Browning Of White Fat Research Articles

Muscle-Organ Crosstalk: The Emerging Roles of Myokines.

Physical activity decreases the risk of a network of diseases, and exercise may be prescribed as medicine for lifestyle-related disorders such as type 2 diabetes, dementia, cardiovascular diseases, and cancer. During the past couple of decades, it has been apparent that skeletal muscle works as an endocrine organ, which can produce and secrete hundreds of myokines that exert their effects in either autocrine, paracrine, or endocrine manners. Recent advances show that skeletal muscle produces myokines in response to exercise, which allow for crosstalk between the muscle and other organs, including brain, adipose tissue, bone, liver, gut, pancreas, vascular bed, and skin, as well as communication within the muscle itself. Although only few myokines have been allocated to a specific function in humans, it has been identified that the biological roles of myokines include effects on, for example, cognition, lipid and glucose metabolism, browning of white fat, bone formation, endothelial cell function, hypertrophy, skin structure, and tumor growth. This suggests that myokines may be useful biomarkers for monitoring exercise prescription for people with, for example, cancer, diabetes, or neurodegenerative diseases.

SAT-LB105 A Transcribed Ultraconserved Noncoding RNA, Uc.336-As, Promotes White to Brown Conversion in 3T3-L1 Cells

Brown adipose tissue (BAT) has gained its popularity since it shows great potential in counteracting obesity and metabolic diseases development. Transcribed ultraconserved regions (T-UCRs), a novel class of long non-coding RNA (lncRNAs), have been implicated in regulating diverse biological processes, including the process of white fat browning. However, the functional and mechanistic details of T-UCRs in the browning process are poorly understood. Here, we identified that a T-UCR, uc.336-as, played an important role during the browning process. Uc.336-as was significantly elevated during browning process induced by glucagon-like peptide-1 receptor agonist (exendin-4) or β3-adrenergic agonist (CL316,243). Overexpression of uc.336-as reduces the differentiation of 3T3-L1 preadipocytes into white adipocytes (inhibited lipid accumulation and decreased the expression of several adipogenesis markers) and induces brown characteristics during differentiation of 3T3-L1 preadipocytes (spurred browning adipocytes phenotypes and increased the expression of the browning associated genes). Moreover, we found that uc.336-as inhibited adipogenesis and promoted browning process via influencing the serine/threonine kinase (AKT)-mammalian target of rapamycin (mTOR) axis, an essential signal pathway in adipocyte metabolism. Taken together, our data show that uc.336-as acts as a negative regulator in white adipocyte differentiation and promotes the browning process, suggesting a potential therapeutic role for uc.336-as in controlling obesity.

SAT-584 Uc.336-As Inhibits White Adipocyte Differentiation and Promotes White to Brown Conversion

Brown adipose tissue (BAT) has gained its popularity since it shows great potential in counteracting obesity and metabolic diseases development. Transcribed ultraconserved regions (T-UCRs), a novel class of long non-coding RNA (lncRNAs), have been implicated in regulating diverse biological processes, including the process of white fat browning. However, the functional and mechanistic details of T-UCRs in the browning process are poorly understood. Here, we identified that a T-UCR, uc.336-as, played an important role during the browning process. uc.336-as was significantly elevated during browning process induced by exendin-4 or β3-adrenergic agonist (CL316,243). Moreover, we found that uc.336-as promoted browning process and inhibited adipogenesis. Finally, we identified that uc.336-as promoted the expression of browning-related genes via influencing the p38 mitogen-activated protein kinase (p38 MAPK) signaling, an essential signal pathway in metabolism. Taken together, our data show that uc.336-as acts as a negative regulator in white adipocyte differentiation and promotes the browning process, suggesting a potential therapeutic role for uc.336-as in controlling obesity.

AJP-Regulatory, Integrative and Comparative Physiology: Looking Toward the Future

<i>AJP-Regulatory, Integrative and Comparative Physiology</i>: Looking Toward the Future

Exercise Reverses the Alterations in Gut Microbiota Upon Cold Exposure and Promotes Cold-Induced Weight Loss.

