Global gene expression profiling of perirenal brown adipose tissue whitening in goat kids reveals novel genes linked to adipose remodeling

Background Brown adipose tissue(BAT)is known to be capable of non-shivering thermogenesis under cold stimulation,which is related to the mortality of animals.In the previous study,we observed that goat BAT is mainly located around the kidney at birth,and changes to white adipose tissue(WAT)in the perirenal adipose tissue of goats within one month after birth.However,the regulatory factors underlying this change is remain unclear.In this study,we systematically studied the perirenal adipose tissue of goat kids in histological,cytological,and accompanying molecular level changes from 0 to 28 d after birth.Results Our study found a higher mortality rate in winter-born goat kids,with goat birthing data statistics.Then we used thermal imaging revealing high temperature in goat hips at postnatal 0 d and gradually decrease during 28 d.This is consistent with the region of perirenal BAT deposition and highlights its critical role in energy expenditure and body temperature regulation in goat kids.Additionally,we found a series of changes of BAT during the first 28 d after birth,such as whitening,larger lipid droplets,decreased mitochondrial numbers,and down-regulation of key thermogenesis-related genes(UCP1,DIO2,UCP2,CIDEA,PPARGC1a,C/EBPb,and C/EBPa).Then,we used RNA-seq found specific marker genes for goat adipose tissue and identified 12 new marker genes for BAT and 10 new marker genes for WAT of goats.Furthermore,12 candidate genes were found to potentially regulate goat BAT thermogenesis.The mechanism of the change of this biological phenomenon does not involve a large-scale death of brown adipocytes and subsequent proliferation of white adipocytes.While apoptosis may play a limited role,it is largely not critical in this transition process.Conclusions We concluded that perirenal BAT plays a crucial role in thermoregulation in newborn goat kids,with notable species differences in the expression of adipose tissue marker genes,and we highlighted some potential marker genes for goat BAT and WAT.Additionally,the change from BAT to WAT does not involve a large-scale death of brown adipocytes and subsequent proliferation of white adipocytes.

Medium-Chain Triglyceride Activated Brown Adipose Tissue and Induced Reduction of Fat Mass in C57BL/6J Mice Fed High-fat Diet

Objective To investigate activation of brown adipose tissue （BAT） stimulated by medium-chain triglyceride （MCT）. Methods 30 Male C57BL/6J obese mice induced by fed high fat diet （HFD） were divided into 2 groups, and fed another HFD with 2% MCT or long-chain triglyceride （LCT） respectively for 12 weeks. Body weight, blood biochemical variables, interscapular brown fat tissue （IBAT） mass, expressions of mRNA and protein of beta 3-adrenergic receptors （β3-AR）, uncoupling protein-1 （UCP1）, hormone sensitive lipase （HSL）, protein kinase A （PKA）, and adipose triglyceride lipase （ATGL） in IBAT were measured. Results Significant decrease in body weight and body fat mass was observed in MCT group as compared with LCT group （P〈O.05） after 12 weeks. Greater increases in IBAT mass was observed in MCT group than in LCT group （P〈O.05）. Blood TG, TC, LDL-C in MCT group were decreased significantly, meanwhile blood HDL-C, ratio of HDL-C/LDL-C and norepinephrine were increased markedly. Expressions of mRNA and protein of β3-AR, UCP1, PKA, HSL, ATGL in BAT were greater in MCT group than in LCT group （P〈O.05）. Conclusion Our results suggest that MCT stimulated the activation of BAT, possible via norepinephrine pathway, which might partially contribute to reduction of the body fat mass in obese mice fed high fat diet.

