Metformin and metabolic diseases： a focus on hepatic aspects

Metformin has been widely used as a diabetes （T2D）. As a drug that primarily targets first-line anti-diabetic medicine for the treatment ot type Z the liver, metformin suppresses hepatic glucose production （HGP）, serving as the main mechanism by which metformin improves hyperglycemia of T2D. BiochemicaUy, metformin suppresses gluconeogenesis and stimulates glycolysis. Metformin also inhibits glycogenolysis, which is a pathway that critically contributes to elevated HGP. While generating beneficial effects on hyperglycemia, metformin also improves insulin resistance and corrects dyslipidemia in patients with T2D. These beneficial effects of metformin implicate a role for metformin in managing non-alcoholic fatty liver disease. As supported by the results from both human and animal studies, metformin improves hepatic steatosis and suppresses liver inflammation. Mechanistically, the beneficial effects of metformin on hepatic aspects are mediated through both adenosine monophosphate-activated protein kinase （AMPK）-dependent and AMPK-independent pathways. In addition, metformin is generally safe and may also benefit patients with other chronic liver diseases.

Glycolysis in the control of blood glucose homeostasis

Glycolysis,a simple pathway of glucose metabolism,critically regulates insulin secretion and metabolic functions of various cells.Depending on cell types,rates of glycolysis are determined at various steps of glycolysis that are subjected to the control of key metabolic and regulatory enzyme(S),which include glucokinase,6-phosphofructo-I-kinase,and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase.These enzymes are regulated by both nutritional and hormonal signals at the levels of transcription,translation,and post-translational modifications.In hepatocytes,glycolysis is involved in the control of hepatic glucose production.The latter,when excessive,contributes to hyperglycemia in diabetes.In pancreatic β cells,glycolysis couples glucose-stimulated insulin secretion.Absolute or relatively low levels of circulating insulin causes hyperglycemia.In adipocytes,glycolysis generates metabolites for lipogenesis and channels fatty acids from excessive oxidation to triglyceride synthesis,thereby reducing oxidative stress.With increased proinflammatory status,adipocytes produce pro-hyperglycemic factors and bring about hyperglycemia and insulin resistance.In hypotha lamic neurons,glycolysis conveys nutrient sensing that is related to feeding control.Dysregulation of glycolysis occurs in conditions of insulin deficiency or resistance,and is attributable to inappropriate amount and/or activities of metabolic and regulatory enzymes of glycolysis.Targeting key metabolic and regulatory enzymes to enhance glycolysis may offer viable approaches for treatment of diabetes.

CMHX008,a PPAR γ partial agonist,enhances insulin sensitivity with minor influences on bone loss

Traditional thiazolidinediones(TZDs),such as rosiglitazone,are peroxisome proliferator-activated receptor g(PPARg)potent agonists that can be used to treat type 2 diabetes but carry unwanted effects,including increased risk for fracture.The present work aimed to compare the insulin-sensitizing efficacies and bone-loss side effects of CMHX008,a novel TZDs-like PPARg partial agonist,with those of rosiglitazone.A TR-FRET PPARg competitive binding assay was used to compare the binding affinity between CMHX008 and rosiglitazone.Mice were administered vehicle,CMHX008 or rosiglitazone for 16 weeks.Mesenchymal stem cells(MSCs)were used to examine differences in differentiation into osteoblasts after compounds treatment.TR-FRET showed lower affinity to PPARg by CMHX008 compared with rosiglitazone.Mice treated with CMHX008 showed insulin sensitization similar to that of mice treated with rosiglitazone,which was related to the significant inhibition of PPARg Ser273 phosphorylation and improved insulin sensitivity by facilitating the phosphorylation of insulin receptor and Akt in adipose tissues.Micro-CT and histomorphometric analyses demonstrated that the degree of trabecular bone loss after treatment with CMHX008 was weaker than that observed with rosiglitazone,as evidenced by consistent changes in BV/TV,Tb.N,Tb.Th,Tb.Sp,and the mineral apposition rate.MSCs treated with CMHX008 showed higher ALP activity and mRNA levels of bone formation markers than did cells treated with rosiglitazone in the osteoblast differentiation test.Thus,CMHX008 showed insulin-sensitizing effects similar to those of rosiglitazone with a lower risk of bone loss,suggesting that PPARg sparing eliminates the skeletal side effects of TZDs while maintaining their insulin-sensitizing properties.

Hippocampal overexpression of TREM2 ameliorates high fat diet induced cognitive impairment and modulates phenotypic polarization of the microglia

