Food intake regulation by leptin:Mechanisms mediating gluconeogenesis and energy expenditure

Regulation of blood glucose levels and body fat is critical for survival.Leptin circulates freely in blood and controls body weight and food intake mainly through hypothalamic receptors and regulates glucose metabolism in the liver both directly through leptin receptors and indirectly via the hypothalamic receptors of central nervous system.Leptin affects food intake regulation and eventually glucose metabolism, lipometabolism,endocrine and immune functions, reproductive function, adipose tissue metabolism and energy expenditure.Leptin also exerts peripheral effects directly on glucose metabolism and gluconeogenesis.Most of obese human subjects have elevated plasma levels of leptin associated to the size of their total adipose tissue mass.Hence gluconeogenic function may be an essential factor in the regulation of nutritional intake and weight gain.The aim of this review is therefore to identify and module the possible effects of leptin with special application in gluconeogenesis.In addition, this review includes the study of fat consumption and energy expenditure in the body.Specific modulation of leptin receptors and adipose tissues functioning could have important inference on therapeutic strategies.

Berberine Inhibits Gluconeogenesis in Skeletal Muscles and Adipose Tissues in Streptozotocin-induced Diabetic Rats via LKB1-AMPK-TORC2 Signaling Pathway

The effect and potential molecular mechanisms of berberine on gluconeogenesis in skeletal muscles and adipose tissues were investigated.After adaptive feeding for one week,8 rats were randomly selected as the normal group and fed on a standard diet.The remaining 32 rats were fed on a high-fat diet and given an intravenous injection of streptozotocin(STZ)for 2 weeks to induce the diabetic models.The diabetic rat models were confirmed by oral glucose tolerance test(OGTT)and randomly divided into 4 groups(n=8 each),which were all fed on a high-fat diet.Berberine(3 g/kg per day)or metformin(183 mg/kg per day)was intragastrically administered to the diabetic rats for 12 weeks,serving as berberine group and metformin group respectively.5-aminoimidazole-4-carboxamide1-β-D-ribofuranoside[AICAR,an agonist of AMP-activated protein kinase(AMPK),0.5 mg/kg per day]was subcutaneously injected to the diabetic rats for 12 weeks,serving as AICAR group.The remaining 8 diabetic rats served as the model group,which was given a 0.5%carboxyl methylcellulose solution by oral gavage.Fasting serum insulin(FINS),OGTT as well as lipid parameters were tested by commercial kit.The protein levels of liver kinase B1(LKB1),AMPK,phosphorylated AMP-activated protein kinase(p-AMPK),transducer of regulated CREB activity 2(TORC2),phosphorylated transducer of regulated CREB activity 2(p-TORC2),phosphoenolpyruvate carboxykinase(PEPCK),and glucose-6-phosphatase(G6Pase)in skeletal muscles and adipose tissues were examined by Western blotting.The results showed that berberine significantly decreased the body weight,plasma glucose,insulin levels,and homeostatic model assessment for insulin resistance(HOMA-IR)of diabetic rats compared with those in the model group.Meanwhile,the serum total triglyceride(TG),total cholesterol(TC),and low-density lipoprotein cholesterol(LDL-C)levels were markedly decreased and high-density lipoprotein cholesterol(HDL-C)level was significantly increased after the treatment with berberine.In addition,we found that berberine significantly increased the expression of p-AMPK and LKB1,while decreasing the p-TORC2 levels in skeletal muscles and adipose tissues.Moreover,the expression of PEPCK and G6Pase was significantly down-regulated after the treatment with berberine compared to the model group.It was suggested that the mechanism by which berberine inhibited peripheral tissue gluconeogenesis may be attributed to the activation of the LKB1-AMPK-TORC2 signaling pathway.