ICA-Unet:An improved U-net network for brown adipose tissue segmentation

Brown adipose tissue(BAT)is a kind of adipose tissue engaging in thermoregulatory thermogenesis,metaboloregulatory thermogenesis,and secretory.Current studies have revealed that BAT activity is negatively correlated with adult body weight and is considered a target tissue for the treatment of obesity and other metabolic-related diseases.Additionally,the activity of BAT presents certain differences between different ages and genders.Clinically,BAT segmentation based on PET/CT data is a reliable method for brown fat research.However,most of the current BAT segmentation methods rely on the experience of doctors.In this paper,an improved U-net network,ICA-Unet,is proposed to achieve automatic and precise segmentation of BAT.First,the traditional 2D convolution layer in the encoder is replaced with a depth-wise overparameterized convolutional(Do-Conv)layer.Second,the channel attention block is introduced between the double-layer convolution.Finally,the image information entropy(IIE)block is added in the skip connections to strengthen the edge features.Furthermore,the performance of this method is evaluated on the dataset of PET/CT images from 368 patients.The results demonstrate a strong agreement between the automatic segmentation of BAT and manual annotation by experts.The average DICE coeffcient(DSC)is 0.9057,and the average Hausdorff distance is 7.2810.Experimental results suggest that the method proposed in this paper can achieve effcient and accurate automatic BAT segmentation and satisfy the clinical requirements of BAT.

Orexin receptor type 2 agonism inhibits thermogenesis in brown adipose tissue by attenuating afferent innervation

Orexin signaling has been associated with energy expenditure and brown adipose tissue(BAT)function.However,conflicting data exist in the field about how orexin signaling regulates BAT thermogenesis.In this study,we show that a specific orexin receptor type 2(OX2R)agonist[Ala11,D-Leu15]-OxB(OB-Ala)inhibited intrascapular brown adipose tissue(iBAT)thermogenesis by reducing sympathetic output to iBAT.This effect is mediated by OX2Rs located on afferent nerve endings innervating iBAT instead of brown adipocyte itself.Microinjection of OB-Ala into iBAT inhibited iBAT thermogenesis in mice upon cold exposure and neuronal activity in the paraventricular nucleus.Findings suggest that OB-Ala could inhibit iBAT thermogenesis by attenuating sensory input thereby inhibiting the sympathetic-sensory iBAT feedback loop.Our study uncovers a novel primary action site of orexin in the regulation of energy balance.

Preliminary PET/CT Study of ^(18)F-FDG Uptake in Cervical and Supraclavicular Brown Adipose Tissue

OBJECTIVE The clinical use of PET/CT in oncology has led to the realization that 18F-FDG uptake in brown adipose tissue(BAT) can be a common cause of potentially misleading false-positive PET scans.The goal of this study was to study 18F-FDG uptake in cervical and supraclavicular regions and its characteristics with PET/CT.METHODSAll the PET/CT scans obtained at our institutionfrom July 2007 to January 2008 were retrospectively reviewed forincreased 18F-FDG uptake in BAT.The cases in which increased18F-FDG in cervical and supraclavicular regions was not localizedto a so -tissue mass or lymph node or muscle on the CT images,were included in this study.The following features were recorded:body weight,body mass index(BMI) and maximal standardizeduptake value(SUVmax).In these selected patients,the BAT uptake in other area of the body was also recorded.RESULTS PET/CT scans were obtained in 457 patients(259 males and 198 females).In all of the scans,cervical and supraclavicular BAT uptake was observed in 12 patients(2 males and 10 females) and was typically bilateral,symmetric and intense.The range of the SUVmax was 3.6～12.82(mean 6.9 ± 2.6).BAT uptake was more common in females than in males,showing a significant difference(P = 0.004).Although 18F-FDG uptake in BAT occurred more o en in underweight patients with low BMI,there was no difference in the body weight(P = 0.607) or BMI(P = 0.491) of these patients with hypermetabolic BAT compared with controls.CONCLUSION Hypermetabolic BAT uptake can be localized in cervical and supraclavicular regions with it occurring more commonly in females compared to males.Knowledge of this potential pitfall with PET/CT is important in improving diagnostic interpretation and accurate staging.

Role of brown adipose tissue in metabolic syndrome, aging, and cancer cachexia

Brown adipose tissue （BAT） plays a fundamental role in maintaining body temperature by producing heat. BAT that had been know to exist only in mammals and the human neonate has received great attention for the treatment of obesity and diabetes due to its important function in energy metabolism, ever since it is recently reported that human adults have functional BAT. In addition, beige adipocytes, brown adipocytes in white adipose tissue （WAT）, have also been shown to take part in whole body metabolism. Multiple lines of evidence demonstrated that transplantation or activation of BAT or/and beige adipocytes reversed obesity and improved insulin sensitivity. Furthermore, many genes involved in BAT activation and/or the recruitment of beige cells have been found, thereby providing new promising strategies for future clinical application of BAT activation to treat obesity and metabolic diseases. This review focuses on recent advances of BAT function in the metabolic aspect and the relationship between BAT and cancer cachexia, a pathological process accompanied with decreased body weight and increased energy expenditure in cancer patients. The underlying possible mechanisms to reduce BAT mass and its activity in the elderly are also discussed.

