and systemic energy consumption. However, in a cold environment, lnc266 promotes white fat browning and thermogenic gene expression in obese mice. Moreover, lnc266 increases core body temperature and reduces body weight gain. Mechanistically, lnc266 does not directly regulate Ucp1 expression. Instead, lnc266 sponges miR-16-1-3p and thus abolishes the repression of miR-16-1-3p on Ucp1 expression. As a result, lnc266 promotes preadipocyte differentiation toward brown-like adipocytes and stimulates thermogenic gene expression. Overall, lnc266 is a cold-inducible lncRNA in iWAT, with a key role in white fat browning and the thermogenic program.

1507-P: Carnosic Acid–Induced Browning in 3T3-L1 Adipocytes Is Dependent on AMPK Activation

Background: Increased adiposity has long been associated with insulin resistance and adipose tissue plays a crucial role in regulating metabolic homeostasis, as its dysfunction in obesity leads to insulin resistance and type 2 diabetes (T2D). The primary function of white adipose tissue (WAT) is to store energy as lipids while brown adipose tissue (BAT) regulates thermogenesis by dissipating energy in a form of heat. The process of browning involves transdifferention of WAT into brown-like or beige adipocytes, which exhibit the same functional properties as BAT. Browning of WAT is an attractive approach against obesity and insulin resistance. In addition, evidence indicate that activation of the energy sensor AMP-activated protein kinase (AMPK) could counteract insulin resistance. The aim of this study is to examine if carnosic acid (CA), induces browning via activation of AMPK in 3T3-L1 white adipocytes. Material and methods: Cell morphology, lipid accumulation, mitochondrial density, and browning markers such as uncoupling protein-1 (UCP-1) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) levels were assessed using Cytation5 microscope, Oil-O-Red (ORO), MitoTracker Red, immunoblotting and immunocytochemistry. Results: Microscopic investigation revealed that CA reduced the size and number of lipid droplets in the cells, giving a rise to a brown-like phenotype. The reduction of lipid accumulation was also confirmed by ORO stain. Next, CA increased mitochondrial density and protein expression of UCP-1 and PGC-1-α in 3T3-L1 adipocytes. Most importantly, pre-treatment with compound C, prevented the CA-induced reduction in lipid accumulation, and mitochondrial density and blocked the CA-induced increase in UCP-1 and PGC-1 expression. Conclusion: This study demonstrates that CA has a pronounced potential in stimulating browning of adipocytes via AMPK-dependent mechanism. Future in vivo studies are required to fully examine the effects of CA. Disclosure F.Vlavcheski: None. N.Tsakiridis: None. A.Giacca: None. E.Tsiani: None. Funding Natural Science and Engineering Research Council of Canada (RGPIN-2018-06666)

Combination therapy of metformin and p-coumaric acid mitigates metabolic dysfunction associated with obesity and nonalcoholic fatty liver disease in high-fat diet obese C57BL/6 mice

Metformin (MET) has been demonstrated to have favorable impact on nonalcoholic fatty liver disease (NAFLD); however, the combined effect of this drug with p-coumaric acid (PCA) on liver steatosis is unclear. The aim of the current study was to evaluate the combined effects of MET and PCA on NAFLD in a high-fat diet (HFD)-induced NAFLD mouse model. The obese mice received MET (230 mg/kg), PCA (200 mg/kg) monotherapies, and MET combination with PCA in the diet for 10 weeks. Our results showed that the combination of MET and PCA markedly ameliorated weight gain and fat deposition in HFD fed mice. Furthermore, the combination of MET and PCA lowered liver triglyceride (TG) content which was accompanied by decreased expression of lipogenic and increased expression of β-oxidation related genes and proteins. In addition, combination therapy of MET and PCA mitigated liver inflammation through inhibiting hepatic macrophage infiltration (F4/80), switching macrophage from M1 into M2 phenotype, and ameliorating nuclear factor-κB (NF-κB) activity in comparison with the monotherapy of MET or PCA. Furthermore, we found that MET and PCA combination therapy upregulated thermogenesis-related genes in BAT and sWAT. Combination therapy results in stimulating brown-like adipocyte (beige) formation in the sWAT of HFD mice. Taken together, these findings indicate that MET combined with PCA can improve NAFLD through decreasing lipid accumulation, inhibiting inflammation and inducing thermogenesis, and adipose tissue browning.