Renal gluconeogenesis in insulin resistance:A culprit for hyperglycemia in diabetes

Renal gluconeogenesis is one of the major pathways for endogenous glucose production.Impairment in this process may contribute to hyperglycemia in cases with insulin resistance and diabetes.We reviewed pertinent studies to elucidate the role of renal gluconeogenesis regulation in insulin resistance and diabetes.A consensus on the suppressive effect of insulin on kidney gluconeogenesis has started to build up.Insulin-resistant models exhibit reduced insulin receptor(IR)expression and/or post-receptor signaling in their kidney tissue.Reduced IR expression or post-receptor signaling can cause impairment in insulin’s action on kidneys,which may increase renal gluconeogenesis in the state of insulin resistance.It is now established that the kidney contributes up to 20%of all glucose production via gluconeogenesis in the post-absorptive phase.However,the rate of renal glucose release excessively increases in diabetes.The rise in renal glucose release in diabetes may contribute to fasting hyperglycemia and increased postprandial glucose levels.Enhanced glucose release by the kidneys and renal expression of the gluconeogenic-enzyme in diabetic rodents and humans further point towards the significance of renal gluconeogenesis.Overall,the available literature suggests that impairment in renal gluconeogenesis in an insulinresistant state may contribute to hyperglycemia in type 2 diabetes.

Enhanced glucose homeostasis via Clostridium symbiosummediated glucagon-like peptide 1 inhibition of hepatic gluconeogenesis in mid-intestinal bypass surgery

BACKGROUND The small intestine is known to play a crucial role in the development and remission of diabetes mellitus(DM).However,the exact mechanism by which mid-small intestinal bypass improves glucose metabolism in diabetic rats is not fully understood.AIM To elucidate the mechanisms by which mid-small intestinal bypass improves glucose metabolism.METHODS Streptozotocin(STZ)was used to induce DM in Sprague-Dawley(SD)rats at a dose of 60 mg/kg.The rats were then randomly divided into two groups:The mid-small intestine bypass(MSIB)group and the sham group(underwent switch laparotomy).Following a 6-wk recovery period post-surgery,the rats underwent various assessments,including metabolic parameter testing,analysis of liver glycogen levels,measurement of key gluconeogenic enzyme activity,characterization of the gut microbiota composition,evaluation of hormone levels,determination of bile acid concentrations,and assessment of the expression of the intestinal receptors Takeda G protein-coupled receptor 5 and farnesoid X receptor.RESULTS The MSIB group of rats demonstrated improved glucose metabolism and lipid metabolism,along with increased hepatic glycogen content.Furthermore,there was a decrease in the expression of the key gluconeogenic enzymes phosphoenolpyruvate carboxykinase 1 and glucose-6-phosphatase.Importantly,the MSIB group exhibited a substantial increase in the abundances of intestinal Lactobacillus,Clostridium symbiosum,Ruminococcus gnavus,and Bilophila.Moreover,higher levels of secondary bile acids,such as intestinal lithocholic acid,were observed in this group.Remarkably,the changes in the gut microbiota showed a significant correlation with the expression of key gluconeogenic enzymes and glucagon-like peptide 1(GLP-1)at 6 wk postoperatively,highlighting their potential role in glucose regulation.These findings highlight the beneficial effects of mid-small intestine bypass on glucose metabolism and the associated modulation of the gut microbiota.CONCLUSION The findings of this study demonstrate that the introduction of postoperative intestinal Clostridium symbiosum in the mid-small intestine contributes to the enhancement of glucose metabolism in nonobese diabetic rats.This improvement is attributed to the increased inhibition of hepatic gluconeogenesis mediated by GLP-1,resulting in a favorable modulation of glucose homeostasis.

Liver or kidney:Who has the oar in the gluconeogenesis boat and when?