Brown adipose tissue and its therapeutic application

In addition to white adipose tissue （WAT） that stores energy, human and small mammals also have brown adipose tissue （BAT） that dissipates chemical energy for thermogenesis. BAT contains multilocular lipid droplets and much higher numbers of mitochondria than WAT. The mitochondria in BAT uncouple large amounts of fuel oxidation from ATP for heat generation. Accumulating evidences have demonstrated that increased activity and/or amount of BAT can reverse obesity and improve insulin resistance, which highlights that BAT plays an important role in energy metabolism. In this review, we summarized recent findings that shows advantageous effects of BAT activation in metabolic diseases. In addition, we presented the function and role of brown and beige fat cells and regulatory factors for them. Finally, we discussed the potential application of brown adipocytes-based therapy and pharmacological intervention to increase BAT activity for the treatment of obesity and related diseases including insulin resistance, cardiovascular diseases and type 2 diabetes.

Effect of electroacupuncture on the expression of PGC-1α and UCP-1 in the brown adipose tissue of obese rats

Objective： To explore the effect of peroxisome proliferators-activated receptor γ coactivator-1α（PGC-1α） and uncoupling protein-1（UCP-1） in the brown adipose tissue（BAT） of obese rats in the process of acupuncture treatment for obesity.Methods： Fifty clean-grade male Wistar rats with the age of 3 months were randomly divided into highfat diet group（n = 40） and normal diet group（control group, n = 10）. Nutritional obesity animal models were established through feeding with high-fat diet. Twenty-four animal models in the high-fat diet group were established successfully, and then they were randomly divided into model group, acupuncture group and non-acupoint group,with 8 rats in each group. In acupuncture group, Zusanli（足三里ST36） and Tianshu（天枢ST 25） were selected. In non-acupoint group,the non-acupoints located on 5 mm beside ST 36 and ST 25 were selected as acupuncture points, and electroacupuncture intervention was adopted for 5 times/week for 8 weeks. The body mass of obese rats was measured, the body fat ratio in BAT of rats was calculated, and the expression levels of PGC-1α and UCP-1 in BAT of rats were detected by immunohistochemical method.Results： ① After treatment, the body mass of rats in acupuncture group reduced significantly, which increased in the other three groups. The changing value of body mass of rats in acupuncture group was higher than that in model group（P 0.05）, the changing value of body mass of rats in acupuncture group was higher than that in non-acupoint group（P 0.05） and the difference in body mass changing value of rats between non-acupoint group and model group was not statistically significant（P 0.05）,the body fat ratio in BAT of rats in non-acupoint group was lower than that in acupuncture group, and the differences were statistically significant（P0.05）. ② Compared with model group, the body fat ratio in BAT of rats in acupuncture group increased significantly（P 0.05）,and the difference in body fat ratio in BAT of rats between non-acupoint group and model group was not statistically significant（P 0.05）.③ Compared with model group, the PGC-la and UCP-1 levels in BAT of obese rats in acupuncture group increased（P 0.05）, and the difference in expression levels of PGC-la and UCP-1 in BAT of rats between non-acupoint group and model group was not statistically significant（P 0.05）, the expression levels in non-acupoint group were lower than that in acupuncture group, and the differences were statistically significant（P 0.05）.Conclusion： Electroacupuncture at ＂ST 36＂ and ＂ST 25＂ can effectively up-regulate the expression levels of PGC-la and UCP-1 of diet induced obesity rats, it indicates that ＂ST 36＂ and ＂ST 25＂ have close relationship with obesity and it is may be one of the effect mechanisms of electroacupuncture in losing weight through facilitating the ＂browning reaction＂ of white adipose tissue.