The combination of metformin with morin alleviates hepatic steatosis via modulating hepatic lipid metabolism, hepatic inflammation, brown adipose tissue thermogenesis, and white adipose tissue browning in high-fat diet-fed mice

AimThe valuable effects of metformin (MET) and morin (MOR) in the improvement of NAFLD have been proposed, nevertheless, their combination impacts were not investigated so far. We determined the therapeutic effects of combined MET and MOR treatment in high-fat diet (HFD)-induced Non-alcoholic fatty liver disease (NAFLD) mice. MethodsC57BL/6 mice were fed on an HFD for 15 weeks. Animals were allotted into various groups and supplemented with MET (230 mg/kg), MOR (100 mg/kg), and MET + MOR (230 mg/kg + 100 mg/kg). Key findingsMET in combination with MOR reduced body and liver weight in HFD-fed mice. A significant decrease in fasting blood glucose and improvement in glucose tolerance was observed in HFD mice treated with MET + MOR. Supplementation with MET + MOR led to a decline in hepatic triglyceride levels and this impact was associated with diminished expression of fatty-acid synthase (FAS) and elevated expression of carnitine palmitoyl transferase 1 (CPT1) and phospho-Acetyl-CoA Carboxylase (p-ACC). Moreover, MET combined with MOR alleviates hepatic inflammation through the polarization of macrophages to the M2 phenotype, decreasing the infiltration of macrophages and lowering the protein level of NF-kB. MET and MOR in combination reduce the size and weight of epididymal white adipose tissue (eWAT), and subcutaneous WAT (sWAT), whereas improves cold tolerance, BAT activity, and mitochondrial biogenesis. Combination therapy results in stimulating brown-like adipocyte (beige) formation in the sWAT of HFD mice. SignificanceThese results suggest that the combination of MET and MOR has a protective effect on hepatic steatosis, which may use as a candidate therapeutic for the improvement of NAFLD.

Knocking Down CDKN2A in 3D hiPSC-Derived Brown Adipose Progenitors Potentiates Differentiation, Oxidative Metabolism and Browning Process.

Human induced pluripotent stem cells (hiPSCs) have the potential to be differentiated into any cell type, making them a relevant tool for therapeutic purposes such as cell-based therapies. In particular, they show great promise for obesity treatment as they represent an unlimited source of brown/beige adipose progenitors (hiPSC-BAPs). However, the low brown/beige adipocyte differentiation potential in 2D cultures represents a strong limitation for clinical use. In adipose tissue, besides its cell cycle regulator functions, the cyclin-dependent kinase inhibitor 2A (CDKN2A) locus modulates the commitment of stem cells to the brown-like type fate, mature adipocyte energy metabolism and the browning of adipose tissue. Here, using a new method of hiPSC-BAPs 3D culture, via the formation of an organoid-like structure, we silenced CDKN2A expression during hiPSC-BAP adipogenic differentiation and observed that knocking down CDKN2A potentiates adipogenesis, oxidative metabolism and the browning process, resulting in brown-like adipocytes by promoting UCP1 expression and beiging markers. Our results suggest that modulating CDKN2A levels could be relevant for hiPSC-BAPs cell-based therapies.

Differentiation of Human Pluripotent Stem Cells (hPSCs) into Brown-Like Adipocytes.