Gluconeogenesis is an endogenous process of glucose production from noncarbohydrate carbon substrates.Both the liver and kidneys express the key enzymes necessary for endogenous glucose production and its export into circulation.We would be remiss to add that more recently gluconeogenesis has been described in the small intestine,especially under high-protein,lowcarbohydrate diets.The contribution of the liver glucose release,the net glucose flux,towards systemic glucose is already well known.The liver is,in most instances,the primary bulk contributor due to the sheer size of the organ(on average,over 1 kg).The contribution of the kidney(at just over 100 g each)to endogenous glucose production is often under-appreciated,especially on a weight basis.Glucose is released from the liver through the process of glycogenolysis and gluconeogenesis.Renal glucose release is almost exclusively due to gluconeogenesis,which occurs in only a fraction of the cells in that organ(proximal tubule cells).Thus,the efficiency of glucose production from other carbon sources may be superior in the kidney relative to the liver or at least on the level.In both these tissues,gluconeogenesis regulation is under tight hormonal control and depends on the availability of substrates.Liver and renal gluconeogenesis are differentially regulated under various pathological conditions.The impact of one source vs the other changes,based on post-prandial state,acid-base balance,hormonal status,and other less understood factors.Which organ has the oar(is more influential)in driving systemic glucose homeostasis is still inconclusive and likely changes with the daily rhythms of life.We reviewed the literature on the differences in gluconeogenesis regulation between the kidneys and the liver to gain an insight into who drives the systemic glucose levels under various physiological and pathological conditions.

Integration of network pharmacology with experimental verification reveals the hypoglycemic mechanism of coptisine in Jinqi Jiangtang tablets:inhibition of the FoxO1 signaling pathway and hepatic gluconeogenesis

Background:Jinqi Jiangtang tablets(JQJT)have been approved for the treatment of type 2 diabetes mellitus(T2DM)in China for many years.Exploring the effective substances and mechanisms of JQJT is important for its clinical application and further drug research and development.This study aimed to explore the chemical basis and mechanisms of JQJT in the treatment of T2DM.Methods:With network pharmacology,we screened substances in JQJT and their possible targets,then constructed the action network and enriched the biological functions and pathways associated with the active components,and identified the potential targets and mechanisms of JQJT in the treatment of T2DM.Based on the network pharmacology data,we explored the hypoglycemic mechanisms of coptisine in JQJT through western blot and quantitative real-time polymerase chain reaction.Results:Forty-three compounds with good pharmacokinetic properties were identified in JQJT,together with 146 potential biological targets.Among these potential targets,74 were associated with treatment of T2DM.A compound-target network of the 43 compounds against T2DM was constructed.Biological process and signal pathway enrichment analysis of the network highlighted the FoxO signaling pathway.Western blot and quantitative real-time polymerase chain reaction results showed that coptisine,but not epiberberine,significantly inhibited expression of key genes involved in hepatocyte gluconeogenesis by regulating the FoxO1 signaling pathway.Conclusion:Network pharmacology analysis and cell experiments showed that coptisine regulated glucose homeostasis by inhibiting the FoxO1 signaling pathway and hepatic gluconeogenesis,which may be one of the mechanisms of JQJT in the treatment of T2DM.

The Adenosine Receptor Agonist 5’-<i>N</i>-Ethylcarboxamide-Adenosine Increases Glucose 6-Phosphatase Expression and Gluconeogenesis

Intraperitoneal administration of the non-selective adenosine receptor agonist 5’-N-ethylcarboxamide-adenosine (NECA) (0.1 or 0.3 mg/kg) increased fasting serum glucose levels in mice. To clarify the mechanism responsible for this, the expression of liver glucose 6-phosphatase (G6Pase: a gluconeogenic enzyme) was analyzed, and it was found that G6Pase mRNA was increased by NECA treatment. Administration of 0.3 mg/kg NECA resulted in elevated serum glucose levels at 1 h and were further elevated at 6 h. Administration of 0.1 mg/kg NECA increased serum glucose levels at 1 h and had returned to control levels by 6 h. The increase in fasting serum glucose levels induced by NECA are thought to be caused, in part, by elevated G6Pase expression.

