Uncoupling protein 2 deficiency of non-cancerous tissues inhibits the progression of pancreatic cancer in mice

Background: Pancreatic ductal adenocarcinoma(PDAC) is a disease of the elderly mostly because its development from preneoplastic lesions depends on the accumulation of gene mutations and epigenetic alterations over time. How aging of non-cancerous tissues of the host affects tumor progression, however, remains largely unknown. Methods: We took advantage of a model of accelerated aging, uncoupling protein 2-deficient( Ucp2 knockout, Ucp2 KO) mice, to investigate the growth of orthotopically transplanted Ucp2 wild-type(WT) PDAC cells(cell lines Panc02 and 6606PDA) in vivo and to study strain-dependent differences of the PDAC microenvironment. Results: Measurements of tumor weights and quantification of proliferating cells indicated a significant growth advantage of Panc02 and 6606PDA cells in WT mice compared to Ucp2 KO mice. In tumors in the knockout strain, higher levels of interferon-γ m RNA despite similar numbers of tumor-infiltrating T cells were observed. 6606PDA cells triggered a stronger stromal reaction in Ucp2 KO mice than in WT animals. Accordingly, pancreatic stellate cells from Ucp2 KO mice proliferated at a higher rate than cells of the WT strain when they were incubated with conditioned media from PDAC cells. Conclusions: Ucp2 modulates PDAC microenvironment in a way that favors tumor progression and implicates an altered stromal response as one of the underlying mechanisms.

Effect of Acupuncture on Uncoupling Protein 1 Gene Expression for Brown Adipose Tissue of Obese Rats

Objective:To explore the effects of acupuncture on the expression of uncoupling protein 1（UCP1）gene of brown adipose tissue （BAT）in obese rats.Methods:The expression of UCP1gene ofBAT was determined with RT-PCR technique.The changes of body weight,Lee’s index,body fat,andthe expression of UCP1gene of BAT in obese rats were observed before and after acupuncture.Results:The body weight,Lee’s indeX,body fat in obese rats were all markedly higher than those in normal rats,but the expression of UCP1gene of BAT in obese rats was all lower than that in normal rats.There werenegative correlation between the Obesity index and the expression of UCP1gent in BAT.After acupunc-ture the marked effect of weight loss was achieved while the expression of UCP1gene of BAT Obviously in-creased in obese rats.Conclusion:The abnormal reduction for expression of UCP1gene of BAT might bean important cause for the obesity.To promote the expression of UCP1in obese organism might be an im-portant cellular and mole

Uncoupling protein 2 in the glial response to stress:implications for neuroprotection

Reactive oxygen species（ROS） are free radicals thought to mediate the neurotoxic effects of several neurodegenerative disorders.In the central nervous system,ROS can also trigger a phenotypic switch in both astrocytes and microglia that further aggravates neurodegeneration,termed reactive gliosis.Negative regulators of ROS,such as mitochondrial uncoupling protein 2（UCP2） are neuroprotective factors that decrease neuron loss in models of stroke,epilepsy,and parkinsonism.However,it is unclear whether UCP2 acts purely to prevent ROS production,or also to prevent gliosis.In this review article,we discuss published evidence supporting the hypothesis that UCP2 is a neuroprotective factor both through its direct effects in decreasing mitochondrial ROS and through its effects in astrocytes and microglia.A major effect of UCP2 activation in glia is a change in the spectrum of secreted cytokines towards a more anti-inflammatory spectrum.There are multiple mechanisms that can control the level or activity of UCP2,including a variety of metabolites and micro RNAs.Understanding these mechanisms will be key to exploitingthe protective effects of UCP2 in therapies for multiple neurodegenerative conditions.