Brown adipose tissue and its therapeutic application

In addition to white adipose tissue(WAT) that stores energy, human and small mammals also have brown adipose tissue(BAT) that dissipates chemical energy for thermogenesis. BAT contains multilocular lipid droplets and much higher numbers of mitochondria than WAT. The mitochondria in BAT uncouple large amounts of fuel oxidation from ATP for heat generation. Accumulating evidences have demonstrated that increased activity and/or amount of BAT can reverse obesity and improve insulin resistance, which highlights that BAT plays an important role in energy metabolism. In this review, we summarized recent findings that shows advantageous effects of BAT activation in metabolic diseases. In addition, we presented the function and role of brown and beige fat cells and regulatory factors for them. Finally, we discussed the potential application of brown adipocytes-based therapy and pharmacological intervention to increase BAT activity for the treatment of obesity and related diseases including insulin resistance, cardiovascular diseases and type 2diabetes.

Ginsenoside F1 administration promotes UCP1-dependent fat browning and ameliorates obesity-associated insulin resistance

Obesity-induced type 2 diabetes is mainly due to excessive free fatty acids leading to insulin resistance.Increasing thermogenesis is regarded as an effective strategy for hypolipidemia and hypoglycemia.Ginsenoside is a natural active component in Panax ginseng C.A.Meyer,and some of them enhance thermogenesis.However,there are few studies on the mechanism and target of ginsenosides enhancing thermogenesis.Using thermogenic protein uncoupling protein 1(UCP1)-luciferase reporter assay,we identifi ed ginsenoside F1 as a novel UCP1 activator in the ginsenosides library.Using pull down assay and inhibitor interference,we found F1 binds toβ3-adrenergic receptors(β3-AR)to enhance UCP1 expression via cAMP/PKA/CREB pathway.We also investigated the ability of F1 on energy metabolism in obesity-induced diabetic mice,including body weight,body composition and energy expenditure.The results of proteomics showed that F1 signifi cantly up-regulated thermogenesis proteins and lipolytic proteins,but down-regulated fatty acid synthesis proteins.Ginsenoside F1 increased thermogenesis and ameliorated insulin resistance specifi cally by promoting the browning of white adipose tissue in obese mice.Additionally,ginsenoside F1 improves norepinephrine-induced insulin resistance in adipocytes and hepatocytes,and shows a stronger mitochondria respiration ability than norepinephrine.These fi ndings suggest that ginsenoside F1 is a promising lead compound in the improvement of insulin resistance.

Cidea controls lipid droplet fusion and lipid storage in brown and white adipose tissue

Excess lipid storage in adipose tissue results in the development of obesity and other metabolic disorders including diabetes,fatty liver and cardiovascular diseases.The lipid droplet(LD)is an important subcellular organelle responsible for lipid storage.We previously observed that Fsp27,a member of the CIDE family proteins,is localized to LD-contact sites and promotes atypical LD fusion and growth.Cidea,a close homolog of Fsp27,is expressed at high levels in brown adipose tissue.However,the exact role of Cidea in promoting LD fusion and lipid storage in adipose tissue remains unknown.Here,we expressed Cidea in Fsp27-knockdown adipocytes and observed that Cidea has similar activity to Fsp27 in promoting lipid storage and LD fusion and growth.Next,we generated Cidea and Fsp27 double-deficient mice and observed that these animals had drastically reduced adipose tissue mass and a strong lean phenotype.In addition,Cidea/Fsp27 double-deficient mice had improved insulin sensitivity and were intolerant to cold.Furthermore,we observed that the brown and white adipose tissues of Cidea/Fsp27double-deficient mice had significantly reduced lipid storage and contained smaller LDs compared to those of Cidea or Fsp27single deficient mice.Overall,these data reveal an important role of Cidea in controlling lipid droplet fusion,lipid storage in brown and white adipose tissue,and the development of obesity.