Glutamine or Glutamine Dipeptide Supplementation Improves Gluconeogenesis and Liver Glycogenosis in Type 1 Diabetic Rats

The effects of the supplementation with L-glutamine(GLN)or L-alanyl-L-glutamine(GDP)on the progression of the systemic and hepatic metabolic status of rats having untreated type 1 diabetes mellitus(T1DM)were investigated.Male Wistar diabetic rats(streptozotocin,60 mg/kg)were allotted to four groups supplemented by gavage for thirty days as follows:control and diabetic receiving saline;diabetic receiving GLN(248 mg/kg);and diabetic receiving GDP(400 mg/kg).Body weight,plasmatic parameters and kidney function were analyzed.Isolated hepatocytes were used to assess gluconeogenic capacity.Liver and kidney were used for morphological analyses.T1DM decreased the number and increased the area of the hepatocytes,possibly because of the observed enlargement of glycogen stores.Kidney weight,glomerular area and proteinuria increased,and glomerular filtration rate decreased,in non-supplemented T1DM rats.Glomerular area and proteinuria were reversed by both supplementations.The T1DM hepatocytes released less glucose,which could have been diverted to glycogen synthesis and secondary glycogenosis observed in T1DM;this was partially reversed by the supplementations.The results point to a possible beneficial effect of glutamine on the metabolic and hepatic impairments of T1DM.

LONP1 ameliorates liver injury and improves gluconeogenesis dysfunction in acute-on-chronic liver failure

Background:Acute-on-chronic liver failure(ACLF)is a severe liver disease with complex pathogenesis.Clinical hypoglycemia is common in patients with ACLF and often predicts a worse prognosis.Accumulating evidence suggests that glucose metabolic disturbance,especially gluconeogenesis dysfunction,plays a critical role in the disease progression of ACLF.Lon protease-1(LONP1)is a novel mediator of energy and glucose metabolism.However,whether gluconeogenesis is a potential mechanism through which LONP1 modulates ACLF remains unknown.Methods:In this study,we collected liver tissues from ACLF patients,established an ACLF mouse model with carbon tetrachloride(CCl 4),lipopolysaccharide(LPS),and D-galactose(D-gal),and constructed an in vitro hypoxia and hyperammonemia-triggered hepatocyte injury model.LONP1 overexpression and knockdown adenovirus were used to assess the protective effect of LONP1 on liver injury and gluconeogenesis regulation.Liver histopathology,biochemical index,mitochondrial morphology,cell viability and apoptosis,and the expression and activity of key gluconeogenic enzymes were detected to explore the underlying protective mechanisms of LONP1 in ACLF.Results:We found that LONP1 and the expressions of gluconeogenic enzymes were downregulated in clinical ACLF liver tissues.Furthermore,LONP1 overexpression remarkably attenuated liver injury,which was characterized by improved liver histopathological lesions and decreased serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST)in ACLF mice.Moreover,mitochondrial morphology was improved upon overexpression of LONP1.Meanwhile,the expression and activity of the key gluconeogenic enzymes were restored by LONP1 overexpression.Similarly,the hepatoprotective effect was also observed in the hepatocyte injury model,as evidenced by improved cell viability,reduced cell apoptosis,and improved gluconeogenesis level and activity,while LONP1 knockdown worsened liver injury and gluconeogenesis disorders.Conclusion:We demonstrated that gluconeogenesis dysfunction exists in ACLF,and LONP1 could ameliorate liver injury and improve gluconeogenic dysfunction,which would provide a promising therapeutic target for patients with ACLF.

Glycolysis and gluconeogenesis are involved of glucose metabolism adaptation during fasting and re-feeding in black carp(Mylopharyngodon piceus)