Effect of Target-directed Regulation of Uncoupling Protein-2 Gene Expression on Ischemia-reperfusion Injury of Hepatocytes

The effect of target-directed regulation of the uncoupling protein-2 （UCP-2） gene expression on the ischemia-reperfusion injury of hepatocytes under different conditions was investigated. The expression plasmid and RNAi plasmid targeting UCP-2 gene were constructed and trans- fected into normal hepatocytes and fatty liver cells, respectively. The expression of UCP-2 mRNA was detected by real time PCR. The cells were divided into normal cell group （NCG）, group of normal cells transfected with empty vector （EVNCG）, group of normal cells transfected with expression plasmid （EPNCG）, fatty liver cell group （FCG） and group of fatty liver cells transfected with RNAi plasmid （RPFCG）. The ischemia-reperfusion model in vitro was established. One, 6, 12 and 24 h after reperfusion, Annexin V/PI flow cytometry was used to measure cell necrosis rate, apoptosis rate and survival rate. Simultaneously, the intracellular ATP, ROS and MDA levels were determined. The re- sults showed that 1, 6, 12 and 24 h after ischemia-reperfusion, the intracellular ROS, MDA and ATP levels and cell survival rate in EPNCG were significantly lower, and cell necrosis rate significantly higher than in NCG and EVNCG, but there was no significant difference in apoptosis rate among NCG, EVNCG and EPNCG （P〉005）. Six, 12 and 24 h after reperfusion there was no significant dif- ference in ROS, MDA levels and apoptosis rate between FCG and RPFCG （P〉0.05）, but the ATP level and survival rate of cells in RPFCG were higher than in FCG （P〈0.05）. It was concluded that down-regulation of the UCP-2 gene expression in steatotic hepatocytes could alleviate the ische- mia-reperfusion injury of liver cells.

Uncoupling protein 2 regulates glucagon-like peptide-1 secretion in L-cells

AIM:To investigate whether uncoupling protein 2(UCP2) affects oleic acid-induced secretion of glucagonlike peptide-1(GLP-1) in L-cells.METHODS:mRNA and protein expression of UCP2 were analyzed in human NCI-H716 cells,which serve as a model for enteroendocrine L-cells,by quantitative reverse transcription-polymerase chain reaction and Western blotting before and after treatment with oleic acid.Localization of UCP2 and GLP-1 in NCI-H716 cells was assessed by immunofluorescence labeling.NCI-H716 cells were transiently transfected with a small interfering RNA(siRNA) that targets UCP2(siUCP2) or with a nonspecific siRNA using Lipofectamine 2000.The concentrations of bioactive GLP-1 in the medium were measured by enzyme linked immunosorbent assay.RESULTS:Both GLP-1 and UCP2 granules were expressed mainly in the cytoplasm of NCI-H716 cells.NCI-H716 cells that secreted GLP-1 also expressed UCP2.Time-course experiments revealed that release of GLP-1 from NCI-H716 cells into the medium reached a maximum at 120 min and remained stable until at least 180 min after treatment with oleic acid(the level of GLP-1 increased about 2.3-fold as compared with the level of GLP-1 in the control cells,P < 0.05).In an experiment to determine dose dependence,stimulation of NCI-H716 cells with ≤ 8 mmol oleic acid led to a concentration-dependent release of GLP-1 into the medium;10 mmol oleic acid diminished the release of GLP-1.Furthermore,GLP-1 secretion induced by oleic acid from NCI-H716 cells that were transfected with siUCP2 decreased to 41.8%,as compared with NCI-H716 cells that were transfected with a non-specific siRNA(P < 0.01).CONCLUSION:UCP2 affected GLP-1 secretion induced by oleic acid.UCP2 plays an important role in L-cell secretion that is induced by free fatty acids.

Uncoupling protein 2 deficiency reduces proliferative capacity of murine pancreatic stellate cells

