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Intestinal monocarboxylate transporter 1 mediates lactate transport in the gut and regulates metabolic homeostasis of mouse in a sex-dimorphic pattern

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Life Metabolism 2024年第1期3卷 21-36页

作者： Shuo Wang Lingling Zhang Jingyu Zhao Meijuan Bai Yijun Lin Qianqian Chu Jue Gong Ju Qiu Yan Chen CAS Key Laboratory of nutrition Metabolism and Food SafetyShanghai Institute of Nutrition and HealthUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai 200031China CAS Key Laboratory of Tissue Microenvironment and Tumor Shanghai Institute of Nutrition and HealthUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai 200031China

The monocarboxylate transporter 1(MCT1),encoded by gene Slc16a1,is a proton-coupled transporter for lactate and other monocar***1-mediated lactate transport was recently found to regulate various biological ***,how MCT1 and lactate in the intestine modulate the physiology and pathophysiology of the body is *** this study,we generated a mouse model with specific deletion of Slc16a1 in the intestinal epithelium(Slc16a1IKO mice)and investigated the functions of MCT1 in the *** fed a high-fat diet,Slc16a1IKO male mice had improvement in glucose tolerance and insulin sensitivity,while Slc16a1IKO female mice only had increased *** of intestinal MCT1 in male mice was associated with downregulation of pro-inflammatory pathways,together with decreased circulating levels of inflammatory cytokines including tumor necrosis factor alpha(TNFα)and C-C motif chemokine ligand 2(CCL2).Lactate had a stimulatory effect on pro-inflammatory macrophages in *** number of intestinal macrophages was reduced in Slc16a1IKO male mice in *** deletion of Slc16a1 in male mice reduced interstitial lactate level in the *** addition,treatment of male mice with estrogen lowered interstitial lactate level in the intestine and abolished the difference in glucose homeostasis between Slc16a1IKO and wild-type *** of intestinal MCT1 also blocked the transport of lactate and short-chain fatty acids from the intestine to the portal *** effect of Slc16a1 deletion on glucose homeostasis in male mice was partly mediated by alterations in gut *** conclusion,our work reveals that intestinal MCT1 regulates glucose homeostasis in a sex-dependent manner.

关键词： MCT1 intestine lactate short-chain fatty acids insulin resistance obesity

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Secondary male hypogonadism： a prevalent but overlooked comorbidity of obesity

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Asian Journal of Andrology 2018年第6期20卷 531-538页

作者： Maria Molina-Vega Araceli Mufioz-Garach Miguel Damas-Fuentes JosO Carlos Fernfindez-Garcia Francisco J inahones Department of Endocrinology and nutrition Virgen de la Victoria Universitary HospitalMalaga 29010Spain Institute of Biomedical Research in Malaga（IBIMA） Virgen de la Victoria Universitary HospitalMalaga 29010Spain ciber pathophysiology of obesity and nutrition（CB06/003） Institute of Health Carlos III（ISClII）Madrid 28029Spain.

Male hypogonadism associated with obesity is a very prevalent condition and is increasing in parallel with the epidemic prevalence of obesity. Low testosterone levels promote higher fat mass with reduced lean mass. Male hypogonadism is related to an increase in associated cardiometabolic complications, such as hypertension, type 2 diabetes mellitus, the metabolic syndrome, and cardiovascular disease. Its influence as a comorbidity of obesity is becoming more evident and should be evaluated and treated in at-risk patients. Mechanisms involved in this relationship include body composition changes, the presence of adipokines, insulin resistance, and other factors, some of which are still unknown. Weight loss and treatment to replace testosterone levels improve the metabolic profile and quality of life in patients with obesity and hypogonadism; these beneficial effects depend on treatment modality and duration of therapy. The use of testosterone replacement therapy may be indicated, as it has not been shown to increase cardiovascular risk, and retrospective studies suggest a reduction in events in men with metabolic syndrome and type 2 diabetes.