Both in nature and in aquaculture,fish may experience periods of food scarcity or hunger.The metabolic regulation of fish when nutritional state changes is a complex process that involves many factors.To study glucose metabolism adaptability during fasting and re-feeding in the black carp(Mylopharyngodon piceus),we measured changes in some biochemical indicators related to glucose metabolism.Five fish were sampled on days 0,1,3,5,and 10 of fasting(F,S1,S3,S5,and S10,respectively)and days 1,3,and 5 of re-feeding(RF1,RF3,and RF5,respectively).The serum glucose concentration decreased significantly at S1,reached the lowest point at S10,and increased significantly at RF1(P<0.05).The concentration of liver glycogen decreased significantly at S1 and reached the lowest level at S3,whereas the muscle glycogen level decreased significantly at S5 and reached the lowest value at S10(P<0.05).Both liver and muscle glycogen levels returned to the pre-fasting level at RF5(P<0.05).Regarding glycolysis,the concentrations of pyruvate kinase(PK)and hexokinase(HK)decreased significantly at S5 and increased significantly at RF5 and RF1,respectively(P<0.05).The concentrations of glucokinase(GCK)and insulin decreased significantly at S1 and increased significantly at RF1 and RF3,respectively(P<0.05).The mRNA expression levels of liver GCK and glucose transporter 2(GLUT2)decreased significantly at S1 and increased significantly at RF1 and RF5,respectively(P<0.05).As for gluconeogenesis,the concentration of glucose-6-phosphatase(G6PC)increased significantly at S1 and decreased significantly at RF1(P<0.05).The concentrations of glucagon and glucocorticoid(GC)increased significantly at S3 and significantly decreased at RF1 and RF5,respectively(P<0.05).The mRNA expression levels of liver G6PC and phosphoenolpyruvate carboxykinase(PEPCK)increased significantly at S3 and S1,and both decreased significantly at RF1(P<0.05).These results indicate that coordination between glycolysis and gluconeogenesis might be crucial for glucose homeostasis during fasting and re-feeding in the black carp.

Gluconeogenesis during starvation and refeeding phase is affected by previous dietary carbohydrates levels and a glucose stimuli during early life in Siberian sturgeon(Acipenser baerii)

Gluconeogenesis responses was assessed during a short starvation period and subsequent refeeding in Siberian sturgeon(Acipenser baerii) previously fed different dietary carbohydrates levels and experienced to a glucose stimuli during early life. The sturgeon larvae were previously fed either a high glucose diet(G) or a low glucose diet(F) from the first feeding to yolk absorption(8 to 12 d post-hatching [dph]). Each group of fish was sub-divided into 2 treatments at 13 dph and was fed either a high-carbohydrate diet(H) or a low carbohydrate diet(L) until 20 wk. In the current study, the fish in 4 groups(GL, FL, GH and FH) were experienced to starvation for 21 d following by re-feeding of their corresponding diets for 21 d.Fish were sampled at postprandial 6 and 24 h before starvation(P6 h and P24 h), starvation 7,14 and 21 d(S7, S14 and S21) and 1, 7,14 and 21 d during refeeding(R1, R7, R14 and R21). Plasma samples during refeeding were taken at P6 h at each time point. Glycaemia levels, liver and muscle glycogen contents,activities and mRNA levels of hepatic gluconeogenic enzymes were examined. We found that both dietary carbohydrate levels and early glucose stimuli significantly affected the metabolic responses to starvation and refeeding in Siberian sturgeon(P < 0.05). During prolonged starvation, Siberian sturgeon firstly mobilized the liver glycogen and then improved gluconeogenesis when the dietary carbohydrates were abundant, whereas preserved the liver glycogen stores at a stable level and more effectively promoted gluconeogenesis when the dietary carbohydrates are absent to maintain glucose homoeostasis.During refeeding, as most teleostean, Siberian sturgeon failed controlling the activities and mRNA levels of phosphoenolpyruvate carboxykinase cytosolic forms(PEPCK-C), fructose-1,6-bisphosphatase(FBPase),but particularly controlled phosphoenolpyruvate carboxykinase mitochondrial forms(PEPCK-M) activities and mRNA expression of glucose-6-phosphatase(G6 Pase, except in GL group). Siberian sturgeon has a full compensatory ability on growth, but this ability would be obstructed by early glucose stimuli when refeeding the low carbohydrate diet after S21.