BACKGROUND： Uncoupling protein 2 （UCP2） has been suggested to inhibit mitochondrial production of reactive oxygen species （ROS） by decreasing the mitochondrial membrane potential. Experimental acute pancreatitis is associated with increased UCP2 expression, whereas UCP2 deficiency retards regeneration of aged mice from acute pancreatitis. Here, we have addressed biological and molecular functions of UCP2 in pancreatic stellate cells （PSCs）, which are involved in pancreatic wound repair and fibrogenesis. METHODS： PSCs were isolated from 12 months old （aged） UCP2^-/- mice and animals of the wild-type （WT） strain C57BL/6. Proliferation and cell death were assessed by em- ploying trypan blue staining and a 5-bromo-2＇-deoxyuridine incorporation assay. Intracellular fat droplets were visualized by oil red O staining. Levels of mRNA were determined by RT-PCR, while protein expression was analyzed by immunoblotting and immunofluorescence analysis. Intracellular ROS levels were measured with 2＇,7＇-dichlorofluorescin diacetate. Expression of senescence-associated β-galactosidase （SA β-Gal） was used as a surrogate marker of cellular senescence. RESULTS： PSCs derived from UCP2^-/- mice proliferated at a lower rate than cells from WT mice. In agreement with this observation, the UCP2 inhibitor genipin displayed dose- dependent inhibitory effects on WT PSC growth. Interestingly, ROS levels in PSCs did not differ between the two strains, and PSCs derived from UCP2^-/- mice did not senesce faster than those from corresponding WT cells. PSCs from UCP2^-/- mice and WT animals were also indistinguishable with respect to the activation-dependent loss of intracellular fat droplets, expression of the activation marker α-smooth muscle actin, type I collagen and the autocrine/paracrine mediators interleukin-6 and transforming growth factor-I~ 1. CONCLUSIONS： A reduced proliferative capacity of PSC from aged UCP2^-/- mice may contribute to the retarded regeneration after acute pancreatitis. Apart from their slower growth, PSC of UCP2^-/- mice displayed no functional abnormalities. The antifibrotic potential of UCP2 inhibitors deserves further attention.

A Statistical Evaluation of Uncoupling Protein 1 in the Limited Area of Brown Adipose Tissue by Immunoelectron Microscopy

Uncoupling protein 1 (UCP1) expressed by the brown adipose tissue (BAT) in the mitochondrial crista acts as a homeostatic thermogenerator of eutherians. The evaluation of UCP1 expression in the BAT offers significant scientific insight, especially in studies targeting limited areas such as the periarterial and pericardial regions of small experimental mammals. However, the negligible amount of this adipose tissue would render the general quantitative evaluation of the protein unreliable because of lipid contamination and low protein concentration. To address this problem, we quantitatively evaluated UCP1 expression in the mitochondrion of the mouse interscapular BAT using immunoelectron microscopy and immunohistochemical studies using a combination of primary and secondary antibodies in scheme A (rabbit anti-UCP1 IgG/gold particle-conjugated goat anti-rabbit IgG), B (rabbit IgG/gold particle-conjugated goat anti-rabbit IgG), C (rabbit anti-UCP1 IgG/gold particle-unconjugated goat anti-rabbit IgG), and D (rabbit IgG/gold particle-unconjugated goat anti-rabbit IgG). Scheme A shows the immunopositive reaction of obvious gold particles in the mitochondrial area, whereas other procedures revealed less distinctive reactions. The distinctive gold particle immunoreaction comprised electrical high-density spots with a mean diameter of >5 nm. However, in scheme B, the electrical high-density spots were scattered outside the mitochondrion and were significantly smaller than 4 nm;schemes C and D demonstrated few immunoreactions. Logistic regression analysis between schemes A and B showed that the threshold diameter of the electrical high-density spots measuring >5 nm indicated a true positive immunoreaction to anti-UCP1 antibody specifically in the mitochondrial area. Minor statistical difference was observed in the primary anti-UCP1 antibody between polyclonal IgG and monoclonal antibodies. Therefore, immunoelectron microscopy might be useful for evaluating negligible protein expression in some limited areas, such as UCP1 expression in the BAT of small experimental animals.

Obesity and Protein Metabolism

A conceptual model of the interdependence between the metabolism of proteins,fats and carbohydrates taking into account the transport of the carbon skeleton and the stages of the relationship between the processes of formation and utilization of ATP(Adenosine Triphosphate)energy,which demonstrates the key role of protein metabolism and the maintenance of glucose homeostasis with different organism availability in energy was proposed.In supporting the processes of vital activity of the body,two periods should be analyzed.The first one is absorptive period,which is for providing rehabilitation processes,the expression of which is the“food pyramid”and the second one is postabsorptive period,which is for the energetic provision of physical and mental work,the expression of which is the“energy pyramid”.These pyramids differ in the ratio of macronutrients,and in their composition,which must be taken into account when developing the principles of human nutrition.Although obesity is seen as a simple discrepancy between the amount of intake of food calories and their utilization for physical activity,however,do not take into account the large energy expenditure on volatile processes,in particular,the process of protein synthesis.The process of protein synthesis depends on the availability in the substrate(amino acids),the intensity of mRNA expression(transcription)and the speed of reproduction(translation),so the violation at each of these stages will affect the energy balance and promote the development of obesity.Half of the protein mass is muscle,so it largely determines the homeostasis of glucose and the development of energy balance,which is presented in the form of an interdisciplinary model for the development of diabetes,obesity and cardiovascular diseases.In conclusion,technologies were proposed to support the process of protein synthesis and ways of preventing and treating obesity.