关键词： adipose tissue male hypogonadism obesity testosterone

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NLRP3 inflammasome blockade reduces adipose tissue inflammation and extracellular matrix remodeling

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Cellular & Molecular Immunology 2021年第4期18卷 1045-1057页

作者： Xabier Unamuno Javier Gomez-Ambrosi Beatriz Ramirez Amaia Rodriguez Sara Becerril Victor Valenti Rafael Moncada Camilo Silva Javier Salvador Gema Fruhbeck Victoria Catalan Metabolic Research Laboratory Clfnica Universidad de NavarraPamplonaSpain ciber Fisiopatologfa de la Obesidad y Nutricion(ciberOBN) Instituto de Salud Carlos ⅢPamplonaSpain obesity and Adipobiology Group Instituto de Investigaci6n Sanitaria de Navarra(IdiSNA)PamplonaSpain Department of Surgery Clinica Universidad de NavarraPamplonaSpain Department of Anesthesia Clinica Universidad de NavarraPamplonaSpain Department of Endocrinology&nutrition Clfnica Universidad de NavarraPamplonaSpain

The NLRP3-IL-1β pathway plays an important role in adipose tissue(AT)-induced inflammation and the development of obesityassociated *** aimed to determine the impact of NLRP3 on obesity and its associated metabolic alterations as well as its role in adipocyte inflammation and extracellular matrix(ECM)*** obtained from 98 subjects were used in a case-control *** expression of different components of the inflammasome as well as their main effectors and inflammation-and ECM remodeling-related genes were *** impact of blocking NLRP3 using siRNA in lipopolysaccharide(LPS)-mediated inflammation and ECM remodeling signaling pathways was *** demonstrated that obesity(Pobesity-associated T2D(P<0.01)and NAFLD(P<0.05)increased the expression of different com ponents of the inflammasome as well as the expression and release of IL-1β and IL-18 in *** also found that obese patients with T2D exhibited increased(P<0.05)hepatic gene expression levels of NLRP3,IL1B and *** showed that NLRP3,but not NLRP1,is regulated by inflammation and hypoxia in visceral *** revealed that the inhibition of NLRP3 in human visceral adipocytes significantly blocked(P<0.01)LPS-induced inflammation by downregulating the mRNA levels of CCL2,IL1B,IL6,IL8,S100A8,S100A9,TLR4 and TNF as well as inhibiting(P<0.01)the secretion of IL1-β into the culture ***,blocking NLRP3 attenuated(P<0.01)the LPS-induced expression of important molecules involved in AT fibrosis(COL1A1,COL4A3,COL6A3 and MMP2).These novel findings provide evidence that blocking the expression of NLRP3 reduces AT inflammation with significant fibrosis attenuation.

关键词： NLRP3 Inflammasone Inflammation obesity Type 2 diabetes Nonalcoholic fatty liver disease

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Healthy diet,depression and quality of life:A narrative review of biological mechanisms and primary prevention opportunities

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World Journal of Psychiatry 2021年第11期11卷 997-1016页

作者： Octavio Pano Elena H Martínez-Lapiscina Carmen Sayón-Orea Miguel Angel Martinez-Gonzalez Jose Alfredo Martinez Almudena Sanchez-Villegas Preventive Medicine and Public Health University of NavarrePamplona 31008Spain Department of Neurology Center of Neuroimmunology Hospital Clinic of BarcelonaInstitut d’Investigacions Biomèdiques August Pi SunyerBarcelona 08036Spain Department of Preventive Medicine and Public Health University of NavarraPamplona 31008Spain IdiSNA Navarra Institute for Health ResearchPamplona 31008Spain Department of Public Health Navarra Institute of Public Health and EpidemiologyPamplona 31003Spain ciber pathophysiology of obesity and nutrition Institute of Health Carlos IIIMadrid 28049Spain Department of nutrition Harvard T.H.Chan School of Public HealthBostonMA 02115United States Department of Food Sciences and Physiology University of NavarrePamplona 31008Spain Precision nutrition and Cardiometabolic Health Program IMDEA Food InstituteMadrid 28049Spain Department of Clinical Sciences University of Las Palmas Gran CanariaLas Palmas Gran Canaria 35080Spain

