Insulin resistance contributes to metabolic disorders in obesity and type 2 diabetes.In mechanisms of insulin resistance,the roles of glucose,fatty acids,and amino acids have been extensively documented in literature....Insulin resistance contributes to metabolic disorders in obesity and type 2 diabetes.In mechanisms of insulin resistance,the roles of glucose,fatty acids,and amino acids have been extensively documented in literature.However,the activities of nucleotides remain to be reviewed comprehensively in the regulation of insulin sensitivity.Nucleotides are well known for their activities in biosynthesis of DNA and RNA as well as their signaling activities in the form of c AMP and c GAMP.Their activities in insulin resistance are dependent on the derivatives and corresponding receptors.ATP and NADH,derivatives of adenosine,inhibit insulin signaling inside cells by downregulation of activities of AMPK and SIRT1,respectively.ATP,ADP and AMP,the well-known energy carriers,regulate cellular responses to insulin outside cells through the purinergic receptors in cell surface.Current evidence suggests that ATP,NADH,c GAMP,and uridine are potential biomarkers of insulin resistance.However,GTP and c GMP are likely the markers of insulin sensitization.Here,studies crossing the biomedical fields are reviewed to characterize nucleotide activities in the regulation of insulin sensitivity.The knowledge brings new insights into the mechanisms of insulin resistance.展开更多
Alzheimer’s disease(AD)is the leading cause of dementia worldwide.Traditionally,pathological studies have concentrated on the abnormal buildup of amyloid b(Ab)plaques and neurofibrillary tangles(NFTs),which arise fro...Alzheimer’s disease(AD)is the leading cause of dementia worldwide.Traditionally,pathological studies have concentrated on the abnormal buildup of amyloid b(Ab)plaques and neurofibrillary tangles(NFTs),which arise from the excessive phosphorylation of tau proteins in the brain1,2.Despite extensive research.展开更多
The Apolipoprotein E(APOE)genotype is closely associated with risk of Alzheimer’s disease(AD),a progressive neurodegenerative disorder that impairs cognitive functions of the brain.APOE2 reduces while APOE4 increases...The Apolipoprotein E(APOE)genotype is closely associated with risk of Alzheimer’s disease(AD),a progressive neurodegenerative disorder that impairs cognitive functions of the brain.APOE2 reduces while APOE4 increases the risk of AD.展开更多
Extrachromosomal DNA(ecDNA),a circular DNA molecule first identified in 19651,is now recognized as a key carrier of extra copies of oncogenes.Originating from chromosomal DNA,ecDNA primarily forms through mechanisms a...Extrachromosomal DNA(ecDNA),a circular DNA molecule first identified in 19651,is now recognized as a key carrier of extra copies of oncogenes.Originating from chromosomal DNA,ecDNA primarily forms through mechanisms associated with chromosomal instability,such as DNA damage repair,chromothripsis,episome formation,and the breakage–fusion–bridge cycle.展开更多
Insulin resistance(IR)is a risk factor of type 2 diabetes and cardiovascular diseases^(1).IR is a result of energy surplus often associated with obesity,non-alcoholic fatty liver disease(NAFLD),and aging^(2).Regarding...Insulin resistance(IR)is a risk factor of type 2 diabetes and cardiovascular diseases^(1).IR is a result of energy surplus often associated with obesity,non-alcoholic fatty liver disease(NAFLD),and aging^(2).Regarding the mechanism of insulin resistance,there are several hypotheses^(3).However,these hypotheses do not cover the role of nervous system in the mechanism^(3).展开更多
Mitochondria contain over 1000 types of proteins,most of which are imported from the cytosol1.This import process is intricate and energy-dependent,in which mitochondrial energy deficits and oxidative stress pose sign...Mitochondria contain over 1000 types of proteins,most of which are imported from the cytosol1.This import process is intricate and energy-dependent,in which mitochondrial energy deficits and oxidative stress pose significant threats to the import efficiency.When the import is compromised,it can initiate mitochondrial import stress,potentially triggering the integrated stress response(ISR).Persistent ISR may escalate into broader cellular stress2,3.Under normal conditions,the body maintains mitochondrial and cellular equilibrium through intricate stress response pathways.展开更多
The mechanism of lipid droplet(LD)formation in glial cells is an active area in the field of Alzheimer's disease(AD)pathology.A recent study titled“Amyloid-βinduces lipid droplet-mediated microglial dysfunction ...The mechanism of lipid droplet(LD)formation in glial cells is an active area in the field of Alzheimer's disease(AD)pathology.A recent study titled“Amyloid-βinduces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer's disease”by Prakash et al.1 is published in Immunity to report a role of Aβprotein in the induction of LD formation in microglia for the phagocytosis dysfunction in AD.In this context,diacylglycerol O-acyltransferase 2(DGAT2)is identified as a potential therapeutic target for its role in LD formation.展开更多