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.

Diabetes exacerbates inflammatory bowel disease in mice with dietinduced obesity

BACKGROUND The increased prevalence of inflammatory bowel disease(IBD)among patients with obesity and type 2 diabetes suggests a causal link between these diseases,potentially involving the effect of hyperglycemia to disrupt intestinal barrier integrity.AIM To investigate whether the deleterious impact of diabetes on the intestinal barrier is associated with increased IBD severity in a murine model of colitis in mice with and without diet-induced obesity.METHODS Mice were fed chow or a high-fat diet and subsequently received streptozotocin to induce diabetic-range hyperglycemia.Six weeks later,dextran sodium sulfate was given to induce colitis.In select experiments,a subset of diabetic mice was treated with the antidiabetic drug dapagliflozin prior to colitis onset.Endpoints included both clinical and histological measures of colitis activity as well as histochemical markers of colonic epithelial barrier integrity.RESULTS In mice given a high-fat diet,but not chow-fed animals,diabetes was associated with significantly increased clinical colitis activity and histopathologic markers of disease severity.Diabetes was also associated with a decrease in key components that regulate colonic epithelial barrier integrity(colonic mucin layer content and epithelial tight junction proteins)in diet-induced obese mice.Each of these effects of diabetes in diet-induced obese mice was ameliorated by restoring normoglycemia.CONCLUSION In obese mice,diabetes worsened clinical and pathologic outcomes of colitis via mechanisms that are reversible with treatment of hyperglycemia.Hyperglycemia-induced intestinal barrier dysfunction offers a plausible mechanism linking diabetes to increased colitis severity.These findings suggest that effective diabetes management may decrease the clinical severity of IBD.

Mitochondrial uncoupling protein 2 expression in colon cancer and its clinical significance

AIM: To detect the expression of mitochondrial uncoupling protein 2 (UCP2) in colon cancer and analyze the relation between UCP2 expression and clinical pathological features of colon cancer.METHODS: Fifteen colon tissue samples and 15 its adjacent tissue samples were obtained from colon cancer patients during surgical interventions. UCP2 expression was detected with immunohistochemical method in 10 normal controls, 10 hyperplastic polyp patients, 20 tubular adenoma patients and 78 colon cancer patients. Patients with rectal cancer were excluded. Quantitative reverse transcription polymerase chain reaction and Western blotting were used to detect UCP2 expressions in colon cancer tissue samples and its adjacent tissue samples. Relation between UCP2 expression and clinical pathological features of colon cancer was also analyzed. RESULTS: The UCP2 mRNA expression level was fourfold higher in colon cancer tissue samples than in its adjacent tissue samples. The UCP2 protein expression level was three-fold higher in colon cancer tissue samples than in its adjacent normal tissue samples. The UCP2 was mainly expressed in cytoplasm. The UCP2 was not expressed in normal colon mucosa. Strong positive staining for UCP2 with a diffuse distribution pattern was identified throughout the mucosa in colon cancer tissue samples with a positive expression rate of 85.9%. The UCP2 expression level was higher in colon cancer tissue samples at clinical stages Ⅲ and Ⅳ than in those at stageⅠ+ Ⅱ. Univariate analysis showed that the high UCP2 expression level was significantly correlated to colon cancer metastasis (hazard ratio = 4.321, confidence interval = 0.035-0.682, P = 0.046). CONCLUSION: UCP2 is highly expressed in human colon cancer tissue and may be involved in colon cancer metastasis.