Gut microbiota has been reported to contribute to reduced diet-induced obesity upon cold exposure. Furthermore, gut microbiome fermentation determines the efficacy of exercise for diabetes prevention and enhances exercise performance. However, there have been no systematic examinations of changes in gut microbiome composition in relation to exercise performed under low-temperature conditions. In this study, we investigated the effects of exercise performed under different conditions (room temperature, acute cold, intermittent cold, and sustained cold) in obese rats maintained on a high-fat diet at four time points during experimental trials (days 0, 1, 3, and 35), including observations on white fat browning, weight loss, cardiovascular effects, and changes in gut microbiota among treatment groups. We found that exercise under sustained cold conditions produced a remarkable shift in microbiota composition. Unexpectedly, exercise was found to reverse the alterations in gut microbiota alpha-diversity and the abundance of certain bacterial phyla observed in response to cold exposure (e.g., Proteobacteria decreased upon cold exposure but increased in response to exercise under cold conditions). Moreover, exercise under cold conditions (hereafter referred to “cold exercise”) promoted a considerably higher level of white fat browning and greater weight loss and protected against the negative cardiovascular effects of cold exposure. Correlation analysis revealed that cold exercise-related changes in gut microbial communities were significantly correlated with white fat browning and cardiovascular phenotypes. These results could reveal novel mechanisms whereby additional health benefits attributable to both cold and exercise are mediated via altered gut microbes differently compared with either of them alone.

Ketoprofen alleviates diet-induced obesity and promotes white fat browning in mice via the activation of COX-2 through mTORC1-p38 signaling pathway.

The nonsteroidal anti-inflammatory drug (NSAID) ketoprofen is commonly used as a pain reliever, but its role in mediating the energy metabolism in lipids is unclear. This paper reports for the first time the critical role of ketoprofen in ameliorating white fat browning and alleviating diet-induced obesity. The effects of ketoprofen were evaluated using C57BL/6 mice fed a high fat diet and the expression levels of the target genes and proteins in the lipid metabolisms were determined by quantitative real-time PCR, immunoblot analysis, histopathology study, immunofluorescence, and molecular docking techniques. Ketoprofen induced browning in cultured 3T3-L1 white adipocytes and inguinal white adipose tissue by increasing the expression of core fat browning marker proteins as well as beige-specific genes through COX-2 activation. Ketoprofen also led to the robust activation of brown adipocytes and enhanced brown fat adipogenesis. In addition, ketoprofen elevated lipolysis, thereby increasing mitochondrial biogenesis resulting in higher fat oxidation. Furthermore, the molecular docking and mechanistic study demonstrated the recruitment of beige fat by ketoprofen via mTORC1-p38-mediated activation of the COX-2 pathway. Overall, these results indicate the unique role of ketoprofen in body weight reduction by enhancing thermogenesis, suggesting its therapeutic potential in the treatment of obesity.

Intramuscular Brown Fat Activation Decreases Muscle Atrophy and Fatty Infiltration and Improves Gait After Delayed Rotator Cuff Repair in Mice

Background: Successful repair of large and massive rotator cuff (RC) tears remains a challenge at least partially because of secondary muscle atrophy and fatty infiltration. β3 Adrenergic agonists are a group of drugs that promote fat resorption through “white fat browning” of intramuscular stem cells. Purpose: To test the role of a β3 adrenergic receptor agonist, amibegron, in improving muscle quality and forelimb function in a delayed RC repair model via promoting brown/beige adipose tissue activation. Study Design: Controlled laboratory study. Methods: Three-month-old PDGFRα-GFP reporter mice, wild type C57BL/6J mice, and uncoupling protein 1 (UCP-1) knockout mice underwent unilateral supraspinatus tendon transection with a 6-week delayed tendon repair. Animals with sham surgery served as controls. Amibegron was given either immediately after tendon transection or after repair. Gait analysis was conducted to measure forelimb function at 6 weeks after tendon repair. Animals were sacrificed at 6 weeks after repair. Supraspinatus muscles were harvested and analyzed histologically. Reverse transcription polymerase chain reaction was performed to quantify gene expression related to atrophy, fibrosis, and fatty infiltration. Results: Histology of PDGFRα reporter mice showed significantly increased UCP-1 expression, suggesting white fat browning in muscle after RC repair. As administered either immediately after tendon transection or after tendon repair, amibegron significantly reduced muscle atrophy and fatty infiltration and resumed normal upper extremity gait in wild type mice. However, the effect of amibegron was not present in UCP-1 knockout mice, suggesting that the effect of amibegron in treating RC muscle atrophy and fatty infiltration is through a UCP 1–dependent mechanism. Conclusion: Amibegron reduced muscle atrophy and fatty infiltration and improved forelimb function after delayed RC repair through a UCP 1–dependent mechanism. This may be an effective clinical treatment strategy for patients to improve muscle quality after RC repair. Clinical Relevance: β3 Adrenergic agonists may serve as a new pharmacologic modality to treat RC muscle atrophy and fatty infiltration to improve clinical outcome of RC repair.