The mechanistic target of rapamycin complex 1 pathway involved in hepatic gluconeogenesis through peroxisome-proliferator-activated receptorγcoactivator-1a

Cattle can efficiently perform de novo generation of glucose through hepatic gluconeogenesis to meet post-weaning glucose demand.Substantial evidence points to cattle and non-ruminant animals being characterized by phylogenetic features in terms of their differing capacity for hepatic gluconeogenesis,a process that is highly efficient in cattle yet the underlying mechanism remains unclear.Here we used a variety of transcriptome data,as well as tissue and cell-based methods to uncover the mechanisms of high-efficiency hepatic gluconeogenesis in cattle.We showed that cattle can efficiently convert propionate into pyruvate,at least partly,via high expression of acyl-CoA synthetase short-chain family member 1(ACSS1),propionyl-CoA carboxylase alpha chain(PCCA),methylmalonyl-CoA epimerase(MCEE),methylmalonyl-CoA mutase(MMUT),and succinate-CoA ligase(SUCLG2)genes in the liver(P<0.01).Moreover,higher expression of the rate-limiting enzymes of gluconeogenesis,such as phosphoenolpyruvate carboxykinase(PCK)and fructose 1,6-bisphosphatase(FBP),ensures the efficient operation of hepatic gluconeogenesis in cattle(P<0.01).Mechanistically,we found that cattle liver exhibits highly active mechanistic target of rapamycin complex 1(mTORC1),and the expressions of PCCA,MMUT,SUCLG2,PCK,and FBP genes are regulated by the activation of mTORC1(P<0.001).Finally,our results showed that mTORC1 promotes hepatic gluconeogenesis in a peroxisome proliferator-activated receptor γ coactivator 1a(PGC-1a)dependent manner.Collectively,our results not only revealed an important mechanism responsible for the quantitative differences in the efficiency of hepatic gluconeogenesis in cattle versus non-ruminant animals,but also established that mTORC1 is indeed involved in the regulation of hepatic gluconeogenesis through PGC-1a.These results provide a novel potential insight into promoting hepatic gluconeogenesis through activated mTORC1 in both ruminants and mammals.

Hepatic retinaldehyde deficiency is involved in diabetes deterioration by enhancing PCK1-and G6PC-mediated gluconeogenesis

Type 2 diabetes(T2D) is often accompanied with an induction of retinaldehyde dehydrogenase 1(RALDH1 or ALDH1A1) expression and a consequent decrease in hepatic retinaldehyde(Rald)levels. However, the role of hepatic Rald deficiency in T2D progression remains unclear. In this study, we demonstrated that reversing T2D-mediated hepatic Rald deficiency by Rald or citral treatments, or liverspecific Raldh1 silencing substantially lowered fasting glycemia levels, inhibited hepatic glucogenesis,and downregulated phosphoenolpyruvate carboxykinase 1(PCK1) and glucose-6-phosphatase(G6PC)expression in diabetic db/db mice. Fasting glycemia and Pck1/G6pc mRNA expression levels were strongly negatively correlated with hepatic Rald levels, indicating the involvement of hepatic Rald depletion in T2D deterioration. A similar result that liver-specific Raldh1 silencing improved glucose metabolism was also observed in high-fat diet-fed mice. In primary human hepatocytes and oleic acidtreated HepG2 cells, Rald or Rald + RALDH1 silencing resulted in decreased glucose production and downregulated PCK1/G6PC mRNA and protein expression. Mechanistically, Rald downregulated direct repeat 1-mediated PCK1 and G6PC expression by antagonizing retinoid X receptor a, as confirmed by luciferase reporter assays and molecular docking. These results highlight the link between hepatic Rald deficiency, glucose dyshomeostasis, and the progression of T2D, whilst also suggesting RALDH1 as a potential therapeutic target for T2D.

