Punicalagin prevents obesity-related cardiac dysfunction through promoting DNA demethylation in mice

The aim of this study was to investigate whether punicalagin(PU)could prevent obesity-related cardiac dysfunction by promoting DNA demethy lation,and to explore its possible mechanism.C57BL/6J mice were fed with standard diet,high-fat diet(HFD),HFD supplemented with resveratrol,low-dose PU(LPU)and high-dose PU(HPU)for 8 weeks.Compared with HFD group,body weight was significantly lower in PU treatment groups,number of cardionwocytes and the protein level of myosin heavy chain 7B were significantly higher in PU treatment groups.Levels of 5-hydroxymethylcytosine and 5-formylcytosine were significantly lower in HFD group than in other groups.Compared with the HFD group,the protein level of ten-eleven translocation enzyme(TET)2 was significantly higher in PU treatment groups,p-AMP-activated protein kinase(AMPK)was significantly higher in LPU group.Levels of total antioxidant capacity and the protein levels of complexesⅡ/Ⅲ/Ⅴ,oxoglutarate dehydrogenase,succinate dehydrogenase B and fumarate hdrolase were significantly lower in HFD group than PU treatment group.The ratio of(succinic acid+fumaric acid)/a-ketoglutarate was significantly higher in HFD group than other groups.In conclusion,PU up-regulated TETs enzyme activities and TET2 protein stability through alleviating mitochondrial dysfunction and activating AMPK,so as to promote DNA demethylation,thus preventing obesity-related cardiac dysfunction.

Clinical characteristics and treatment compounds of obesity-related kidney injury

Disorders in energy homeostasis can lead to various metabolic diseases,particularly obesity.The obesity epidemic has led to an increased incidence of obesityrelated nephropathy(ORN),a distinct entity characterized by proteinuria,glomerulomegaly,progressive glomerulosclerosis,and renal function decline.Obesity and its associated renal damage are common in clinical practice,and their incidence is increasing and attracting great attention.There is a great need to identify safe and effective therapeutic modalities,and therapeutics using chemical compounds and natural products are receiving increasing attention.However,the summary is lacking about the specific effects and mechanisms of action of compounds in the treatment of ORN.In this review,we summarize the important clinical features and compound treatment strategies for obesity and obesityinduced kidney injury.We also summarize the pathologic and clinical features of ORN as well as its pathogenesis and potential therapeutics targeting renal inflammation,oxidative stress,insulin resistance,fibrosis,kidney lipid accumulation,and dysregulated autophagy.In addition,detailed information on natural and synthetic compounds used for the treatment of obesity-related kidney disease is summarized.The synthesis of detailed information aims to contribute to a deeper understanding of the clinical treatment modalities for obesity-related kidney diseases,fostering the anticipation of novel insights in this domain.

Management of male obesity-related secondary hypogonadism:A clinical update

The global obesity pandemic has resulted in a rise in the prevalence of male obesity-related secondary hypogonadism(MOSH)with emerging evidence on the role of testosterone therapy.We aim to provide an updated and practical approach towards its management.We did a comprehensive literature search across MEDLINE(via PubMed),Scopus,and Google Scholar databases using the keywords“MOSH”OR“Obesity-related hypogonadism”OR“Testosterone replacement therapy”OR“Selective estrogen receptor modulator”OR“SERM”OR“Guidelines on male hypogonadism”as well as a manual search of references within the articles.A narrative review based on available evidence,recommendations and their practical implications was done.Although weight loss is the ideal therapeutic strategy for patients with MOSH,achievement of significant weight reduction is usually difficult with lifestyle changes alone in real-world practice.Therefore,androgen administration is often necessary in the management of hypogonadism in patients with MOSH which also improves many other comorbidities related to obesity.However,there is conflicting evidence for the appropriate use of testosterone replacement therapy(TRT),and it can also be associated with complications.This evidence-based review updates the available evidence including the very recently published results of the TRAVERSE trial and provides comprehensive clinical practice pearls for the management of patients with MOSH.Before starting testosterone replacement in functional hypogonadism of obesity,it would be desirable to initiate lifestyle modification to ensure weight reduction.TRT should be coupled with the management of other comorbidities related to obesity in MOSH patients.Balancing the risks and benefits of TRT should be considered in every patient before and during longterm management.