Urolithin A exerts antiobesity effects through enhancing adipose tissue thermogenesis in mice.

Obesity leads to multiple health problems, including diabetes, fatty liver, and even cancer. Here, we report that urolithin A (UA), a gut-microflora–derived metabolite of pomegranate ellagitannins (ETs), prevents diet-induced obesity and metabolic dysfunctions in mice without causing adverse effects. UA treatment increases energy expenditure (EE) by enhancing thermogenesis in brown adipose tissue (BAT) and inducing browning of white adipose tissue (WAT). Mechanistically, UA-mediated increased thermogenesis is caused by an elevation of triiodothyronine (T3) levels in BAT and inguinal fat depots. This is also confirmed in UA-treated white and brown adipocytes. Consistent with this mechanism, UA loses its beneficial effects on activation of BAT, browning of white fat, body weight control, and glucose homeostasis when thyroid hormone (TH) production is blocked by its inhibitor, propylthiouracil (PTU). Conversely, administration of exogenous tetraiodothyronine (T4) to PTU-treated mice restores UA-induced activation of BAT and browning of white fat and its preventive role on high-fat diet (HFD)-induced weight gain. Together, these results suggest that UA is a potent antiobesity agent with potential for human clinical applications.

Dlgap1 negatively regulates browning of white fat cells through effects on cell proliferation and apoptosis

BackgroundObesity is a metabolic imbalance characterized by excessive deposition of white fat. The browning of white fat can effectively treat obesity and related diseases. Although Dlgap1 (Discs, Large (Drosophila) Homolog-Associated Protein 1) is suspected to have an effect on this process, no empirical evidence is available.MethodsTo understand the role of Dlgap1, we cultured white and brown fat cells, then performed overexpression and knockout experiments.ResultsWe found that Dlgap1 overexpression in brown adipocytes inhibits brown-fat-related gene expression, promotes white-fat-related genes, while also increasing brown-adipocyte proliferation and apoptosis. However, the gene overexpression has no effect on brown adipocyte maturation. Knocking out Dlgap1 in white fat cells promotes the expression and inhibition of brown-fat-related and white-fat-related genes, respectively. Additionally, the knockout inhibits white fat cell proliferation and apoptosis, while also promoting their maturation.ConclusionsDlgap1 negatively regulates the browning of white adipocytes by influencing cell proliferation and apoptosis.