Unipolar depressive disorder(UDD)affects more than 264 million people worldwide and was projected well before the severe acute respiratory syndrome coronavirus 2 pandemic to be the leading cause of disability-adjusted life years lost in *** is imperative for leading economies to implement preventive strategies targeted towards UDD,given consistent policies are currently *** established similarities between the aetiological hypotheses of depression and cardiometabolic diseases are shifting paradigms within this *** is believed that dietary practices could potentially reduce the incidence of depression;similar to their effects on ***,the aim of this review was to compile current evidence on healthy dietary patterns as suitable contributors towards primary prevention strategies against *** of the well-known biological mechanisms behind depression have been positively associated with healthful diets and dietary patterns to varying ***,a common factor of UDD is the production and overall effects of inflammatory cytokines,such as interleukin-6,tumor necrosis factor-α,and Creactive *** compounds have been associated with depressive symptoms,disturbances in neuroendocrine function,leaky gut,monoamine activity and brain function,while also being key factors in the development of cardiometabolic *** Mediterranean diet(MD)in particular,is well supported by first-level evidence regarding its preventive qualities against metabolic and cardiovascular diseases and thus considered a model for healthy eating by various *** one of the few clinical trials investigating these associations,the PREDIMED trial,individuals with diabetes assigned to a MD supplemented with mixed tree nuts experienced a 41%relative risk reduction for developing ***,there is a need to include health related quality of life as an indicator of physical and mental well-being,considering its putative associations

关键词： Depression nutrition Mediterranean Quality of life Primary prevention Epidemiology

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FNDC4 and FNDC5 reduce SARS-CoV-2 entry points and spike glycoprotein S1-induced pyroptosis, apoptosis, and necroptosis in human adipocytes

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Cellular & Molecular Immunology 2021年第10期18卷 2457-2459页

作者： Gema Frühbeck Victoria Catalán Víctor Valentí Rafael Moncada Javier Gómez-Ambrosi Sara Becerril Camilo Silva Piero Portincasa Javier Escalada Amaia Rodríguez Metabolic Research Laboratory Clínica Universidad de NavarraPamplonaSpain ciber Fisiopatología de la Obesidad y Nutrición(ciberOBN) Instituto de Salud Carlos IIIMadridSpain obesity and Adipobiology Group Instituto de Investigación Sanitaria de Navarra(IdiSNA)PamplonaSpain Department of Endocrinology and nutrition Clínica Universidad de NavarraPamplonaSpain Department of Surgery Clínica Universidad de NavarraPamplonaSpain Department of Anesthesia Clínica Universidad de NavarraPamplonaSpain Department of Biomedical Sciences and Human Oncology Clinica Medica“A.Murri”University of Bari Medical SchoolPoliclinico HospitalBariItaly.

A sedentary lifestyle and obesity are important risk factors for severe COVID-19 complications and death[1,2].Excessive adipose tissue(AT)might contribute to more extensive viral spread with increased shedding,immune activation,and cytokine amplification[3].Several factors secreted by contracting muscle,termed myokines,mediate the beneficial effects of exercise in a wide range of diseases,including obesity[4].Thus,we conducted a study to explore the potential role of myokines of the fibronectin type III domain-containing family,FNDC4 and FNDC5,in mechanisms underlying the increased susceptibility to COVID-19 complications in obesity.

关键词： FNDC5 obesity FND

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NGM282: a step forward in the nonalcoholic steatohepatitis treatment landscape?