Recent developments in natural products for white adipose tissue browning

Excess accumulation of white adipose tissue(WAT) causes obesity which is an imbalance between energy intake and energy expenditure. Obesity is a serious concern because it has been the leading causes of death worldwide, including diabetes, stroke,heart disease and cancer. Therefore, uncovering the mechanism of obesity and discovering anti-obesity drugs are crucial to prevent obesity and its complications. Browning, inducing white adipose tissue to brown or beige(brite) fat which is brown-like fat emerging in WAT, becomes an appealing therapeutic strategy for obesity and metabolic disorders. Due to lack of efficacy or intolerable side-effects, the clinical trials that promote brown adipose tissue(BAT) thermogenesis and browning of WAT have not been successful in humans. Obviously, more specific means still need to be developed to activate browning of white adipose tissue. In this review, we summarized seven kinds of natural products(alkaloids, flavonoids, terpenoids, long chain fatty acids, phenolic acids, else and extract) promoting white adipose tissue browning which can ameliorate the metabolic disorders, including obesity, dislipidemia, insulin resistance and diabetes. Since natural products are important drug sources and the browning property plays a significant role in not only obesity treatment but also in type 2 diabetes(T2 DM) improvement, natural products of inducing browning may be an irreplaceable drug discovery orientation for obesity, diabetes and even other metabolic disorders.

Common and distinct regulation of human and mouse brown and beige adipose tissues： a promising therapeutic target for obesity

Obesity, which underlies various metabolic and cardio- vascular diseases, is a growing public health challenge for which established therapies are inadequate. Given the current obesity epidemic, there is a pressing need for more novel therapeutic strategies that will help adult individuals to manage their weight. One promising therapeutic intervention for reducing obesity is to enhance energy expenditure. Investigations into human brown fat and the recently discovered beige/brite fat have galvanized intense research efforts during the past decade because of their pivotal roles in energy dissi- pation. In this review, we summarize the evolution of human brown adipose tissue （hBAT） research and dis- cuss new in vivo methodologies for evaluating energy expenditure in patients. We highlight the differences between human and mouse BAT by integrating and comparing their cellular morphology, function, and gene expression profiles. Although great advances in hBAT biology have been achieved in the past decade, more cellular models are needed to acquire a better under- standing of adipose-specific processes and molecular mechanisms. Thus, this review also describes the development of a human brown fat cell line, which could provide promising mechanistic insights into hBAT function, signal transduction, and development. Finally, we focus on the therapeutic potential and current limi- tations of hBAT as an anti-glycemic, anti-lipidemic, and weight loss-inducing ＇metabolic panacea＇.

Intercellular and inter-organ crosstalk in browning of white adipose tissue:molecular mechanism and therapeutic complications

Adipose tissue(AT)is highly plastic and heterogeneous in response to environmental and nutritional changes.The development of heat-dissipating beige adipocytes in white AT(WAT)through a process known as browning(or beiging)has garnered much attention as a promising therapeutic strategy for obesity and its related metabolic complications.This is due to its inducibility in response to thermogenic stimulation and its association with improved metabolic health.WAT consists of adipocytes,nerves,vascular endothelial cells,various types of immune cells,adipocyte progenitor cells,and fibroblasts.These cells contribute to the formation of beige adipocytes through the release of protein factors that significantly influence browning capacity.In addition,inter-organ crosstalk is also important for beige adipocyte biogenesis.Here,we summarize recent findings on fat depot-specific differences,secretory factors participating in intercellular and inter-organ communications that regulate the recruitment of thermogenic beige adipocytes,as well as challenges in targeting beige adipocytes as a potential anti-obese therapy.

Impact of a single bout of high-intensity interval exercise and short-term interval training on interleukin-6, FNDC5, and METRNL mRNA expression in human skeletal muscle