Neurons are the main organizers of neurological activities in the brain.However,its role remains largely unknown in regulating waste clearance in the brain.This issue is addressed in a recent study published in Nature...Neurons are the main organizers of neurological activities in the brain.However,its role remains largely unknown in regulating waste clearance in the brain.This issue is addressed in a recent study published in Nature on neuronal dynamics in control of waste removal through cerebrospinal fluid perfusion1.Brain contains billions of neurons that are connected through synapses for precise spatial coordination and high-speed operation in support of functions like thoughts,emotions,and body movements in a dynamic manner.展开更多
Weight regain(WR)is a significant challenge in clinical treatment of obesity after successful weight loss.WR happens frequently after weight loss(WL)by dietary or life style adjustment although it also occurs in WL by...Weight regain(WR)is a significant challenge in clinical treatment of obesity after successful weight loss.WR happens frequently after weight loss(WL)by dietary or life style adjustment although it also occurs in WL by bariatric surgery and medications1-3.A general mechanism of WR is“obesity memory”,which refers to a stable gene expression pattern in adipose tissue from obesity.However,the molecular mechanisms underlying obesity memory remain unclear.Recently,Hinte et al.1 reported that obesity memory is mediated by an epigenetic mechanism in adipocytes of adipose tissue in a Nature article.展开更多
The presence of glial lipid droplet(LD)and the apolipoprotein E4(APOE4)genotype have been documented as two major risk factors for the development of Alzheimer’s disease(AD)1,2.However,the intricate molecular interpl...The presence of glial lipid droplet(LD)and the apolipoprotein E4(APOE4)genotype have been documented as two major risk factors for the development of Alzheimer’s disease(AD)1,2.However,the intricate molecular interplay between these two factors remains elusive and warrants further investigation.A recent study published in Nature has shed light on this issue by offering valuable insights into APOE4 activity in control of LD formation in the human brain3.The brain is rich in lipid content with cholesterol,fatty acids and triglycerides.The brain lipid disorder is a pathological marker of AD,a progressive neurodegenerative disorder from aging characterized by cognitive decline and memory impairment,posing a significant public health challenge for aging populations globally1.Despite decades of intensive research in both clinical and laboratory settings,the search for an effective and safe therapeutic intervention to reverse or delay the progression of AD remains unsuccessful,primarily due to a lack of comprehensive understanding of AD etiology1.Intriguingly,Alois Alzheimer’s initial report on AD described the presence of adipocyte-like morphology in brain cells of AD patients,a pathological feature that was observed together with the accumulation of Ab plaques and Tau tangles in the AD brain1.展开更多
Communication between the brain and the heart is finely tuned by numerous factors,with sleep being particularly crucial.It is well known that sleep plays a vital role in cardiovascular health,and poor sleep can exacer...Communication between the brain and the heart is finely tuned by numerous factors,with sleep being particularly crucial.It is well known that sleep plays a vital role in cardiovascular health,and poor sleep can exacerbate myocardial infarction(MI)by interfering heart energy metabolism and triggering oxidative stress1.However,it remains unclear whether the immune system conveys information about cardiac homeostasis to the brain.A recent study2,published in Nature,has addressed this question by demonstrating immune-mediated pathways that connect acute ischemic cardiac injury to the brain’s sleep circuits,subsequently impact in the sympathetic outflow from the brain to the heart to govern cardiac healing and recovery,which may be a potential therapeutic target for drug development to MI therapy.展开更多
Control of obesity has been a challenging task worldwide with increasing global burden of obesity-associated complications.Dietary interventions have emerged as a popular approach in obesity control,encompassing appro...Control of obesity has been a challenging task worldwide with increasing global burden of obesity-associated complications.Dietary interventions have emerged as a popular approach in obesity control,encompassing approaches such as carbohydrate restriction,fat restriction,and amino acid restriction.Notably,a recent study published in Nature reports that animo acid cysteine restriction can induce a rapid weight loss in cystathionineγ-lyase(CSE)-knockout(KO)mice^(1).展开更多