Type 2 diabetes mellitus(T2DM)and Alzheimer's disease(AD)share several common pathophysiological features.Rare variants of triggering receptor expressed on myeloid cells 2(TREM2)increase the risk of developing AD,suggesting the involvement of TREM2 and innate immunity in AD development.It is still unknown whether TREM2 is related to cognitive impairment in T2DM.Here,we investigated the effects of the hippocampal overexpression of TREM2 on cognitive in long-term high-fat diet(HFD)-fed mice.Male C57BL/6J mice were maintained on HFD for 50 weeks.TREM2 was overexpressed in the hippocampus 36 weeks after HFD feeding using adeno-associated virus vector(AAV)-mediated gene delivery.The results showed that the HFD feeding induced rapid and persistent weight gain,glucose intolerance and significant impairments in learning and memory.Compared with AAV-con,AAV-TREM2 significantly ameliorated cognitive impairment without altering body weight and glucose homeostasis in HFD mice.The overexpression of TREM2 upregulated the synaptic proteins spinophilin,PSD95 and synaptophysin,suggesting the improvement in synaptic transmission.Dendritic complexity and spine density in the CA1 region were rescued after TREM2 overexpression.Furthermore,TREM2 markedly increased the number of iba-1/Arg-1-positive microglia in the hippocampus,suppressed neuroinflammation and microglial activation.In sum,hippocampal TREM2 plays an important role in improving HFD-induced cognitive dysfunction and promoting microglial polarization towards the M2 anti-inflammatory phenotype.Our study also suggests that TREM2 might be a novel target for the intervention of obesity/diabetes-associated cognitive decline.

Referential significance of sulfur isotopes and separation of S species in black shales of Southwest China

The states of S species in black shales are very complex, such as organic sulfur, pyrite sulfur and sulphate sulfur. The mineral microtexture, sulfur content and sulfur isotope can indicate the formation conditions and diagenetic processes of the black shales. The S species are separated perfectly and the relation between the content, mineral microtexture and

Adoptive transfer of Pfkfb3-disrupted hematopoietic cells to wild-type mice exacerbates diet-induced hepatic steatosis and inflammation

Background and objectives:Hepatic steatosis and inflammation are key characteristics of non-alcoholic fatty liver disease(NAFLD).However,whether and how hepatic steatosis and liver inflammation are differentially regulated remains to be elucidated.Considering that disruption of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3(Pfkfb3/iPfk2)dissociates fat deposition and inflammation,the present study examined a role for Pfkfb3/iPfk2 in hematopoietic cells in regulating hepatic steatosis and inflammation in mice.Methods:Pfkfb3-disrupted(Pfkfb3^(+/-))mice and wild-type(WT)littermates were fed a high-fat diet(HFD)and examined for NAFLD phenotype.Also,bone marrow cells isolated from Pfkfb3^(+/-)mice andWT mice were differentiated into macrophages for analysis of macrophage activation status and for bone marrow transplantation(BMT)to generate chimeric(WT/BMT-Pfkfb3^(+/-))mice in which Pfkfb3 was disrupted only in hematopoietic cells and control chimeric(WT/BMT-WT)mice.The latter were also fed an HFD and examined for NAFLD phenotype.In vitro,hepatocytes were co-cultured with bone marrowderived macrophages and examined for hepatocyte fat deposition and proinflammatory responses.Results:After the feeding period,HFD-fed Pfkfb3^(+/-)mice displayed increased severity of liver inflammation in the absence of hepatic steatosis compared with HFD-fed WT mice.When inflammatory activation was analyzed,Pfkfb3^(+/-)macrophages revealed increased proinflammatory activation and decreased anti-proinflammatory activation.When NAFLD phenotype was analyzed in the chimeric mice,WT/BMT-Pfkfb3^(+/-) mice displayed increases in the severity of HFD-induced hepatic steatosis and inflammation compared with WT/BMT-WT mice.At the cellular level,hepatocytes co-cultured with Pfkfb3^(+/-) macrophages revealed increased fat deposition and proinflammatory responses compared with hepatocytes co-cultured with WT macrophages.Conclusions:Pfkfb3 disruption only in hematopoietic cells exacerbates HFD-induced hepatic steatosis and inflammation whereas the Pfkfb3/iPfk2 in nonhematopoietic cells appeared to be needed for HFD feeding to induce hepatic steatosis.As such,the Pfkfb3/iPfk2 plays a unique role in regulating NAFLD pathophysiology.

Seismic Imaging of the Sedimentary System of the Upper Cretaceous Nenjiang Formation in the Northern Songliao Basin

This paper studied seismic imaging of the sedimentary system of the Nenjiang Formation in the Northern Songliao Basin based on seismic sedimentology. An accurate and detailed depiction and explanation is provided for underground geological bodies within a relative geological period using the stratal slice technology,based on three-order sequence correlations of well logging and seismic data for the purpose of obtaining high-resolution pictures of the sedimentary system. Research results have revealed that the sedimentary system of the Upper Cretaceous Nenjiang Formation in the Northern Songliao Basin includes meandering streams,anastomosing streams,lake deltas,and sediment gravity flow channels. Based on seismic imaging analysis,the genesis and seismic geomorphology of the sedimentary system of the Nenjiang Formation are explored in order to understand the spatial distribution of typical sedimentary bodies and the evolution of streams in the Nenjiang Formation. According to the research results,the sedimentation of the Nenjiang Formation was subject to the delta system in the east and northeast of the formation. The provenance in the northeastern part played a dominant role during the deposition of the Nenjiang Formation for some time;after the earlier maximum flooding in the second and third members of the Nenjiang Formation,the northeastern system began to decline and was gradually replaced by the eastern system. Stratal slices have revealed that a well-developed gravity flow channel system was developed in the first member of the Nenjiang Formation,and massive slip blocks occurred in the second and third members of the formation. The research results indicated that the large gravity flow channel system in the first member of the Nenjiang Formation was formed by streams that emptied directly into the lake;and the slip blocks in the second and third members were the results of gravity sliding of sediments along steep slopes at the delta front.