Background: Exercise promotes numerous phenotypic adaptations in skeletal muscle that contribute to improved function and metabolic capacity. An emerging body of evidence suggests that skeletal muscle also releases a myriad of factors during exercise, termed "myokines". The purpose of this study was to examine the effects of high-intensity interval training(HIIT) on the acute regulation of the mRNA expression of several myokines, including the prototypical myokine interleukin-6(IL-6), and recently identified myokines fibronectin type III domain-containing protein 5(FNDC5)(irisin) and meteorin-like protein(METRNL).Methods: Both before and after a 20-day period of twice-daily high-volume HIIT, 9 healthy males(20.5 ± 1.5 years performed a standardized bout of high-intensity interval exercise(HIIE; 5 × 4 min at ~80% pretraining peak power output) with skeletal muscle biopsy samples(vastus lateralis) obtained at rest, immediately following exercise, and at 3 h recovery.Results: Before training, a single bout of HIIE increased IL-6(p < 0.05) and METRNL(p < 0.05) mRNA expression measured at 3 h recovery when compared to rest. Following 20 days of HIIT, IL-6 and FNDC5 mRNA were increased at 3 h recovery from the standardized HIIE bout when compared to rest(both p < 0.05). Resting METRNL and FNDC5 mRNA expression were higher following training(p < 0.05), and there was an overall increase in FNDC5 mRNA post-training(main effect of training, p < 0.05).Conclusion: In human skeletal muscle(1) an acute bout of HIIE can induce upregulation of skeletal muscle IL-6 mRNA both before and after a period of intensified HIIT;(2) Resting and overall FNDC5 mRNA expression is increased by 20 days of HIIT; and(3) METRNL mRNA expression is responsive to both acute HIIE and short-term intense HIIT. Future studies are needed to confirm these findings at the protein and secretion level in humans.

Population genomics reveals that natural variation in PRDM16 contributes to cold tolerance in domestic cattle

Environmental temperature serves as a major driver of adaptive changes in wild organisms.To discover the mechanisms underpinning cold tolerance in domestic animals,we sequenced the genomes of 28 cattle from warm and cold areas across China.By characterizing the population structure and demographic history,we identified two genetic clusters,i.e.,northern and southern groups,as well as a common historic population peak at 30 kilo years ago.Genomic scan of cold-tolerant breeds determined potential candidate genes in the thermogenesis-related pathways that were under selection.Specifically,functional analysis identified a substitution of PRDM16(p.P779 L)in northern cattle,which maintains brown adipocyte formation by boosting thermogenesis-related gene expression,indicating a vital role of this gene in cold tolerance.These findings provide a basis for genetic variation in domestic cattle shaped by environmental temperature and highlight the role of reverse mutation in livestock species.

Human pluripotent stem cells:Towards therapeutic development for the treatment of lifestyle diseases

There are two types of human pluripotent stem cells: Embryonic stem cells(ESCs) and induced pluripotent stem cells(iPSCs),both of which launched themselves on clinical trials after having taken measures to overcome problems: Blocking rejections by immunosuppressants regarding ESCs and minimizing the risk of tumorigenicity by depleting exogenous gene components regarding iP SCs.It is generally assumed that clinical applications of human pluripotent stem cells should be limited to those cases where there are no alternative measures for treatments because of the risk in transplanting those cells to living bodies.Regarding lifestyle diseases,we have already several therapeutic options,and thus,development of human pluripotent stem cell-based therapeutics tends to be avoided.Nevertheless,human pluripotent stem cells can contribute to the development of new therapeutics in this field.As we will show,there is a case where only a short-term presence of human pluripotent stem-derived cells can exert long-term therapeutic effects even after they are rejected.In those cases,immunologically rejections of ESC-or allogenic iP SC-derived cells may produce beneficial outcomes by nullifying the risk of tumorigenesis without deterioration of therapeutic effects.Another utility of human pluripotent stem cells is the provision of an innovative tool for drug discovery that are otherwise unavailable.For example,clinical specimens of human classical brown adipocytes(BAs),which has been attracting a great deal of attention as a new target of drug discovery for the treatment of metabolic disorders,are unobtainable from living individuals due to scarcity,fragility and ethical problems.However,BA can easily be produced from human pluripotent stem cells.In this review,we will contemplate potential contribution of human pluripotent stem cells to therapeutic development for lifestyle diseases.

Role of Nociceptive Arcuate Nucleus Neurons in Chloroquine-induced Pruritic Behaviors in Mice

Despite its clinical importance, the underlying central mechanisms of pruritic behaviors are poorly understood. To investigate the role of nociceptive arcuate nucleus neurons in chloro-quine-induced pruritic behaviors in mice, we tested the effect of arcuate nucleus neurons and interscapular brown adipose tissue (IBAT) on itch produced by intradermal injection of chloroquine in the nape of the neck. Our results provide several lines of evidence for an important role of nociceptive arcuate nucleus neurons in chloroquine-induced pruritic behavior: (1) Intradermal microinjection of chloro-quine resulted in a dramatic increase in itch behaviors accompanied by the activation of c-Fos positive neurons in arcuate nucleus; (2) Microinjection of chloroquine significantly increased IBAT temperature in the mice. These findings suggested that chloroquine-induced pruritic behaviors were associated with the activity of nociceptive arcuate nucleus neurons.