The brain lymphatic system has been a promising target in the treatment of Alzheimer’s disease(AD)1.Induction of the lymphatic system function is an ideal approach in the development of new therapy for AD.A study pub...The brain lymphatic system has been a promising target in the treatment of Alzheimer’s disease(AD)1.Induction of the lymphatic system function is an ideal approach in the development of new therapy for AD.A study published in Nature in 2024 introduced an innovative non-invasive approach in the promotion of the lymphatic function,which uses visual and auditory stimulation at specific frequencies to modulate neuron activity,inducing the brain lymphatic function for clearance of Amyloid-β(Aβ)from the neurons’microenvironment of brain2.展开更多
Obesity increases the risk for type 2 diabetes through induction of insulin resistance.Treatment of type 2 diabetes has been limited by little translational knowledge of insulin resistance although there have been sev...Obesity increases the risk for type 2 diabetes through induction of insulin resistance.Treatment of type 2 diabetes has been limited by little translational knowledge of insulin resistance although there have been several well-documented hypotheses for insulin resistance.In those hypotheses,inflammation,mitochondrial dysfunction,hyperinsulinemia and lipotoxicity have been the major concepts and have received a lot of attention.Oxidative stress,endoplasmic reticulum(ER)stress,genetic background,aging,fatty liver,hypoxia and lipodystrophy are active subjects in the study of these concepts.However,none of those concepts or views has led to an effective therapy for type 2 diabetes.The reason is that there has been no consensus for a unifying mechanism of insulin resistance.In this review article,literature is critically analyzed and reinterpreted for a new energy-based concept of insulin resistance,in which insulin resistance is a result of energy surplus in cells.The energy surplus signal is mediated by ATP and sensed by adenosine monophosphate-activated protein kinase(AMPK)signaling pathway.Decreasing ATP level by suppression of production or stimulation of utilization is a promising approach in the treatment of insulin resistance.In support,many of existing insulin sensitizing medicines inhibit ATP production in mitochondria.The effective therapies such as weight loss,exercise,and caloric restriction all reduce ATP in insulin sensitive cells.This new concept provides a unifying cellular and molecular mechanism of insulin resistance in obesity,which may apply to insulin resistance in aging and lipodystrophy.展开更多
Sennoside A(SA) is a bioactive component of Chinese herbal medicines with an activity of irritant laxative, which is often used in the treatment of constipation and obesity. However, its activity remains unknown in th...Sennoside A(SA) is a bioactive component of Chinese herbal medicines with an activity of irritant laxative, which is often used in the treatment of constipation and obesity. However, its activity remains unknown in the regulation of insulin sensitivity. In this study, the impact of SA on insulin sensitivity was tested in high fat diet(HFD)-induced obese mice through dietary supplementation. At a dosage of 30 mg/kg/day, SA improved insulin sensitivity in the mice after 8-week treatment as indicated by HOMA-IR(homeostatic model assessment for insulin resistance) and glucose tolerance test(GTT). SA restored plasma level of glucagon-like peptide 1(GLP1) by 90% and mRNA expression of Glp1 by 80% in the large intestine of HFD mice. In the mechanism, SA restored the gut microbiota profile, short chain fatty acids(SCFAs), and mucosal structure in the colon. A mitochondrial stress was observed in the enterocytes of HFD mice with ATP elevation, structural damage, and complex dysfunction. The mitochondrial response was induced in enterocytes by the dietary fat as the same responses were induced by palmitic acid in the cell culture. The mitochondrial response was inhibited in HFD mice by SA treatment. These data suggest that SA may restore the function of microbiota–GLP1 axis to improve glucose metabolism in the obese mice.展开更多