Mitochondrial uncoupling protein 2 and pancreatic cancer:A new potential target therapy

Overall 5-years survival of pancreatic cancer patients is nearly 5%,making this cancer type one of the most lethal neoplasia.Furthermore,the incidence rate of pancreatic cancer has a growing trend that determines a constant increase in the number of deceases caused by this pathology.The poor prognosis of pancreatic cancer is mainly caused by delayed diagnosis,early metastasis of tumor,and resistance to almost all tested cytotoxic drugs.In this respect,the identification of novel potential targets for new and efficient therapies should be strongly encouraged in order to improve the clinical management of pancreatic cancer.Some studies have shown that the mitochondrial uncoupling protein 2(UCP2) is over-expressed in pancreatic cancer as compared to adjacent normal tissues.In addition,recent discoveries established a key role of UCP2 in protecting cancer cells from an excessive production of mitochondrial superoxide ions and in the promotion of cancer cell metabolic reprogramming,including aerobic glycolysis stimulation,promotion of cancer progression.These observations together with the demonstration that UCP2 repression can synergize with standard chemotherapy to inhibit pancreatic cancer cell growth provide the molecular rationale to consider UCP2 as a potential therapeutic target for pancreatic cancer.In this editorial,recent advances describing the relationship between cancer development and mitochondrial UCP2 activity are critically provided.

Decreased uncoupling protein 2 expression in aging retinal pigment epithelial cells

AIM: To analyze the expression of uncoupling protein 2(UCP2) in retinal pigment epithelium(RPE) cells at the different human age, further explore the possible new target of RPE cells protection.METHODS: Adult retinal pigment epithelial-19(ARPE-19) cells and the primary RPE cells at the different age(9-20 y,50-55 y, 60-70 y, >70 y) were cultured and harvested. The expression of UCP2 in these cells was detected by reverse transcription-polymerase chain reaction(RT-PCR), Western blot and confocal microscopy.RESULTS: Cells from the donors more than 60 y are larger and more fibroblastic in appearance compared to ARPE-19 cells and those primary cultures obtained from the younger individuals by using phase-contrast micrographs. Results of RT-PCR, Western blot and confocal microscopy all showed that UCP2 was highly expressed in ARPE-19 cells and in the younger primary cultured human RPE cells at the age of 9-20 y and 50-55 y, whereas lower expression of UCP2 was measured in the older primary cultured human RPE cells at the age more than 60 y.CONCLUSION: Expression of UCP2 gene is decreased in aged RPE cells, promoting the lower ability of anti-oxidation in these cells. It is indicated that UCP2 gene might be a new target for protecting the cells from oxidative stress damage.

Uncoupling protein 2 regulates myocardial apoptosis via the diabetogenic action of streptozotocin

Objective: Determine the role of uncoupling protein 2 (UCP2) in the myocardial apoptosis of diabetic mellitus(DM). Methods: DM animal models were induced by streptozotocinon (STZ) on UCP2 knock-out mice (UCP2KO) and wild-type mice (WT), which were reared for 7 and 28 days after successful modeling, respectively. The expressions of relative protein for myocardial apoptosis, pro-caspase-9, were investigated using western blot. However, the terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) was used to explain apoptosis at the DNA level. Results: Image analysis showed that the expression of pro-caspase-9 protein levels increased slightly in UCP-/- + DM-7-day group comparing with DM-7-day group (P > 0.05). The expression of pro-caspase-9 protein levels increased significantly (P < 0.05)in UCP-/- + DM-28-day group comparing with DM-28-day group. TUNEL analysis indicated that UCP2 reduced the number of apoptotic myocytes in the DM-28-day group by 70% in comparison to DM-7-day group by 30% (P < 0.05). Conclusion UCP2 may be one of the most important factors that contribute to the myocardial apoptosis of DM.