Increasing brown adipose tissue (BAT) mass and activation is a therapeutic strategy to prevent and treat obesity and associated complications. Obese and diabetic patients possess less BAT; thus, finding an efficient way to expand their mass is necessary. There is limited knowledge about how human BAT develops, differentiates, and is optimally activated. Accessing human BAT is challenging, given its scarcity and anatomical dispersion. These constraints make detailed BAT-related developmental and functional mechanistic studies in human subjects virtually impossible. We have developed a new chemically defined protocol for differentiating human pluripotent stem cells (hPSCs) into bona fide brown adipocytes (BAs) that overcomes current limitations. This protocol recapitulates step by step the physiological developmental path of human BAT.

Epigenetic regulation of white adipose tissue plasticity and energy metabolism by nucleosome binding HMGN proteins

White adipose tissue browning is a key metabolic process controlled by epigenetic factors that facilitate changes in gene expression leading to altered cell identity. We find that male mice lacking the nucleosome binding proteins HMGN1 and HMGN2 (DKO mice), show decreased body weight and inguinal WAT mass, but elevated food intake, WAT browning and energy expenditure. DKO white preadipocytes show reduced chromatin accessibility and lower FRA2 and JUN binding at Pparγ and Pparα promoters. White preadipocytes and mouse embryonic fibroblasts from DKO mice show enhanced rate of differentiation into brown-like adipocytes. Differentiating DKO adipocytes show reduced H3K27ac levels at white adipocyte-specific enhancers but elevated H3K27ac levels at brown adipocyte-specific enhancers, suggesting a faster rate of change in cell identity, from white to brown-like adipocytes. Thus, HMGN proteins function as epigenetic factors that stabilize white adipocyte cell identity, thereby modulating the rate of white adipose tissue browning and affecting energy metabolism in mice.

Dihydromyricetin contributes to weight loss via pro-browning mediated by mitochondrial fission in white adipose

Dihydromyricetin (DHM) is a natural bioactive flavonoid extracted from Ampelopsis Grossedentata, a commonly used Chinese herbal medicine. It has multiple beneficial pharmacological effects including lowering blood glucose and lipid, as well as anti-inflammation, anti-oxidation and hepato-protection. In this study, we elucidated its actions on mitochondrial dynamics and browning of white adipose. In the experiments in vivo, six-week-old male C57BL/6 mice were fed with normal diet (ND), high-fat diet (HFD), or HFD with intragastric administration of DHM (250 mg/kg.d−1); in the experiments in vitro, 3T3-L1 and mouse primary preadipocytes were induced and treated with various concentrations of DHM. The mouse metabolic phenotype, lipid accumulation, the browning and mitochondrial dynamics of white adipocytes were examined. It was found that DHM treatment reduced body weight and fat mass, improved glucose tolerance, insulin resistance and cold tolerance in mice with obesity. DHM treatment increased the expressions of classical brown adipocyte markers (UCP-1, PGC-1α, PRDM16) and mitochondrial dynamics-related proteins (DRP1, FIS1, OPA1, MFN2) in adipose tissue. Likewise, DHM treatment induced the differentiation of mature 3T3-L1 cells into brown-like adipocytes and also enhanced the expressions of mitochondrial dynamics-related proteins in vitro. Moreover, the pro-browning effect of DHM can be abrogated by mitochondrial fission inhibitor Mdivi-1. These findings indicate that DHM treatment induces the browning-remodeling of white adipose by enhancing mitochondrial fission and manifests an anti-obesity property via pro-browning mediated by mitochondrial fission, which implies it may play important roles in prevention and therapy of obesity and related diseases.

Olanzapine induces weight gain in offspring of prenatally exposed poly I:C rats by reducing brown fat thermogenic activity.