Obesity increases the risk of type 2 diabetes through the induction of insulin resistance.The mechanism of insulin resistance has been extensively investigated for more than 60 years,but the essential pathogenic signa...Obesity increases the risk of type 2 diabetes through the induction of insulin resistance.The mechanism of insulin resistance has been extensively investigated for more than 60 years,but the essential pathogenic signal remains missing.Existing hypotheses include inflammation,mitochondrial dysfunction,hyperinsulinemia,hyperglucagonemia,glucotoxicity,and lipotoxicity.Drug discoveries based on these hypotheses are unsuccessful in the development of new medicines.In this review,multidisciplinary literature is integrated to evaluate ATP as a primary signal for insulin resistance.The ATP production is elevated in insulin-sensitive cells under obese conditions independent of energy demand,which we have named“mitochondrial overheating.”Overheating occurs because of substrate oversupply to mitochondria,leading to extra ATP production.The ATP overproduction contributes to the systemic insulin resistance through several mechanisms,such as inhibition of AMPK,induction of mTOR,hyperinsulinemia,hyperglucagonemia,and mitochondrial dysfunction.Insulin resistance represents a feedback regulation of energy oversupply in cells to control mitochondrial overloading by substrates.Insulin resistance cuts down the substrate uptake to attenuate mitochondrial overloading.The downregulation of the mitochondrial overloading by medicines,bypass surgeries,calorie restriction,and physical exercise leads to insulin sensitization in patients.Therefore,ATP may represent the primary signal of insulin resistance in the cellular protective response to the substrate oversupply.The prevention of ATP overproduction represents a key strategy for insulin sensitization.展开更多
Insulin resistance is a major risk factor for type 2 diabetes.AMP-activated protein kinase(AMPK)is a drug target in the improvement of insulin sensitivity.Several insulin-sensitizing medicines are able to activate AMP...Insulin resistance is a major risk factor for type 2 diabetes.AMP-activated protein kinase(AMPK)is a drug target in the improvement of insulin sensitivity.Several insulin-sensitizing medicines are able to activate AMPK through inhibition of mitochondrial functions.These drugs,such as metformin and STZ,inhibit ATP synthesis in mitochondria to raise AMP/ATP ratio in the.process of A MPK activation.However,chemicals that activate AMPK directly or by activating its upstream kinases have not been approved for treatment of type 2 diabetes in humans.In an early study,we reported that berberine inhibited oxygen consumption in mitochondria,and increased AMP/ATP ratio in cells.The observation suggests an indirect mechanism for AMPK activation by berberine.Berberine stimulates glycolysis for ATP production that offsets the cell toxicity after mitochondria inhibition.The study suggests that mitochondrial inhibition is an approach for AMPK activation.In this review article,literature is critically reviewed to interpret the role of mitochondria function in the mechanism of insulin resistance,which supports that mitochondria inhibitors represent a new class of AMPK activator.The inhibitors are promising candidates for insulin sensitizers.This review provides a guideline in search for small molecule AMPK activators in the drug discovery for type 2 diabetes.展开更多
The transcription factor nuclear factor kappa B(NF-κB)is activated in hepatoctes in the pathogenesis of hepatic steatosis.However,the action mechanism of NF-κB remains to be established in the hepatic steatosis.In t...The transcription factor nuclear factor kappa B(NF-κB)is activated in hepatoctes in the pathogenesis of hepatic steatosis.However,the action mechanism of NF-κB remains to be established in the hepatic steatosis.In this study,the P50 subunit of NF-κB was found to promote the hepatic steatosis through regulation of histone deacetylase 1(HDAC1)in hepatocytes.The activity was supported by the phenotypes of P50 knockout(P50-KO)mice and P65 knockout(P65-KO)mice.Hepatic steatosis was reduced in the P50-KO mice,but not in the P65-KO mice.The reduction was a result of inhibition of HDAC1 activity in the P50-KO cells.Knockdown of Hdac1 gene led to suppression of hepatocyte steatosis in HepG2 cells.A decrease in sterol-regulatory element binding protein lc(SREBP1 c)protein was observed in the liver of P50-KO mice and in cell with Hdac1 knockdown.The decrease was associated with an increase in succinylation of SREBP1 c protein.The study suggests that P50 stabilizes HDAC1 to support the SREBP1 c activity in hepatic steatosis in the pathophysiological condition.Interruption of this novel pathway in the P50-KO,but not the P65-KO mice,may account for the difference in hepatic phenotypes in the two lines of transgenic mice.展开更多