Effect of Dietary Resistant Starch on Prevention and Treatment of Obesity-related Diseases and Its Possible Mechanisms

Overweight or obesity has become a serious public health problem in the world, scientists are concentrating their efforts on exploring novel ways to treat obesity. Nowadays, the availabilities of bariatric surgery and pharmacotherapy have enhanced obesity treatment, but it should has support from diet, physical exercise and lifestyle modification, especially the functional food. Resistant starch, an indigestible starch, has been studied for years for its beneficial effects on regulating blood glucose level and lipid metabolism. The aim of this review is to summarize the effect of resistant starch on weight loss and the possible mechanisms. According to numerous previous studies it could be concluded that resistant starch can reduce fat accumulation, enhance insulin sensitivity, regulate blood glucose level and lipid metabolism. Recent investigations have focused on the possible associations between resistant starch and incretins as well as gut microbiota. Resistant starch seems to be a promising dietary fiber for the prevention or treatment of obesity and its related diseases.

The most important questions in cancer research and clinical oncology Question 2-5.Obesity-related cancers:more questions than answers

Obesity is recognized as the second highest risk factor for cancer. The pathogenic mechanisms underlying tobaccorelated cancers are well characterized and efective programs have led to a decline in smoking and related cancers, but there is a global epidemic of obesity without a clear understanding of how obesity causes cancer. Obesity is heterogeneous, and approximately 25% of obese individuals remain healthy(metabolically healthy obese, MHO), so which fat deposition(subcutaneous versus visceral, adipose versus ectopic) is "malignant"? What is the mechanism of carcinogenesis? Is it by metabolic dysregulation or chronic inflammation? Through which chemokines/genes/signaling pathways does adipose tissue influence carcinogenesis? Can selective inhibition of these pathways uncouple obesity from cancers? Do all obesity related cancers(ORCs) share a molecular signature? Are there common(overlapping) genetic loci that make individuals susceptible to obesity, metabolic syndrome, and cancers? Can we identify precursor lesions of ORCs and will early intervention of high risk individuals alter the natural history? It appears unlikely that the obesity epidemic will be controlled anytime soon; answers to these questions will help to reduce the adverse efect of obesity on human condition.

Obesity-related glomerulopathy： pathogenesis, pathologic, clinical characteristics and treatment

n light of the rapid increase in the number of obesity incidences worldwide, obesity has become an independent risk factor for chronic kidney disease. Obesity-related giomerulopathy （ORG） is characterized by glomerulomegaly in the presence or absence of focal and segmental glomerulosclerosis lesions. IgM and complement 3 （C3） nonspeciflcally deposit in lesions without immune-complex-type deposits during ORG immunofluorescence. ORG-associated glomerulomegaly and focal and segmental glomerulosclerosis can superimpose on other renal pathologies. The mechanisms under ORG are complex, especially hemodynamic changes, inflammation, oxidative stress, apoptosis, and reduced functioning nephrons. These mechanisms synergize with obesity to induce end-stage renal disease. A slow increase of subnephrotic proteinuria （ 〈 3.5 g/d） is the most common clinical manifestation of ORG. Several treatment methods for ORG have been developed. Of these methods, renin-angiotensin-aldosterone system blockade and weight loss are proven effective. Targeting mitochondria may offer a novel strategy for ORG therapy. Nevertheless, more research is needed to further understand ORG.