PPARγ and PPARα synergize to induce robust browning of white fat in vivo

ObjectivePeroxisome proliferator-activated receptors (PPARs) are key transcription factors that regulate adipose development and function, and the conversion of white into brown-like adipocytes. Here we investigated whether PPARα and PPARγ activation synergize to induce the browning of white fat. MethodsA selection of PPAR activators was tested for their ability to induce the browning of both mouse and human white adipocytes in vitro, and in vivo in lean and obese mice. ResultsAll dual PPARα/γ activators tested robustly increased uncoupling protein 1 (Ucp1) expression in both mouse and human adipocytes in vitro, with tesaglitazar leading to the largest Ucp1 induction. Importantly, dual PPARα/γ activator tesaglitazar strongly induced browning of white fat in vivo in both lean and obese male mice at thermoneutrality, greatly exceeding the increase in Ucp1 observed with the selective PPARγ activator rosiglitazone. While selective PPARγ activation was sufficient for the conversion of white into brown-like adipocytes in vitro, dual PPARα/γ activation was superior to selective PPARγ activation at inducing white fat browning in vivo. Mechanistically, the superiority of dual PPARα/γ activators is mediated at least in part via a PPARα-driven increase in fibroblast growth factor 21 (FGF21). Combined treatment with rosiglitazone and FGF21 resulted in a synergistic increase in Ucp1 mRNA levels both in vitro and in vivo. Tesaglitazar-induced browning was associated with increased energy expenditure, enhanced insulin sensitivity, reduced liver steatosis, and an overall improved metabolic profile compared to rosiglitazone and vehicle control groups. ConclusionsPPARγ and PPARα synergize to induce robust browning of white fat in vivo, via PPARγ activation in adipose, and PPARα-mediated increase in FGF21.

Changes in gene expression in human skeletal stem cells transduced with constitutively active Gsα correlates with hallmark histopathological changes seen in fibrous dysplastic bone.

Fibrous dysplasia (FD) of bone is a complex disease of the skeleton caused by dominant activating mutations of the GNAS locus encoding for the α subunit of the G protein-coupled receptor complex (Gsα). The mutation involves a substitution of arginine at position 201 by histidine or cysteine (GsαR201H or R201C), which leads to overproduction of cAMP. Several signaling pathways are implicated downstream of excess cAMP in the manifestation of disease. However, the pathogenesis of FD remains largely unknown. The overall FD phenotype can be attributed to alterations of skeletal stem/progenitor cells which normally develop into osteogenic or adipogenic cells (in cis), and are also known to provide support to angiogenesis, hematopoiesis, and osteoclastogenesis (in trans). In order to dissect the molecular pathways rooted in skeletal stem/progenitor cells by FD mutations, we engineered human skeletal stem/progenitor cells with the GsαR201C mutation and performed transcriptomic analysis. Our data suggest that this FD mutation profoundly alters the properties of skeletal stem/progenitor cells by pushing them towards formation of disorganized bone with a concomitant alteration of adipogenic differentiation. In addition, the mutation creates an altered in trans environment that induces neovascularization, cytokine/chemokine changes and osteoclastogenesis. In silico comparison of our data with the signature of FD craniofacial samples highlighted common traits, such as the upregulation of ADAM (A Disintegrin and Metalloprotease) proteins and other matrix-related factors, and of PDE7B (Phosphodiesterase 7B), which can be considered as a buffering process, activated to compensate for excess cAMP. We also observed high levels of CEBPs (CCAAT-Enhancer Binding Proteins) in both data sets, factors related to browning of white fat. This is the first analysis of the reaction of human skeletal stem/progenitor cells to the introduction of the FD mutation and we believe it provides a useful background for further studies on the molecular basis of the disease and for the identification of novel potential therapeutic targets.

TSH promotes adiposity by inhibiting the browning of white fat

ABSTRACT Adiposity is caused by an imbalance between energy intake and consumption. Promotion of the browning of white fat increases energy expenditure and could combat adiposity. Thyroid-stimulating hormone (TSH) has been confirmed to positively correlate with adiposity. However, the putative connection between TSH and white adipose browning has never been explored. In this study, we sought to assess the effect of TSH on white adipose tissue browning and energy metabolism. Subclinical hypothyroidism mice, thyroid-specific Tshr-knockout mice injected with TSH, adipocyte-specific and global Tshr-knockout micewere subjected to morphological, physiological, genetic or protein expression analyses and metabolic cages to determine the role of TSH on the browning of white adipose tissue and metabolism. 3T3-L1 and primary SVF cells were used to verify the effects and mechanism of TSH on the browning of white adipocytes. We show that increased circulation TSH level decreases energy expenditure, promotes adiposity, impairs glucose and lipid metabolism. Knockout of Tshr decreases adiposity, increases energy expenditureand markedly promotes the development of beige adipocytesin both epididymal and inguinal subcutaneous white fat via a mechanism that likely involves AMPK/PRDM16/PGC1α. Our results reveal an important role of TSH in regulating energy balance and adiposity by inhibiting the browning of white fat.