Berberine from Rhizoma Coptidis is an oral hypoglycemic agent with anti-dyslipidemia and anti-obesity activities.Its metabolic activity of regulating blood glucose and lipids has been widely studied and evidenced in p...Berberine from Rhizoma Coptidis is an oral hypoglycemic agent with anti-dyslipidemia and anti-obesity activities.Its metabolic activity of regulating blood glucose and lipids has been widely studied and evidenced in patients and various animal models.Berberine is known as an AMP-activated protein kinase(A MPK)activator.Its insulin-independent hypoglycemic effect is.related to inhibition of mitochondrial function,stimulation of glycolysis and activation of AMPK pathway.Additionally,berberine may also act as an x-glucosidase inhibitor.In the newly-diagnosed type 2 diabetic patients,berberine is able to lower blood insulin level via enhancing insulin sensitivity.However,in patients with poorβ-cell function,berberine may improve insulin secretion via resuscitating exhausted islets.Furthermore,berberine may have extra beneficial effects on diabetic cardiovascular complications due to its cholesterol-lowering,anti arrhythmias and nitric oxide(NO)inducing properties.The antioxidant and aldose reductase inhibitory activities of berberine may be useful in alleviating dia betic nephropathy.Although evidence from animal and human studies consistently supports the therapeutic activities of berberine,large-scale multicenter trials are still necessary to evaluate the efficacy of berberine on diabetes and its related complications.展开更多
基金supported by the starting funds from the Metabolic Disease Research Center,Zhengzhou University Affiliated Zhengzhou Central Hospital and the Center for Advanced Medicine,College of Medicine,Zhengzhou University,Zhengzhou to Jianping Ye。
文摘Insulin resistance contributes to metabolic disorders in obesity and type 2 diabetes.In mechanisms of insulin resistance,the roles of glucose,fatty acids,and amino acids have been extensively documented in literature.However,the activities of nucleotides remain to be reviewed comprehensively in the regulation of insulin sensitivity.Nucleotides are well known for their activities in biosynthesis of DNA and RNA as well as their signaling activities in the form of c AMP and c GAMP.Their activities in insulin resistance are dependent on the derivatives and corresponding receptors.ATP and NADH,derivatives of adenosine,inhibit insulin signaling inside cells by downregulation of activities of AMPK and SIRT1,respectively.ATP,ADP and AMP,the well-known energy carriers,regulate cellular responses to insulin outside cells through the purinergic receptors in cell surface.Current evidence suggests that ATP,NADH,c GAMP,and uridine are potential biomarkers of insulin resistance.However,GTP and c GMP are likely the markers of insulin sensitization.Here,studies crossing the biomedical fields are reviewed to characterize nucleotide activities in the regulation of insulin sensitivity.The knowledge brings new insights into the mechanisms of insulin resistance.
基金supported by the National Natural Science Foundation of China(Grant No.32271220).
文摘Alzheimer’s disease(AD)is the leading cause of dementia worldwide.Traditionally,pathological studies have concentrated on the abnormal buildup of amyloid b(Ab)plaques and neurofibrillary tangles(NFTs),which arise from the excessive phosphorylation of tau proteins in the brain1,2.Despite extensive research.
基金supported by the National Natural Science Foundation of China(Grant No.32271220).
文摘The Apolipoprotein E(APOE)genotype is closely associated with risk of Alzheimer’s disease(AD),a progressive neurodegenerative disorder that impairs cognitive functions of the brain.APOE2 reduces while APOE4 increases the risk of AD.
基金supported by the National Natural Science Foundation of China(Grant No.82101401).
文摘Extrachromosomal DNA(ecDNA),a circular DNA molecule first identified in 19651,is now recognized as a key carrier of extra copies of oncogenes.Originating from chromosomal DNA,ecDNA primarily forms through mechanisms associated with chromosomal instability,such as DNA damage repair,chromothripsis,episome formation,and the breakage–fusion–bridge cycle.
基金supported by the National Natural Science Foundation of China(Grant No.32271220).
文摘Insulin resistance(IR)is a risk factor of type 2 diabetes and cardiovascular diseases^(1).IR is a result of energy surplus often associated with obesity,non-alcoholic fatty liver disease(NAFLD),and aging^(2).Regarding the mechanism of insulin resistance,there are several hypotheses^(3).However,these hypotheses do not cover the role of nervous system in the mechanism^(3).
基金supported by the National Natural Science Foundation of China(project 32271220)to Jianping Ye.
文摘Mitochondria contain over 1000 types of proteins,most of which are imported from the cytosol1.This import process is intricate and energy-dependent,in which mitochondrial energy deficits and oxidative stress pose significant threats to the import efficiency.When the import is compromised,it can initiate mitochondrial import stress,potentially triggering the integrated stress response(ISR).Persistent ISR may escalate into broader cellular stress2,3.Under normal conditions,the body maintains mitochondrial and cellular equilibrium through intricate stress response pathways.
基金supported by the National Natural Science Foundation of China(Grant No.32271220).