Steroid hormone 20-hydroxyecdysone disturbs fat body lipid metabolism and negatively regulates gluconeogenesis in Hyphantria cunea larvae

The steroid hormone 20-hydroxyecdysone(20E)has been described to regulate fat body lipid metabolism in insects,but its accurate regulatory mechanism,especially the crosstalk between 20E-induced lipid metabolism and gluconeogenesis remains largely unclear.Here,we specially investigated the effect of 20E on lipid metabolism and gluconeogenesis in the fat body of Hyphantria cunea larvae,a notorious pest in forestry.Lipidomics analysis showed that a total of 1907 lipid species were identified in the fat body of H.cunea larvae assigned to 6 groups and 48 lipid classes.The differentially abundant lipids analysis showed a significant difference between 20E-treated and control samples,indicating that 20E caused a remarkable alteration of lipidomics profiles in the fat body of H.cunea larvae.Further studies demonstrated that 20E accelerated fatty acidβ-oxidation,inhibited lipid synthesis,and promoted lipolysis.Meanwhile,the activities of pyruvate carboxylase,phosphoenolpyruvate carboxykinase,fructose-1,6-bisphosphatase,and glucose-6-phosphatase were dramatically suppressed by 20E in the fat body of H.cunea larvae.As well,the transcriptions of genes encoding these 4 rate-limiting gluconeogenic enzymes were significantly downregulated in the fat body of H.cunea larvae after treatment with 20E.Taken together,our results revealed that 20E disturbed fat body lipid homeostasis,accelerated fatty acidβ-oxidation and promoted lipolysis,but negatively regulated gluconeogenesis in H.cunea larvae.The findings might provide a new insight into hormonal regulation of glucose and lipid metabolism in insect fat body.

Propionate promotes gluconeogenesis by regulating mechanistic target of rapamycin(mTOR)pathway in calf hepatocytes

Enhancing hepatic gluconeogenesis is one of the main modes of meeting the glucose requirement of dairy cows.This study attempted to determine whether the gluconeogenesis precursor propionate had an effect on the expression of the main genes involved in gluconeogenesis in calf hepatocytes and elucidate the associated mechanisms.Calf hepatocytes were obtained from 5 healthy calves(1 d old;30to 40 kg)and exposed to 0-,1-,2.5-,or 5-mM sodium propionate(NaP),which is known to promote the expression of genes involved in the gluconeogenesis pathway,including fructose 1,6-bisphosphatase,phosphoenolpyruvate carboxykinase,and glucose-6-phosphatase.With regard to the underlying mechanism,propionate promoted the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha,hepatocyte nuclear factor 4,and forkhead box O1(transcription factors that regulate the expression of hepatic gluconeogenic genes)by promoting mammalian target of rapamycin complex 1(mTORC1),but inhibiting mTORC2 activity(P<0.01).We also established a model of palmitic acid(PA)-induced hepatic injury in calf hepatocytes and found that PA could inhibit the gluconeogenic capacity of calf hepatocytes by suppressing the expression of gluconeogenic genes,inhibiting m TORC1,and promoting the activity of m TORC2(P<0.01).In contrast,NaP provided protection to calf hepatocytes by counteracting the inhibitory effect of PA on the gluconeogenic capacity of calf hepatocytes(P<0.05).Collectively,these findings indicate that NaP enhances the gluconeogenic capacity of calf hepatocytes by regulating the mTOR pathway activity.Thus,in addition to improving the glucose production potential,propionate may have therapeutic potential for the treatment of hepatic injury in dairy cows.

Free fatty acid-induced miR-22 inhibits gluconeogenesis via SIRT-1-mediated PGC-1α expression in nonalcoholic fatty liver disease

Background and aims:Free fatty acids(FFAs)are one of the important regulators of the progression of nonalcoholic fatty liver disease.The FFAs are shown to modulate the metabolic status of the liver by modulating several cellular pathways in hepatocytes.Here,we elucidated the role of miR-22 in modulating FFAs-mediated gluconeogenesis.Methods:Huh7 and WRL68 cells were transfected with nonspecific miRNA,miR-22 premiRs or anti-miR-22 oligos followed by incubation with palmitic acid,oleic acid,and linoleic acid(300μM each)for 48 and 72 h after transfection.The expression of miR-22 was performed using real-time polymerase chain reaction and Western blots were performed for SIRT-1,PGC-1α,PEPCK,and glucose-6-phosphatase.Three groups of C57BL/6 mice(6 mice per group)were fed with standard diet,choline sufficient L-amino acid defined diet or choline-deficient L-amino acid defined(CDAA)diet for 6,18,32,or 54 weeks.Triglycerides content was measured in the serum.Expression of miR-22 and the protein expression of gluconeogenic enzymes were analyzed in the tissue samples.Results:Incubation of miR-22-transfected cells with FFAs inhibited the expression of SIRT-1,PGC-1α,PEPCK,and glucose-6-phosphatase,while miR-22 expression was increased.These changes were reversed when the cells were transfected with anti-miR-22 oligos.CDAA-fed mice showed the significant increase in triglycerides content and miR-22 expression,while there was an inhibition of SIRT-1,PGC-1α,PEPCK,and glucose-6-phosphatase expression in CDAA-fed mice.