QKI regulates adipose tissue metabolism by acting as a brake on thermogenesis and promoting obesity.

Adipose tissue controls numerous physiological processes, and its dysfunction has a causative role in the development of systemic metabolic disorders. The role of posttranscriptional regulation in adipose metabolism has yet to be fully understood. Here, we show that the RNA-binding protein quaking (QKI) plays an important role in controlling metabolic homeostasis of the adipose tissue. QKI-deficient mice are resistant to high-fat-diet (HFD)-induced obesity. Additionally, QKI depletion increased brown fat energy dissipation and browning of subcutaneous white fat. Adipose tissue-specific depletion of QKI in mice enhances cold-induced thermogenesis, thereby preventing hypothermia in response to cold stimulus. Further mechanistic analysis reveals that QKI is transcriptionally induced by the cAMP-cAMP response element-binding protein (CREB) axis and restricts adipose tissue energy consumption by decreasing stability, nuclear export, and translation of mRNAs encoding UCP1 and PGC1α. These findings extend our knowledge of the significance of posttranscriptional regulation in adipose metabolic homeostasis and provide a potential therapeutic target to defend against obesity and its related metabolic diseases.

Polyphenol-rich green tea extract induces thermogenesis in mice by a mechanism dependent on adiponectin signaling

Adiponectin is downregulated in obesity negatively impacting the thermogenesis and impairing white fat browning. Despite the notable effects of green tea (GT) extract in the enhancement of thermogenesis, if its effects are being mediated by adiponectin has been scarcely explored. For this purpose, we investigated the role of adiponectin in the thermogenic actions of GT extract by using an adiponectin-knockout mice model. Male wild-type (WT) and knockout (AdipoKO) C57Bl/6 mice (3 months) were divided into 6 groups: mice fed a standard diet+gavage with water (SD WT, and SD AdipoKO), high-fat diet (HFD)+gavage with water (HFD WT, and HFD AdipoKO), and HFD + gavage with 500 mg/kg of body weight (BW) of GT extract (HFD + GT WT, and HFD + GT AdipoKO). After 20 weeks of experimentation, mice were euthanized and adipose tissue was properly removed. Our findings indicate that treatment with GT extract reversed complications of obesity in WT mice by decreasing final BW gain, adiposity index, adipocyte size and insulin resistance (IR). However, the action of the GT extract was not effective in reversing those markers in the AdipoKO mice, although GT acts independently in the reversal of IR. GT-treatment induced enhancement in energy expenditure (EE), BAT thermogenesis, and promoted browning phenotype in the subcutaneous WAT (scWAT) of WT mice. On the other hand, the thermogenic program was markedly impaired in BAT and scWAT of AdipoKO mice. Our outcomes unveiled adiponectin as a key direct signal for GT extract inducing adaptive thermogenesis and browning in scWAT.

Systems-Genetics-Based Inference of a Core Regulatory Network Underlying White Fat Browning

Recruitment of brite/beige cells, known as browning of white adipose tissue (WAT), is an efficient way to turn an energy-storing organ into an energy-dissipating one and may therefore be of therapeutic value in combating obesity. However, a comprehensive understanding of the regulatory mechanisms mediating WAT browning is still lacking. Here, we exploit the large natural variation in WAT browning propensity between inbred mouse strains to gain an inclusive view of the core regulatory network coordinating this cellular process. Combining comparative transcriptomics, perturbation-based validations, and gene network analyses, we present a comprehensive gene regulatory network of inguinal WAT browning, revealing up to four distinct regulatory modules with key roles for uncovered transcriptional factors, while also providing deep insights into the genetic architecture of brite adipogenesis. The presented findings therefore greatly increase our understanding of the molecular drivers mediating the intriguing cellular heterogeneity and plasticity of adipose tissue.