文摘The mechanism of lipid droplet(LD)formation in glial cells is an active area in the field of Alzheimer's disease(AD)pathology.A recent study titled“Amyloid-βinduces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer's disease”by Prakash et al.1 is published in Immunity to report a role of Aβprotein in the induction of LD formation in microglia for the phagocytosis dysfunction in AD.In this context,diacylglycerol O-acyltransferase 2(DGAT2)is identified as a potential therapeutic target for its role in LD formation.
基金supported by the National Natural Science Foundation of China(Grant No.32271220).
文摘Neurons are the main organizers of neurological activities in the brain.However,its role remains largely unknown in regulating waste clearance in the brain.This issue is addressed in a recent study published in Nature on neuronal dynamics in control of waste removal through cerebrospinal fluid perfusion1.Brain contains billions of neurons that are connected through synapses for precise spatial coordination and high-speed operation in support of functions like thoughts,emotions,and body movements in a dynamic manner.
基金supported by the National Natural Science Foundation of China(Grant No.32271220).
文摘Weight regain(WR)is a significant challenge in clinical treatment of obesity after successful weight loss.WR happens frequently after weight loss(WL)by dietary or life style adjustment although it also occurs in WL by bariatric surgery and medications1-3.A general mechanism of WR is“obesity memory”,which refers to a stable gene expression pattern in adipose tissue from obesity.However,the molecular mechanisms underlying obesity memory remain unclear.Recently,Hinte et al.1 reported that obesity memory is mediated by an epigenetic mechanism in adipocytes of adipose tissue in a Nature article.
基金supported by a project(32271220)from the National Natural Science Foundation of China to Jianping Ye.
文摘The presence of glial lipid droplet(LD)and the apolipoprotein E4(APOE4)genotype have been documented as two major risk factors for the development of Alzheimer’s disease(AD)1,2.However,the intricate molecular interplay between these two factors remains elusive and warrants further investigation.A recent study published in Nature has shed light on this issue by offering valuable insights into APOE4 activity in control of LD formation in the human brain3.The brain is rich in lipid content with cholesterol,fatty acids and triglycerides.The brain lipid disorder is a pathological marker of AD,a progressive neurodegenerative disorder from aging characterized by cognitive decline and memory impairment,posing a significant public health challenge for aging populations globally1.Despite decades of intensive research in both clinical and laboratory settings,the search for an effective and safe therapeutic intervention to reverse or delay the progression of AD remains unsuccessful,primarily due to a lack of comprehensive understanding of AD etiology1.Intriguingly,Alois Alzheimer’s initial report on AD described the presence of adipocyte-like morphology in brain cells of AD patients,a pathological feature that was observed together with the accumulation of Ab plaques and Tau tangles in the AD brain1.
基金supported by the National Natural Science Foundation of China(Grant No.82401554).
文摘Communication between the brain and the heart is finely tuned by numerous factors,with sleep being particularly crucial.It is well known that sleep plays a vital role in cardiovascular health,and poor sleep can exacerbate myocardial infarction(MI)by interfering heart energy metabolism and triggering oxidative stress1.However,it remains unclear whether the immune system conveys information about cardiac homeostasis to the brain.A recent study2,published in Nature,has addressed this question by demonstrating immune-mediated pathways that connect acute ischemic cardiac injury to the brain’s sleep circuits,subsequently impact in the sympathetic outflow from the brain to the heart to govern cardiac healing and recovery,which may be a potential therapeutic target for drug development to MI therapy.
基金the Natural Science Foundation of Henan Province,China(232300421047)Science and Technology Innovation Talents in Universities of Henan Province,China(24HASTIT067)Henan Province Young and Middle-aged Health Science and Technology Innovation Talent Project,China(JQRC2023001).
文摘Control of obesity has been a challenging task worldwide with increasing global burden of obesity-associated complications.Dietary interventions have emerged as a popular approach in obesity control,encompassing approaches such as carbohydrate restriction,fat restriction,and amino acid restriction.Notably,a recent study published in Nature reports that animo acid cysteine restriction can induce a rapid weight loss in cystathionineγ-lyase(CSE)-knockout(KO)mice^(1).
基金supported by the National Natural Science Foundation of China(Grant No.32271220).
文摘The brain lymphatic system has been a promising target in the treatment of Alzheimer’s disease(AD)1.Induction of the lymphatic system function is an ideal approach in the development of new therapy for AD.A study published in Nature in 2024 introduced an innovative non-invasive approach in the promotion of the lymphatic function,which uses visual and auditory stimulation at specific frequencies to modulate neuron activity,inducing the brain lymphatic function for clearance of Amyloid-β(Aβ)from the neurons’microenvironment of brain2.