Weight loss induced by whole grain-rich diet is through a gut microbiota-independent mechanism

The prevalence of overweight and obesity has increased worldwide.Obesity is a well-known risk factor of type 2 diabetes mellitus and cardiovascular disease and raises public health concerns.Many dietary guidelines encourage the replacement of refined grains with whole grains(WGs)to enhance body weight management.Current evidence regarding interrelationships among WGs,body weight,and gut microbiota is limited and inconclusive.In this editorial,we comment on the article by Roager et al published in the recent issue of the Gut 2019;68(1):83-93.In the study,obese patients(25<body mass index<35 kg/m2)were randomly assigned to receive two 8-wk dietary controlling periods with WGs and refined grain-rich diet.The results showed significantly decreased body weight in the WG group.Either the composition of gut microbiota or short-chain fatty acids,the leading end product of fermentation of non-digestible carbohydrate by gut microbiota,did not differ between the two groups.The study highly indicated that a WG-rich diet reduced body weight independent of gut microbiota.We then raised some plausible mechanisms of how WGs might influence body weight and demonstrated more literature in line with WGs enhance body weight control through a microbiota-independent pathway.Possible mechanisms include:(1)The abundant dietary fiber contents of WGs increase satiety,satiation,energy excretion from stool,and energy expenditure simultaneously decreasing energy absorption and fat storage;(2)The plentiful amount of polyphenols of WGs improve energy expenditure by hampering adipocyte maturation and function;(3)The sufficient magnesium and zinc of WGs guarantee lean body mass growth and decrease fat mass;(4)The effect of WGs on brown adipose tissue is a key component of non-shivering thermogenesis;and(5)The increase of adiponectin by WGs enhances glucose utilization,lipid oxidation,and energy expenditure.

Mulberry leaf flavonoids activate BAT and induce browning of WAT to improve type 2 diabetes via regulating the AMPK/SIRT1/PGC-1α signaling pathway

Mulberry (Morus alba L.) leaf is a well-established traditional Chinese botanical and culinary resource. It has found widespread application in the management of diabetes. The bioactive constituents of mulberry leaf, specifically mulberry leaf flavonoids (MLFs), exhibit pronounced potential in the amelioration of type 2 diabetes (T2D). This potential is attributed to their ability to safeguard pancreatic β cells, enhance insulin resistance, and inhibit α-glucosidase activity. Our antecedent research findings underscore the substantial therapeutic efficacy of MLFs in treating T2D. However, the precise mechanistic underpinnings of MLF’s anti-T2D effects remain the subject of inquiry. Activation of brown/beige adipocytes is a novel and promising strategy for T2D treatment. In the present study, our primary objective was to elucidate the impact of MLFs on adipose tissue browning in db/db mice and 3T3-L1 cells and elucidate its underlying mechanism. The results manifested that MLFs reduced body weight and food intake, alleviated hepatic steatosis, improved insulin sensitivity, and increased lipolysis and thermogenesis in db/db mice. Moreover, MLFs activated brown adipose tissue (BAT) and induced the browning of inguinal white adipose tissue (IWAT) and 3T3-L1 adipocytes by increasing the expressions of brown adipocyte marker genes and proteins such as uncoupling protein 1 (UCP1) and beige adipocyte marker genes such as transmembrane protein 26 (Tmem26), thereby promoting mitochondrial biogenesis. Mechanistically, MLFs facilitated the activation of BAT and the induction of WAT browning to ameliorate T2D primarily through the activation of AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) signaling pathway. These findings highlight the unique capacity of MLF to counteract T2D by enhancing BAT activation and inducing browning of IWAT, thereby ameliorating glucose and lipid metabolism disorders. As such, MLFs emerge as a prospective and innovative browning agent for the treatment of T2D.