Identification of key candidate genes and molecular pathways in white fat browning: an anti-obesity drug discovery based on computational biology

BackgroundObesity—with its increased risk of obesity-associated metabolic diseases—has become one of the greatest public health epidemics of the twenty-first century in affluent countries. To date, there are no ideal drugs for treating obesity. Studies have shown that activation of brown adipose tissue (BAT) can promote energy consumption and inhibit obesity, which makes browning of white adipose tissue (WAT) a potential therapeutic target for obesity. Our objective was to identify genes and molecular pathways associated with WAT and the activation of BAT to WAT browning, by using publicly available data and computational tools; this knowledge might help in targeting relevant signaling pathways for treating obesity and other related metabolic diseases.ResultsIn this study, we used text mining to find out genes related to brown fat and white fat browning. Combined with biological process and pathway analysis in GeneCodis and protein-protein interaction analysis by using STRING and Cytoscape, a list of high priority target genes was developed. The Human Protein Atlas was used to analyze protein expression. Candidate drugs were derived on the basis of the drug-gene interaction analysis of the final genes. Our study identified 18 genes representing 6 different pathways, targetable by a total of 33 drugs as possible drug treatments. The final list included 18 peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists, 4 beta 3 adrenoceptor (β3-AR) agonists, 1 insulin sensitizer, 3 insulins, 6 lipase clearing factor stimulants and other drugs.ConclusionsDrug discovery using in silico text mining, pathway, and protein-protein interaction analysis tools may be a method of exploring drugs targeting the activation of brown fat or white fat browning, which provides a basis for the development of novel targeted therapies as potential treatments for obesity and related metabolic diseases.

Adipose PTEN regulates adult adipose tissue homeostasis and redistribution via a PTEN-leptin-sympathetic loop

ObjectiveDespite the large body of work describing the tumor suppressor functions of Phosphatase and tensin homologue deleted on chromosome ten (PTEN), its roles in adipose homeostasis of adult animals are not yet fully understood. Here, we sought to determine the role of PTEN in whole-body adipose homeostasis. MethodsWe genetically manipulated PTEN in specific fat depots through recombinant adeno-associated viral vector (rAAV)-based gene transfer of Cre recombinase to adult PTENflox mice. Additionally, we used a denervation agent, 6OHDA, to assess the role of sympathetic signaling in PTEN-related adipose remodeling. Furthermore, we chemically manipulated AKT signaling via a pan-AKT inhibitor, MK-2206, to assess the role of AKT in PTEN-related adipose remodeling. Finally, to understand the role of leptin and central signaling on peripheral tissues, we knocked down hypothalamic leptin receptor with a microRNA delivered by a rAAV vector. ResultsKnockdown PTEN in individual fat depot resulted in massive expansion of the affected fat depot through activation of AKT signaling associated with suppression of lipolysis and induction of leptin. This hypertrophic expansion of the affected fat depot led to upregulation of PTEN level, higher lipolysis, and induction of white fat browning in other fat depots, and the compensatory reduced fat mass to maintain a set point of whole-body adiposity. Administration of AKT inhibitor MK-2206 prevented the adipose PTEN knockdown-associated effects. 6OHDA-mediated denervation demonstrated that sympathetic innervation was required for the PTEN knockdown-induced adipose redistribution. Knockdown hypothalamic leptin receptor attenuated the adipose redistribution induced by PTEN deficiency in individual fat depot. ConclusionsOur results demonstrate the essential role of PTEN in adipose homeostasis, including mass and distribution in adulthood, and reveal an “adipose PTEN-leptin-sympathetic nervous system” feedback loop to maintain a set point of adipose PTEN and whole-body adiposity.