基金Jianping Ye is supported by the National Institute of Health research projects(DK085495,DK068036).
文摘Obesity increases the risk for type 2 diabetes through induction of insulin resistance.Treatment of type 2 diabetes has been limited by little translational knowledge of insulin resistance although there have been several well-documented hypotheses for insulin resistance.In those hypotheses,inflammation,mitochondrial dysfunction,hyperinsulinemia and lipotoxicity have been the major concepts and have received a lot of attention.Oxidative stress,endoplasmic reticulum(ER)stress,genetic background,aging,fatty liver,hypoxia and lipodystrophy are active subjects in the study of these concepts.However,none of those concepts or views has led to an effective therapy for type 2 diabetes.The reason is that there has been no consensus for a unifying mechanism of insulin resistance.In this review article,literature is critically analyzed and reinterpreted for a new energy-based concept of insulin resistance,in which insulin resistance is a result of energy surplus in cells.The energy surplus signal is mediated by ATP and sensed by adenosine monophosphate-activated protein kinase(AMPK)signaling pathway.Decreasing ATP level by suppression of production or stimulation of utilization is a promising approach in the treatment of insulin resistance.In support,many of existing insulin sensitizing medicines inhibit ATP production in mitochondria.The effective therapies such as weight loss,exercise,and caloric restriction all reduce ATP in insulin sensitive cells.This new concept provides a unifying cellular and molecular mechanism of insulin resistance in obesity,which may apply to insulin resistance in aging and lipodystrophy.
基金supported by the National Natural Science Foundation of China(81874377)to Yongning Sunthe National Natural Science Foundation of China(81220108006)to Weiping Jia and Jianping Yesupported by the internal fund of the Shanghai Jiaotong University Affiliated Sixth People’s Hospital East(Shanghai,China)to Jianping Ye and Yongning Sun
文摘Sennoside A(SA) is a bioactive component of Chinese herbal medicines with an activity of irritant laxative, which is often used in the treatment of constipation and obesity. However, its activity remains unknown in the regulation of insulin sensitivity. In this study, the impact of SA on insulin sensitivity was tested in high fat diet(HFD)-induced obese mice through dietary supplementation. At a dosage of 30 mg/kg/day, SA improved insulin sensitivity in the mice after 8-week treatment as indicated by HOMA-IR(homeostatic model assessment for insulin resistance) and glucose tolerance test(GTT). SA restored plasma level of glucagon-like peptide 1(GLP1) by 90% and mRNA expression of Glp1 by 80% in the large intestine of HFD mice. In the mechanism, SA restored the gut microbiota profile, short chain fatty acids(SCFAs), and mucosal structure in the colon. A mitochondrial stress was observed in the enterocytes of HFD mice with ATP elevation, structural damage, and complex dysfunction. The mitochondrial response was induced in enterocytes by the dietary fat as the same responses were induced by palmitic acid in the cell culture. The mitochondrial response was inhibited in HFD mice by SA treatment. These data suggest that SA may restore the function of microbiota–GLP1 axis to improve glucose metabolism in the obese mice.
基金This work is supported by the National Key R&D Program of China(No.2018YFA0800603).
文摘Obesity increases the risk of type 2 diabetes through the induction of insulin resistance.The mechanism of insulin resistance has been extensively investigated for more than 60 years,but the essential pathogenic signal remains missing.Existing hypotheses include inflammation,mitochondrial dysfunction,hyperinsulinemia,hyperglucagonemia,glucotoxicity,and lipotoxicity.Drug discoveries based on these hypotheses are unsuccessful in the development of new medicines.In this review,multidisciplinary literature is integrated to evaluate ATP as a primary signal for insulin resistance.The ATP production is elevated in insulin-sensitive cells under obese conditions independent of energy demand,which we have named“mitochondrial overheating.”Overheating occurs because of substrate oversupply to mitochondria,leading to extra ATP production.The ATP overproduction contributes to the systemic insulin resistance through several mechanisms,such as inhibition of AMPK,induction of mTOR,hyperinsulinemia,hyperglucagonemia,and mitochondrial dysfunction.Insulin resistance represents a feedback regulation of energy oversupply in cells to control mitochondrial overloading by substrates.Insulin resistance cuts down the substrate uptake to attenuate mitochondrial overloading.The downregulation of the mitochondrial overloading by medicines,bypass surgeries,calorie restriction,and physical exercise leads to insulin sensitization in patients.Therefore,ATP may represent the primary signal of insulin resistance in the cellular protective response to the substrate oversupply.The prevention of ATP overproduction represents a key strategy for insulin sensitization.