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Hepatobiliary Surgery and nutrition 2018年第6期7卷 484-486页

作者： Luca Valenti Valerio Nobili Internal Medicine and Metabolic Diseases Fondazione IRCCS Ca’Granda Ospedale Policlinico MilanoDepartment of Pathophysiology and TransplantationUniversitàdegli Studi di MilanoMilanItaly Hepatology Gastroenterology and Nutrition UnitIRCCS“Bambino Gesù”Children’s HospitalRomeItaly Department of Pediatric University“La Sapienza”RomeItaly

Nonalcoholic fatty liver disease(NAFLD)is becoming the leading cause of liver disease worldwide,and the prevalence is still increasing,especially during the developmental age(1-3).NAFLD is defined in the presence of increased hepatic fat content not explained by at risk alcohol intake,and is epidemiologically associated with obesity,insulin resistance and metabolic disorders.

关键词： NAFLD intake hepatic

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Hepatocellular carcinoma in nonalcoholic fatty liver: Role of environmental and genetic factors

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World Journal of Gastroenterology 2014年第36期20卷 12945-12955页

作者： Paola Dongiovanni Stefano Romeo Luca Valenti Internal Medicine 1B Fondazione IRCCS Ca’ Granda Ospedale Policlinico 20122 Milano Italy Department of pathophysiology and Transplantation Università degli Studi di Milano 20122 Milano Italy Wallenberg Laboratory Department of Molecular and Clinical Medicine University of Gothenburg 40530 Gothenburg Sweden Clinical nutrition Unit Department of Medical and Surgical Sciences University Magna Graecia 88100 Catan-zaro Italy

Hepatocellular carcinoma(HCC) is the fourth cause of cancer related mortality, and its incidence is rapidly increasing. Viral hepatitis, alcohol abuse, and exposure to hepatotoxins are major risk factors, but nonalcoholic fatty liver disease(NAFLD) associated with obesity, insulin resistance, and type 2 diabetes, is an increasingly recognized trigger, especially in developed countries. Older age, severity of insulin resistance and diabetes, and iron overload have been reported to predispose to HCC in this context. Remarkably, HCCs have been reported in non-cirrhotic livers in a higher proportion of cases in NAFLD patients than in other etiologies. Inherited factors have also been implicated to explain the different individual susceptibility to develop HCC, and their role seems magnified in fatty liver, where only a minority of affected subjects progresses to cancer. In particular, the common I148 M variant of the PNPLA3 gene influencing hepatic lipid metabolism influences HCC risk independently of its effect on the progression of liver fibrosis. Recently, rare loss-of-function mutations in Apolipoprotein B resulting in very low density lipoproteins hepatic retention and in Telomerase reverse transcriptase influencing cellular senescence have also been linked to HCC in NAFLD. Indeed, hepatic stellate cells senescence has been suggested to bridge tissue aging with alterations of the intestinal microbiota in the pathogenesis of obesity-related HCC. A deeper understanding of the mechanisms mediating hepatic carcinogenesis during insulin resistance, and the identification of its genetic determinants will hopefully provide new diagnostic and therapeutic tools.

关键词： Nonalcoholic fatty liver disease Steatosis Hepatocellular carcinoma Cirrhosis Fibrogenesis Liver disease Genetics Single nucleotide polymorphism Patatin-like phospholipase domain-containing 3

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production of extracellular lysophosphatidic acid in the regulation of adipocyte functions and liver fibrosis

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World Journal of Gastroenterology 2018年第36期24卷 4132-4151页

作者： Fang Yang Guo-Xun Chen School of Laboratory Medicine Hubei University of Chinese Medicine Department of nutrition University of Tennessee at Knoxville