Background: Olanzapine (OLZ) is an antipsychotic with a high risk of metabolic syndrome, and its induced metabolic disturbance may be related to the thermogenic function of brown adipose tissue (BAT). Of note is that schizophrenia itself appears to be associated with a higher incidence of metabolic syndrome. However, whether OLZ affects metabolic disorders by regulating BAT function and its mechanism in animal models of schizophrenia have not been reported. Methods: We induced maternal immune activation (MIA) in pregnant rodents by injection of synthetic double-stranded RNA-poly I:C (a virus-like substance), and rats were injected with poly I:C, 10 mg/kg) or saline on day 13 of gestation. Rat offspring received OLZ (1 mg/kg, tid) or vehicle from adulthood for 28 days, and body weight and food intake were recorded. Morphological alterations of white adipose tissue (WAT) and BAT were analyzed by HE and oil red staining, and expression of BAT-specific marker proteins/genes was detected by western blot and qRT-PCR. In addition, embryonic stem cells C3H10T1/2 were used to direct differentiation into brown-like adipocytes, and C3H10T1/2 cells were treated with OLZ for the differentiation process. The effects of OLZ on brown-like adipocyte differentiation and activity were analyzed using oil red staining, immunofluorescence and flow cytometry. Results: Compared with the Veh (saline) group, the TG, pWAT weight, adipocyte size and liver weight of the Veh (poly I:C) group were significantly increased, suggesting that the offspring of Poly I:C rats had obvious dyslipidemia and lipid accumulation, which were risk factors for metabolic abnormalities such as obesity. In addition, OLZ treatment resulted in altered WAT and BAT morphology in poly I:C or saline exposed offspring, causing lipid accumulation and weight gain and reducing the expression of the BAT-specific marker molecule UCP1 protein/gene. At the same time, OLZ inhibited the directional differentiation and mitochondrial activity of C3H10T1/2 brown-like adipocytes. Conclusion: Poly I:C-elicited MIA and OLZ differentially inhibited BAT activity and mitochondrial biogenesis, leading to weight gain in adult rats, a process involving PPAR-γ/UCP1-related thermogenic proteins.

Quercetin, Engelitin and Caffeic Acid of Smilax china L. Polyphenols, Stimulate 3T3-L1 Adipocytes to Brown-like Adipocytes Via β3-AR/AMPK Signaling Pathway.

The aim of the present study was to investigate the browning effects mechanism of Smilax china L. polyphenols (SCLP) and its monomer. In this study, polyphenols (SCLP, engeletin, quercetin and caffeic acid) markedly suppressed lipid accumulation. Polyphenols significantly up-graded the expression of protein kinase A (PKA), adipose triglyceride lipase (ATGL), peroxisome proliferators-activated receptors alpha (PPARα), carnitine palmitoyl transferase (CPT) and acyl-CoA oxidase (ACO) to promote lipolysis and β-oxidation. Moreover, polyphenols greatly enhanced mitochondrial biogenesis in adipocytes, as demonstrated by the expression of Nrf1 and Tfam were up-regulated. Furthermore, polyphenols treatment greatly up-regulated the browning program in adipocytes by increased brown-specific genes and proteins uncoupling protein 1 (UCP-1), peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) and PR domain containing 16 (PRDM16), as well as beige-specific genes (Tmem26, Tbx1, CD137, Cited1), especially engeletin. Further research found that the brown-specific markers were decreased by antagonist treatment of AMPK or β3-AR, but polyphenols treatment reversed the effect of antagonists and improved the expression of UCP-1, PRDM16 and PGC-1α. In conclusion, these results indicated that polyphenols stimulate browning in adipocytes via activation of the β3-AR/AMPK signaling pathway, and SCLP and its monomer may be worth investigating to prevent obesity.

Drug-Initiated Activity Metabolomics Identifies Myristoylglycine as a Potent Endogenous Metabolite for Human Brown Fat Differentiation.