Current understanding and dispute on the function of the Wnt signaling pathway effector TCF7L2 in hepatic gluconeogenesis

Approximately 10 years ago,the Wnt signaling pathway effector TCF7L2(ZTCF-4)was recognized as a type 2 diabetes(T2D)risk gene through a genome wide association study(GWAS).As the correlation between TCF7L2 polymorphisms and T2D susceptibility has been reproducibly observed by numerous follow-up investigations among different ethnic groups,great efforts have been made to explore the function of TCF7L2 in metabolic organs including the pancreas,liver and adipose tissues.Although these explorations have enriched our general knowledge on the Wnt signaling cascade in metabolic homeostasis,studies conducted to date have also generated controversial suggestions.Here I will provide a brief review on the Wnt signaling pathway as well as the milestone GWAS discovery and the follow-up studies.I will then discuss the two different opinions on the correlation between TCF7L2 variants and T2D risk,a gain-of-function event versus a loss-of-function event.This will be followed by summarizing the relevant investigations on the metabolic function of hepatic TCF7L2 and presenting our view on the discrepancy and perspectives.

Role of small leucine zipper protein in hepatic gluconeogenesis and metabolic disorder

Hepatic gluconeogenesis is the central pathway for glucose generation in the body.The imbalance between glucose synthesis and uptake leads to metabolic diseases such as obesity,diabetes,and cardiovascular diseases.Small leucine zipper protein(sLZIP)is an isoform of LZIP and it mainly functions as a transcription factor.Although sLZIP is known to regulate the transcription of genes involved in various cellular processes,the role of sLZIP in hepatic glucose metabolism is not known.In this study,we investigated the regulatory role of sLZIP in hepatic gluconeogenesis and its involvement in metabolic disorder.We found that sLZIP expression was elevated during glucose starvation,leading to the promotion of phosphoenolpyruvate carboxylase and glucose-6-phosphatase expression in hepatocytes.However,sLZIP knockdown suppressed the expression of the gluconeogenic enzymes under low glucose conditions.sLZIP also enhanced glucose production in the human liver cells and mouse primary hepatic cells.Fasting-induced cyclic adenosine monophosphate impeded sLZIP degradation.Results of glucose and pyruvate tolerance tests showed that sLZIP transgenic mice exhibited abnormal blood glucose metabolism.These findings suggest that sLZIP is a novel regulator of gluconeogenic enzyme expression and plays a role in blood glucose homeostasis during starvation.

Ginsenoside Rg1 inhibits glucagon-induced hepatic gluconeogenesis through Akt-FoxO1 interaction

With the support by the National Natural Science Foundation of China,a collaborative study by the research groups led by Prof.Qi Lianwen(齐炼文)from the Clinical Metabolomics Center,Profs.Li Ping(李萍)and Liu Baolin(刘保林)from the State Key Laboratory of Natural Medicines。

Expression characteristics of long non-coding RNA-Co7Rik and its impacts on gluconeogenesis

Objective To explore the expression characteristics of long non-coding RNA-Co7Rik and to discuss its potential impacts on hepatic gluconeogenesis.Methods Building fasting-feeding model and high fat diet(HFD)feeding model to detect the expression level of LncRNACo7Rik.Separating different parts of C57BL/6J mice