基金This work is supported by the National Institute of Health research projects(DK085495,DK068036).
文摘Insulin resistance is a major risk factor for type 2 diabetes.AMP-activated protein kinase(AMPK)is a drug target in the improvement of insulin sensitivity.Several insulin-sensitizing medicines are able to activate AMPK through inhibition of mitochondrial functions.These drugs,such as metformin and STZ,inhibit ATP synthesis in mitochondria to raise AMP/ATP ratio in the.process of A MPK activation.However,chemicals that activate AMPK directly or by activating its upstream kinases have not been approved for treatment of type 2 diabetes in humans.In an early study,we reported that berberine inhibited oxygen consumption in mitochondria,and increased AMP/ATP ratio in cells.The observation suggests an indirect mechanism for AMPK activation by berberine.Berberine stimulates glycolysis for ATP production that offsets the cell toxicity after mitochondria inhibition.The study suggests that mitochondrial inhibition is an approach for AMPK activation.In this review article,literature is critically reviewed to interpret the role of mitochondria function in the mechanism of insulin resistance,which supports that mitochondria inhibitors represent a new class of AMPK activator.The inhibitors are promising candidates for insulin sensitizers.This review provides a guideline in search for small molecule AMPK activators in the drug discovery for type 2 diabetes.
基金funded by the National Key Research and Development Program of China(2018YFA0800603 to JY)the starting fund at Shanghai Jiao Tong University Affiliated Sixth People’s Hospital to Jianping Ye
文摘The transcription factor nuclear factor kappa B(NF-κB)is activated in hepatoctes in the pathogenesis of hepatic steatosis.However,the action mechanism of NF-κB remains to be established in the hepatic steatosis.In this study,the P50 subunit of NF-κB was found to promote the hepatic steatosis through regulation of histone deacetylase 1(HDAC1)in hepatocytes.The activity was supported by the phenotypes of P50 knockout(P50-KO)mice and P65 knockout(P65-KO)mice.Hepatic steatosis was reduced in the P50-KO mice,but not in the P65-KO mice.The reduction was a result of inhibition of HDAC1 activity in the P50-KO cells.Knockdown of Hdac1 gene led to suppression of hepatocyte steatosis in HepG2 cells.A decrease in sterol-regulatory element binding protein lc(SREBP1 c)protein was observed in the liver of P50-KO mice and in cell with Hdac1 knockdown.The decrease was associated with an increase in succinylation of SREBP1 c protein.The study suggests that P50 stabilizes HDAC1 to support the SREBP1 c activity in hepatic steatosis in the pathophysiological condition.Interruption of this novel pathway in the P50-KO,but not the P65-KO mice,may account for the difference in hepatic phenotypes in the two lines of transgenic mice.
基金This study is supported by Shanghai Pujiang Program(No.11PJ1407700)National Natural Science Fund Project(No.31171128).
文摘Berberine from Rhizoma Coptidis is an oral hypoglycemic agent with anti-dyslipidemia and anti-obesity activities.Its metabolic activity of regulating blood glucose and lipids has been widely studied and evidenced in patients and various animal models.Berberine is known as an AMP-activated protein kinase(A MPK)activator.Its insulin-independent hypoglycemic effect is.related to inhibition of mitochondrial function,stimulation of glycolysis and activation of AMPK pathway.Additionally,berberine may also act as an x-glucosidase inhibitor.In the newly-diagnosed type 2 diabetic patients,berberine is able to lower blood insulin level via enhancing insulin sensitivity.However,in patients with poorβ-cell function,berberine may improve insulin secretion via resuscitating exhausted islets.Furthermore,berberine may have extra beneficial effects on diabetic cardiovascular complications due to its cholesterol-lowering,anti arrhythmias and nitric oxide(NO)inducing properties.The antioxidant and aldose reductase inhibitory activities of berberine may be useful in alleviating dia betic nephropathy.Although evidence from animal and human studies consistently supports the therapeutic activities of berberine,large-scale multicenter trials are still necessary to evaluate the efficacy of berberine on diabetes and its related complications.