TSH Promotes Adiposity by Inhibiting the Browning of White Fat

Background: Adiposity is caused by an imbalance between energy intake and consumption. Promotion of the browning of white fat increases energy expenditure and could be a promising therapy for adiposity. Thyroid-stimulating hormone (TSH) has been confirmed to positively correlate with adiposity. However, the putative connection between TSH and white adipose browning has never been explored. In this study, we sought to assess the effect of TSH on white adipose tissue browning and energy metabolism. Methods: Subclinical hypothyroidism mice, thyroid-specific Tshr-knockout mice injected with TSH, adipocyte-specific Tshr-knockout mice, global Tshr-knockout mice and their littermates were subjected to morphological, physiological, genetic or protein expression analyses and metabolic cages to determine the role of TSH on the browning of white adipose tissue and metabolism. To activate thermogenesis, some mice were exposed to cold condition for 4 weeks. 3T3-L1 cells and primary SVF cells were used to verify the effects of TSH on the browning of white adipocytes and its mechanism. Findings: We show that TSH decreases energy expenditure, promotes body weight gain, impairs glucose tolerance and lipid metabolism in subclinical hypothyroidism mice and thyroid-specific Tshr-knockout mice injected with TSH. Adipose-specific or global knockout of Tshr decreases adiposity, resists diet-induced obesity and increases energy expenditure. The knockout of Tshr markedly promotes the development of beige adipocytes and increases expression of UCP1 and other thermogenic genes in both epididymal and inguinal subcutaneous white fat via a mechanism that likely involves AMPK/PRDM16/PGC1α. Interpretation: Our results reveal an important role of TSH in regulating energy balance and adiposity by inhibiting the browning of white fat. Funding: This work was supported by grants from the National Natural Science Foundation (81400828) and the Natural Science Foundation of Shandong Province (ZR2014HQ057). This study was also supported by Projects of the Medical and Health Technology Development Program in Shandong Province (2016WS0427) and Shandong Key R&D Program (2017GSF18129). Declaration of Interest: The authors have no competing financial interests to declare. Ethical Approval: All animal experimental protocols were approved by the Animal Care Committee of School of Medicine, Shandong University.

Physiological concentrations of β-hydroxybutyrate do not promote adipocyte browning

AimsPrevious work has demonstrated that ketogenic diets promote white fat browning; however, the exact mechanisms underlying this phenomenom have yet to be elucidated. Recently, an in vitro study showed that supraphysiological concentrations of β-hydroxybutyrate (βHB) had a strong influence on the induction of adipocyte browning. On the other hand, concentrations in the physiological range, achieved through ketogenic diets and prolonged fasting produce values of 1–3 mM and 4–7 mM, respectively. Herein, we investigated the impact of physiological concentrations of βHB on metabolism, and the expression of uncoupling protein 1 (UCP1) and other browning markers in adipose tissues. Main methodsThe effects of βHB on adipocyte browning were investigated in vitro, using primary cultures of isolated visceral and subcutaneous fat cells and cultured 3T3-L1 adipocytes, and in vivo. Key findingsIt was determined that βHB failed to induce changes in the oxidative capacity, citrate synthase activity or browning gene expression patterns in isolated adipocytes, and did not exert a permissive effect on β-adrenergic agonist-induced browning. In addition, 3T3-L1 adipocytes differentiated following βHB treatment exhibited downregulated Ucp1 expression levels, a result that was recapitulated in the subcutaneous adipose tissue of Wistar rats after βHB salt treatment. Rats administered βHB salts also presented reduced brown adipose tissue UCP1 protein expression. SignificanceThe mechanisms underlying ketogenic diet-induced browning of adipocytes are not known. The results from the present study indicate that physiological concentrations of βHB are not responsible for this phenomenon, despite the observed βHB-mediated downregulation of UCP1 expression.

Acute and chronic responses to exercise training-induced irisin in browning of white fat

Nowadays, is well established that the benefits induced by exercise training (ET) affects not only skeletal muscle, but also other non-contractile organs over time. One potential mechanism underlying this crosstalk is the synthesis and secretion of several biological active factors, such as irisin, by muscle contractile activity. This hormone has been described to be able to induce a brown adipocyte-like phenotype in white adipose (WAT), increase whole-body metabolic rate, and therefore prevent and/or treat obesity-related metabolic diseases. Thus, the modulatory impact of ET on WAT may also occur through skeletal muscle - adipose organ axis. In this review, we summarize the acute and chronic adaptations to ET-induced irisin synthesis and secretion on the development of browning of white fat and, thus, providing an overview of the potential preventive and therapeutic role of ET on the obesity-related underlying pathways.