Sheng-jiang powder ameliorates obesity-induced pancreatic inflammatory injury via stimulating activation of the AMPK signalling pathway in rats

AIM To investigate the mechanisms by which Sheng-jiang powder(SJP) ameliorates obesity-induced pancreatic inflammatory injury.METHODS Sprague-Dawley rats were randomized into three groups: normal group(NG), obese group(HLG), or SJP treatment group(HSG). Obesity was induced by feeding a high-fat diet in the HLG and HSG, while the NG received standard chow. Rats were euthanized after 12 wk, and blood and pancreatic tissues were collected for histopathological analyses. Nuclear factor kappa-light-chain-enhancer of activated B cells(NF-κB) and transforming growth factor beta(TGF-β) expression, serum triglyceride and adiponectin levels, and apoptosis in pancreatic acinar cells were assessed. A high-fat AR42 J acinar cell injury model was established using very low-density lipoprotein(VLDL). AR42 J acinar cell culture supernatant, treated with different interventions, was applied to seven groups of pancreatic stellate cells(PSCs). The proliferation of PSCs and the expression of fibronectin and type I collagenase were assessed.RESULTS Compared with the NG, we found higher pathological scores for pancreatic tissues, lower serum adiponectin levels, higher expression levels of NF-κB in pancreatic tissues and TGF-β in pancreatic inflammatory cells, and increased apoptosis among pancreatic acinar cells for the HLG(P < 0.05). Compared with the HLG, we found reduced body weight, Lee's index scores, serum triglyceride levels, and pathological scores for pancreatic tissues; higher serum adiponectin levels; and lower expression levels of NF-κB, in pancreatic tissue and TGF-β in pancreatic inflammatory cells for the HSG(P < 0.05). The in vitro studies showed enhanced PSC activation and increased expression levels of fibronectin and type I collagenase after SJP treatment. An adenosine 5‘-monophosphate-activated protein kinase(AMPK) inhibitor inhibited PSC activation.CONCLUSION SJP may ameliorate obesity-induced pancreatic inflammatory injury in rats by regulating key molecules of the adiponectin-AMPK signalling pathway.

Leucine signaling in the pathogenesis of type 2 diabetes and obesity

Epidemiological evidence points to increased dairy and meat consumption,staples of the Western diet,as major risk factors for the development of type 2 diabetes(T2D).This paper presents a new concept and comprehensive review of leucine-mediated cell signaling explaining the pathogenesis of T2D and obesity by leucine-induced over-stimulation of mammalian target of rapamycin complex 1(mTORC1).mTORC1,a pivotal nutrient-sensitive kinase,promotes growth and cell proliferation in response to glucose,energy,growth factors and amino acids.Dairy proteins and meat stimulate insulin/insulin-like growth factor 1 signaling and provide high amounts of leucine,a primary and independent stimulator for mTORC1 activation.The downstream target of mTORC1,the kinase S6K1,induces insulin resistance by phosphorylation of insulin receptor substrate-1,thereby increasing the metabolic burden of β-cells.Moreover,leucine-mediated mTORC1-S6K1-signaling plays an important role in adipogenesis,thus increasing the risk of obesity-mediated insulin resistance. High consumption of leucine-rich proteins explains exaggerated mTORC1-dependent insulin secretion, increased β-cell growth and β-cell proliferation promoting an early onset of replicative β-cell senescence with subsequent β-cell apoptosis.Disturbances of β-cell mass regulation with increased β-cell proliferation and apoptosis as well as insulin resistance are hallmarks of T2D,which are all associated with hyperactivation of mTORC1.In contrast,the anti-diabetic drug metformin antagonizes leucine-mediated mTORC1 signaling.Plant-derived polyphenols and flavonoids are identified as natural inhibitors of mTORC1 and exert anti-diabetic and anti-obesity effects.Furthermore,bariatric surgery in obesity reduces increased plasma levels of leucine and other branched-chain amino acids.Attenuation of leucine-mediated mTORC1 signaling by defining appropriate upper limits of the daily intake of leucine-rich animal and dairy proteins may offer a great chance for the prevention of T2D and obesity,as well as other epidemic diseases of civilization with increased mTORC1 signaling,especially cancer and neurodegenerative diseases,which are frequently associated with T2D.

White adipose tissue browning and obesity

Obesity and metabolic disorders are major health concems worldwide. Although a range of therapies have been developed, these pharmaceutical treatments often have adverse side effects or limited efficacy. Therefore, there is a growing need of novel therapeutics to prevent or treat obesity. Obesity is thought to be caused by an imbalance between energy intake and energy consumption. Increasing energy consumption is considered as a potential therapeutic strategy to treat obesity and its related disorders.