Purinergic 2X7Receptor is Involved in the Podocyte Damage of Obesity-Related Glomerulopathy via Activating Nucleotide-Binding and Oligomerization Domain-Like Receptor Protein 3 Inflammasome

Background:The nucleotide-binding and oligomerization domain-like receptor protein 3 (NLRP3) inflammasome composed of NLRP3,apoptosis-associated speck-like protein containing CARD (ASC),and caspase-1 is engaged in the inflammatory response of many kidney diseases and can be activated by purinergic 2X7 receptor (P2X7R).This study was conducted to explore whether P2X7R plays a pathogenic role in the podocyte damage of obesity-related glomerulopathy (ORG) and whether this role is mediated by the activation ofNLRP3 inflammasome.Methods:A mouse model of ORG was established by high-fat diet feeding.The conditionally immortalized mouse podocytes were cultured with leptin or with leptin and P2X7R antagonist (KN-62 or A438079).The mRNA and protein expression of the P2X7R and NLRP3 inflammasome components including NLRP3,ASC,and caspase-1,as well as the podocyte-associated molecules including nephrin,podocin,and desmin in mouse renal cortex or cultured mouse podocytes were tested by real-time-polymerase chain reaction and Westem blot analysis,respectively.Results:The significantly upregulated expression of P2X7R and NLRP3 inflammasome components and the NLRP3 inflammasome activation were observed in the renal cortex (in fact their location in podocytes was proved by confocal microscopy) of ORG mice in vivo,which were accompanied with the morphological changes of podocyte damage and the expression changes of podocyte-associated molecules.Similar changes in the expression of P2X7R and NLRP3 inflammasome components as well as in the expression ofpodocyte-associated molecules were also observed in the cultured podocyte studies treated by leptin in vitro,and all of the above changes were significantly attenuated by the P2X7R antagonist KN-62 or A438079.Conclusions:P2X7R could trigger the activation ofNLRP3 inflammasome,and the activated P2X7R/NLRP3 inflammasome in podocytes might be involved in the podocyte damage of ORG.

Single-cell transcriptomic analysis reveals transcript enrichment in oxidative phosphorylation,fluid sheer stress,and inflammatory pathways in obesity-related glomerulopathy

Obesity-related glomerulopathy(ORG)is an independent risk factor for chronic kid-ney disease and even progression to end-stage renal disease.Efforts have been undertaken to elucidate the mechanisms underlying the development of ORG and substantial advances have been made in the treatment of ORG,but relatively little is known about cell-specific changes in gene expression.To define the transcriptomic landscape at single-cell resolution,we analyzed kidney samples from four patients with ORG and three obese control subjects without kidney disease using single-cell RNA sequencing.We report for the first time that immune cells,including T cells and B cells,are decreased in ORG patients.Further analysis indicated that SPP1 was significantly up-regulated in T cells and B cells.This gene is related to inflammation and cell proliferation.Analysis of differential gene expression in glomerular cells(endothelial cells,mesangial cells,and podocytes)showed that these cell types were mainly enriched in genes related to oxidative phosphorylation,cell adhesion,thermogenesis,and inflammatory pathways(PI3K-Akt signaling,MAPK signaling).Furthermore,we found that the podocytes of ORG patients were enriched in genes related to the fluid shear stress pathway.Moreover,an evaluation of cell-cell communications revealed that there were interactions between glomerular parietal epithelial cells and other cells in ORG patients,with major interactions between parietal epithelial cells and podocytes.Altogether,our identification of molecular events,cell types,and differentially expressed genes may facilitate the development of new preventive or therapeutic approaches for ORG.

Leptin signaling and cancer chemoresistance:Perspectives

Obesity is a major health problem and currently is endemic around the world. Obesity is a risk factor for several different types of cancer, significantly promoting cancer incidence, progression, poor prognosis and resistance to anti-cancer therapies. The study of this resistance is critical as development of chemoresistance is a serious drawback for the successful and effective drug-based treatments of cancer. There is increasing evidence that augmented adiposity can impact on chemotherapeutic treatment of cancer and the development of resistance to these treatments, particularly through one of its signature mediators, the adipokine leptin. Leptin is a pro-inflammatory, pro-angiogenic and pro-tumorigenic adipokine that has been implicated in many cancers promoting processes such as angiogenesis, metastasis, tumorigenesis and survival/resistance to apoptosis. Several possible mechanisms that could potentially be developed by cancer cells to elicit drug resistance have been suggested in the literature. Here, we summarize and discuss the current state of the literature on the role of obesity and leptin on chemoresistance, particularly as it relates to breast and pancreatic cancers. We focus on the role of leptin and its significance in possibly driving these proposed chemoresistance mechanisms, and examine its effects on cancer cell survival signals and expansion of the cancer stem cell sub-populations.