Lysophosphatidic acid(LPA), a glycerophospholipid, consists of a glycerol backbone connected to a phosphate head group and an acyl chain linked to sn-1 or sn-2 position. In the circulation, LPA is in submillimolar range and mainly derived from hydrolysis of lysophosphatidylcholine, a process mediated by lysophospholipase D activity in proteins such as autotaxin(ATX). Intracellular and extracellular LPAs act as bioactive lipid mediators with diverse functions in almost every mammalian cell type. The binding of LPA to its receptors LPA1-6 activates multiple cellular processes such as migration, proliferation and survival. The production of LPA and activation of LPA receptor signaling pathways in the events of physiology and pathophysiology have attracted the interest of researchers. Results from studies using transgenic and gene knockout animals with alterations of ATX and LPA receptors genes, have revealed the roles of LPA signaling pathways in metabolic active tissues and organs. The present review was aimed to summarize recent progresses in the studies of extracellular and intracellular LPA production pathways. This includes the functional, structural and biochemical properties of ATX and LPA receptors. The potential roles of LPA production and LPA receptor signaling pathways in obesity, insulin resistance and liver fibrosis are also discussed.

关键词： Autotaxin Lysophosphatidic acid receptors obesity Lysophosphatidic acid Insulin resistance Liver fibrosis

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Glucose-lowering agents and reduced risk of incident non-alcoholic fatty liver disease:new insights

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Hepatobiliary Surgery and nutrition 2022年第1期11卷 156-160页

作者： Alessandro Mantovani Rosa Lombardi Andrea Dalbeni Section of Endocrinology Diabetes and MetabolismDepartment of MedicineUniversity and Azienda Ospedaliera Universitaria Integrata of VeronaVeronaItaly Unit of Internal Medicine and Metabolic Disease Fondazione IRCCS Ca’Granda Ospedale Maggiore PoliclinicoMilanItaly Department of pathophysiology and Transplantation Universitàdegli Studi di MilanoMilanItaly Section of General Medicine C and Liver Unit University and Azienda Ospedaliera Universitaria Integrata of VeronaVeronaItaly

Non-alcoholic fatty liver disease(NAFLD)is classically defined as the hepatic manifestation of metabolic syndrome(1).Histologically,NAFLD covers a range of conditions,spanning from simple steatosis to non-alcoholic steatohepatitis(NASH)and cirrhosis(2).At present,NAFLD is the most frequent chronic liver disease seen in clinical practice in high-income countries,as it affects nearly 30%of adults in the general population,up to 70%of patients with type 2 diabetes(T2DM)and almost all patients with obesity(2).

关键词： NAFLD liver hepatic

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Gut microbiotad-a positive contributor in the process of intermittent fasting-mediated obesity control

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Animal nutrition 2021年第4期7卷 1283-1295页

作者： Bohan Rong Qiong Wu Muhammad Saeed Chao Sun College of Animal Science and Technology Northwest A&F UniversityYanglingShaanxi712100China Department of pathophysiology Qinghai University Medical CollegeXiningQinghaiChina Faculty of Animal Production&Technology Cholistan University of Veterinary and Animal SciencesBahawalpur63100Pakistan

Historically,intermittent fasting(IF)has been considered as an effective strategy for controlling the weight of athletes before *** with excellent insight into its application in various spaces by numerous studies,increasing IF-mediated positive effects have been reported,including anti-aging,neuro protect ion,especially obesity ***,the gut microbiota has been considered as an essential manipulator for host energy metabolism and its structure has been reported to be sensitive to dietary structure and habits,indicating that there is a potential and strong association between IF and gut *** this paper,we focus on the crosstalk between these symbionts and energy metabolism during IF which hold the promise to optimize host energy metabolism at various physical positions,including adipose tissue,liver and intestines,and further improve milieu internal ***,this paper also discusses the positive function of a potential recommendatory strain(Akkermansia muciniphila)based on the observational data for IF-mediated alternated pattern of gut microbiota and a hopefully regulatory pathway(circadian rhythm)for gut microbiota in IF-involved improvement on host energy ***,this review addresses the limitation and perspective originating from these studies,such as the association with tissue-specific bio-clock and single strain research,which may continuously reveal novel viewpoints and mechanisms to understand the energy metabolism and develop new strategies for treating obesity,diabetes,and metabolic disorders.

关键词： Intermittent fasting Gut microbiota obesity Akkermansia muciniphila

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