Common therapeutic target for both cancer and obesity

Obesity and cancer are two interrelated conditions of high epidemiological need, with studies showing that obesity is responsible for nearly 25% of the relative contribution to cancer incidence. Given the connection between these conditions, a drug that can operate on both obesity and cancer is highly desirable. Such a drug is accomplishablethrough the development of potent anti-angiogenesis agents due to the shared underlying role of angiogenesis in the development of both diseases. Prior research has demonstrated a key role of type-2 methionine aminopeptidase(Met AP2) for angiogenesis, which has led to the development of numerous of novel inhibitors. Several irreversible Met AP2 inhibitors have entered clinical trials without great success. Though this lack of success could be attributed to off-target adverse effects, the underlying causes remain unclear. More promising reversible inhibitors have been recently developed with excellent pre-clinical results. However, due to insufficient knowledge of the biological functions of N-terminal protein processing, it is hard to predict whether these novel inhibitors would successfully pass clinical trials and thereby benefit cancer and obesity patients. Significantly more efforts are needed to advance our understanding of the regulation of methionine aminopeptidases and the processes by which they govern the function of proteins.

Jueming Prescription(决明方) Reduces Body Weight by Increasing the mRNA Expressions of Beta3-Adrenergic Receptor and Uncoupling Protein-2 in Adipose Tissue of Diet-Induced Obese Rats

Objective： To investigate the antiobesity effect of Jueming Prescription （决明方, JMP）, a Chinese herbal medicine formula, and its influence on mRNA expressions of beta3 adrenergic receptor （beta3-AR） and uncoupling protein-2 （UCP-2） in adipose tissue of diet-induced obese rats. Methods： Fifty male Sprague-Dawley rats were randomly divided into the normal control group （n=8） that was on a standard chow diet, and the obese model group （n=42） that was on a diet of high fat chow. Two weeks after the high fat diet, 29 obese rats in the obese model group were further randomly divided into 3 groups： the untreated obese model group （n=9）, the met＇formin group （n=10, mefformin 300 mg-kg-1.day-1）, and the JMP group （n=10, JMP 4 g.kg-1.dayl）. After 8-week treatment, body weight, wet weight of visceral fat, and percentage of body fat （PBF） were measured. The levels of fasting blood glucose, serum lipids, and insulin were assessed, and insulin sensitivity index （ISI） was calculated. The adipose tissue section was stained with hematoxylin-Eosin, and the cellular diameter and quantity of adipocytes were evaluated by light microscopy. The mRNA expressions of beta3-AR and UCP-2 from the pet-renal fat tissue were determined by real-time reverse transcription polymerase chain reaction （RT-PCR）. Results： Compared with the obese model group, treatment with JMP resulted in significantly lower body weight, wet weight of visceral fat, PBF, and diameter of adipocytes, and significantly higher level of high-density lipoprotein cholesterol, ISI （all P〈0.01）, JMP increased the mRNA expressions of beta3-AR and UCP-2 from pedrenal fat tissue （P〈0.05, P〈0.01）. Conclusions： JMP could reduce body weight and adipocyte size; and the effect was associated with the up-regulation of beta3-AR and UCP-2 expressions in the adipose tissue and improvement of insulin sensitivity.

Uncoupling protein and nonalcoholic fatty liver disease

Objective To review the current advances on the role of uncoupling protein （UCP） in the pathogenesis and progress of nonalcoholic fatty liver disease （NAFLD）.Data sources A comprehensive search of the PubMed literature without restriction on the publication date was carried out using keywords such as UCP and NAFLD.Study selection Articles containing information related to NAFLD and UCP were selected and carefully analyzed.Results The typical concepts,up-to-date findings,and existing controversies of UCP2 in NAFLD were summarized.Besides,the effect of a novel subtype of UCP （hepatocellular down regulated mitochondrial carrier protein,HDMCP） in NAFLD was also analyzed.Finally,the concept that any mitochondrial inner membrane carrier protein may have,more or less,the uncoupling ability was reinforced.Conclusions Considering the importance of NAFLD in clinics and UCP in energy metabolism,we believe that this review may raise research enthusiasm on the effect of UCP in NAFLD and provide a novel mechanism and therapeutic target for NAFLD.