Worldwide, obesity rates have doubled since the 1980s and in the USA alone, almost 40% of adults are obese, which is closely associated with a myriad of metabolic diseases such as type 2 diabetes and arteriosclerosis. Obesity is derived from an imbalance between energy intake and consumption, therefore balancing energy homeostasis is an attractive target for metabolic diseases. One therapeutic approach consists of increasing the number of brown-like adipocytes in the white adipose tissue (WAT). Whereas WAT stores excess energy, brown adipose tissue (BAT) can dissipate this energy overload in the form of heat, increasing energy expenditure and thus inhibiting metabolic diseases. To facilitate BAT production a high-throughput screening approach was developed on previously known drugs using human Simpson–Golabi–Behmel Syndrome (SGBS) preadipocytes. The screening allowed us to discover that zafirlukast, an FDA-approved small molecule drug commonly used to treat asthma, was able to differentiate adipocyte precursors and white-biased adipocytes into functional brown adipocytes. However, zafirlukast is toxic to human cells at higher dosages. Drug-Initiated Activity Metabolomics (DIAM) was used to investigate zafirlukast as a BAT inducer, and the endogenous metabolite myristoylglycine was then discovered to mimic the browning properties of zafirlukast without impacting cell viability. Myristoylglycine was found to be bio-synthesized upon zafirlukast treatment and was unique in inducing brown adipocyte differentiation, raising the possibility of using endogenous metabolites and bypassing the exogenous drugs to potentially alleviate disease, in this case, obesity and other related metabolic diseases.

Sodium salicylate induces browning of white adipocytes via M2 macrophage polarization by HO-1 upregulation

Browning, a white to brown-like (beige) adipocyte conversion, offers a promising therapeutic strategy for the treatment of human obesity. In the present study, the effects of sodium salicylate, a nonsteroidal anti-inflammatory drug, on adipocyte browning were investigated. We found sodium salicylate altered the macrophage phenotype to M2 in RAW264.7 cells, mediated by up-regulation of heme oxygenase-1 (HO-1), and sodium salicylate-treated conditioned medium from macrophages (Sal-M2 CM) induced browning of fully differentiated 3T3-L1 adipocytes. Conversely, the conditioned medium obtained from macrophages when treated with sodium salicylate in the presence of either ZnPP (a HO-1 inhibitor) or HO-1 siRNA did not induce browning. In association with macrophage HO-1 induction by sodium salicylate, iron production also increased, and deferoxamine (an iron chelator) blunted the browning effects of Sal-M2 CM, suggesting that iron may play a role in the Sal-M2 CM-induced browning. The in vivo browning effects of sodium salicylate were confirmed in ob/ob mice, whereas in vivo macrophage depletion by clodronate as well as HO-1 blockade by either ZnPP or adeno-associated virus carrying HO-1 shRNA (AAV–HO–1 shRNA) attenuated the browning effects of sodium salicylate. These results reveal sodium salicylate induces browning in vitro and in vivo by up-regulating HO-1 thus promoting M2 polarization.

Synbiotics intake improves disturbed metabolism in a rat model of high fat diet-induced obesity; A potential role of adipose tissue browning

Browning of white adipose tissue (WAT) is currently considered a potential therapeutic approach to treat or prevent diet-induced obesity. Synbiotics have protective effects against diet-induced obesity; however, its role in adipose tissue browning has been less investigated. to study the possible effect of synbiotics intake on browning of WAT in obese rats. Twenty-four adult male Wistar rats were randomly divided into four groups; normal diet (ND) control group, high fat diet (HFD) group, ND group receiving synbiotics, and HFD group receiving synbiotics. After eight weeks, all rats were sacrificed; and samples (blood, WAT, brown adipose tissue, and liver) were collected. Lipid profile, liver enzymes, fasting glucose, and fasting insulin levels were measured. The expression of browning-related genes: uncoupler protein-1 (UCP-1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), and peroxisome proliferator-activated receptors gamma (PPARγ) were measured by real-time polymerase chain reaction (PCR) in adipose tissues. Fibroblast growth factor 21 (FGF21) protein level was measured in serum, adipose and liver tissues, and FGF21 receptor expression was performed by real-time PCR in adipose tissues. ynbiotics intake was associated with improvement in lipid profile, liver enzymes, and insulin sensitivity in HFD rats. Moreover, the intake was associated with higher gene expression of brown adipocyte-specific markers. As for the FGF21 and its receptor, intriguing results were obtained that needs further in-depth studies. synbiotics might protect against diet-induced obesity through induction of thermogenic genes resulting in brown-like adipocyte phenotype in WAT.