Association of the Common Genetic Variant Upstream of INSIG2 Gene with Obesity Related Phenotypes in Chinese Children and Adolescents

Objective To study the association between the rs7566605 variant of INSIG2 and obesity-related phenotypes in Chinese children and adolescents. Methods The study sample consisted of two independent cohorts of Chinese children and adolescents. Anthropometric indices, lipids, blood pressure, fasting glucose, insulin and percentage of fat mass were determined. PCR with restriction fragment length polymorphism analysis was performed for genotyping the rs7566605 variant. Results In each of the two independent cohorts, no significant association was observed between rs7566605 and obesity under additive, dominant or recessive model. We also did not detect any difference in the genotype frequency between all the obese children and controls. Furthermore, we did not find evidence of an association between body composition indices and metabolic phenotypes in all children. However, the triglyceride level of CC homozygotes was significantly higher than that of GG＋GC genotypes in obese children （P=0.022）. Additionally, we observed a non-significant trend of severe obesity in a post-hoc test. Conclusion INSIG2 rs7566605 variant is not associated Chinese childhood obesity in two independent cohorts. Further study is needed to verify the effect of rs7566605 on triglyceride in obese children.

Janice Drew's work on diet and cancer

Obesity and associated reduced consumption of plant derived foods are linked to increased risk of colon cancer as well as a number of other organ specific cancers.Inflammatory processes are a contributing factor but the precise mechanisms remain elusive.Obesity and cancer incidence are increasing worldwide,presenting bleak prospects for reducing,or preventing,obesity related cancers.The incidence of these preventable cancers can be achieved with greater understanding of the molecular mechanisms linking diet and carcinogenesis.Janice Drew has developed a research program over recent years to investigate molecular mechanisms related to consumption of anti-inflammatory metabolites generated from consumption of plant based diets,the impact of high fat diets and associated altered metabolism and obesity on regulation of colon inflammatory responses and processes regulating the colon epithelium.Comprehensive strategies have been developed incorporating transcriptomics,including the novel gene expression technology,the GenomeLab System and proteomics,together with biochemical analyses of plasma and tissue samples to assess correlated changes in oxidative stress,inflammation and pathology.The approaches developed have achieved success in establishing antioxidant and anti-inflammatory activity of dietary antioxidants and associated genes and pathways that interact to modulate redox status in the colon.Cellular processes and genes altered in response to obesity and high fat diets have provided evidence of molecular mechanisms that are implicated in obesity related cancer.

CPI-17-mediated contraction of vascular smooth muscle is essential for the development of hypertension in obese mice

Several factors have been implicated in obesity-related hypertension, but the genesis of the hypertension is largely unknown. In this study, we found a significantly upregulated expression of CPI-17(C-kinasepotentiated protein phosphatase 1 inhibitor of 17 kDa) and protein kinase C(PKC) isoforms in the vascular smooth muscles of high-fat diet(HFD)-fed obese mice. The obese wild-type mice showed a significant elevation of blood pressure and enhanced calcium-sensitized contraction of vascular smooth muscles. However, the obese CPI-17-deficient mice showed a normotensive blood pressure, and the calcium-sensitized contraction was consistently reduced. In addition, the mutant muscle displayed an abolished responsive force to a PKC activator and a 30%-50% reduction in both the initial peak force and sustained force in response to various G protein-coupled receptor(GPCR) agonists. Our observations showed that CPI-17-mediated calcium sensitization is mediated through a GPCR/PKC/CPI-17/MLCP/RLC signaling pathway. We therefore propose that the upregulation of CPI-17-mediated calcium-sensitized vasocontraction by obesity contributes to the development of obesity-related hypertension.