Longitudinal assessment of peripheral organ metabolism and the gut microbiota in an APP/PS1 transgenic mouse model of Alzheimer’s disease

Alzheimer’s disease not only affects the brain,but also induces metabolic dysfunction in peripheral organs and alters the gut microbiota.The aim of this study was to investigate systemic changes that occur in Alzheimer’s disease,in particular the association between changes in peripheral organ metabolism,changes in gut microbial composition,and Alzheimer’s disease development.To do this,we analyzed peripheral organ metabolism and the gut microbiota in amyloid precursor protein-presenilin 1(APP/PS1)transgenic and control mice at 3,6,9,and 12 months of age.Twelve-month-old APP/PS1 mice exhibited cognitive impairment,Alzheimer’s disease-related brain changes,distinctive metabolic disturbances in peripheral organs and fecal samples(as detected by untargeted metabolomics sequencing),and substantial changes in gut microbial composition compared with younger APP/PS1 mice.Notably,a strong correlation emerged between the gut microbiota and kidney metabolism in APP/PS1 mice.These findings suggest that alterations in peripheral organ metabolism and the gut microbiota are closely related to Alzheimer’s disease development,indicating potential new directions for therapeutic strategies.

Intermittent fasting boosts antitumor immunity by restricting CD11b^(+)Ly6C^(low)Ly6G^(low) cell viability through glucose metabolism in murine breast tumor model

Intermittent fasting can benefit breast cancer patients undergoing chemotherapy or immunotherapy.However,it is still uncertain how to select immunotherapy drugs to combine with intermittent fasting.Herein we observed that two cycles of fasting treatment significantly inhibited breast tumor growth and lung tissue metastasis,as well as prolonged overall survival in mice bearing 4T1 and 4T07 breast cancer.During this process,both the immunosuppressive monocytic-(M-)and granulocytic-(G-)myeloid-derived suppressor cell(MDSC)decreased,accompanied by an increase in interleukin(IL)7R^(+)and granzyme B^(+)T cells in the tumor microenvironment.Interestingly,we observed that Ly6G^(low)G-MDSC sharply decreased after fasting treatment,and the cell surface markers and protein mass spectrometry data showed potential therapeutic targets.Mechanistic investigation revealed that glucose metabolism restriction suppressed the splenic granulocytemonocyte progenitor and the generation of colony-stimulating factors and IL-6,which both contributed to the accumulation of G-MDSC.On the other hand,glucose metabolism restriction can directly induce the apoptosis of Ly6G^(low)G-MDSC,but not Ly6G^(high)subsets.In summary,these results suggest that glucose metabolism restriction induced by fasting treatment attenuates the immune-suppressive milieu and enhances the activation of CD3^(+)T cells,providing potential solutions for enhancing immune-based cancer interventions.

Intrauterine growth retardation affects liver bile acid metabolism in growing pigs:effects associated with the changes of colonic bile acid derivatives

Background:Intrauterine growth retardation(IUGR)is associated with severely impaired nutrient metabolism and intestinal development of pigs.Our previous study found that IUGR altered intestinal microbiota and metabolites in the colon.However,the consequences of IUGR on bile acid metabolism in pigs remained unclear.The present study aimed to investigate the bile acid metabolism in the liver and the profile of bile acid derivatives in the colon of grow-ing pigs with IUGR using bile acid targeted metabolomics.Furthermore,we determined correlations between colonic microbiota composition and metabolites of IUGR and normal birth weight(NBW)pigs at different growth stages that were 7,21,and 28-day-old,and the average body weight(BW)of 25,50,and 100 kg of the NBW pigs.Results:The results showed that the plasma total bile acid concentration was higher(P<0.05)at the 25 kg BW stage and tended to increase(P=0.08)at 28-day-old in IUGR pigs.The hepatic gene expressions related to bile acid synthe-sis(CYP7A1,CYP27A1,and NTCP)were up-regulated(P<0.05),and the genes related to glucose and lipid metabolism(ATGL,HSL,and PC)were down-regulated(P<0.05)at the 25 kg BW stage in IUGR pigs when compared with the NBW group.Targeted metabolomics analysis showed that 29 bile acids and related compounds were detected in the colon of pigs.The colonic concentrations of dehydrolithocholic acid and apocholic acid were increased(P<0.05),while isodeoxycholic acid and 6,7-diketolithocholic acid were decreased(P<0.05)in IUGR pigs,when compared with the NBW pigs at the 25 kg BW stage.Moreover,Spearman’s correlation analysis revealed that colonic Unclassified_[Mogi-bacteriaceae],Lachnospira,and Slackia abundances were negatively correlated(P<0.05)with dehydrolithocholic acid,as well as the Unclassified_Clostridiaceae abundance with 6,7-diketolithocholic acid at the 25 kg BW stage.Conclusions:These findings suggest that IUGR could affect bile acid and glucolipid metabolism in growing pigs,especially at the 25 kg BW stage,these effects being paralleled by a modification of bile acid derivatives concentra-tions in the colonic content.The plausible links between these modified parameters are discussed.

Gut microbiota and host metabolism in liver cirrhosis

The gut microbiota has the capacity to produce a diverse range of compounds that play a major role in regulatingthe activity of distal organs and the liver is strategically positioned downstream of the gut. Gut microbiota linked compounds such as short chain fatty acids, bile acids, choline metabolites, indole derivatives, vitamins, polyamines, lipids, neurotransmitters and neuroactive compounds, and hypothalamic-pituitary-adrenal axis hormones have many biological functions. This review focuses on the gut microbiota and host metabolism in liver cirrhosis. Dysbiosis in liver cirrhosis causes serious complications, such as bacteremia and hepatic encephalopathy, accompanied by small intestinal bacterial overgrowth and increased intestinal permeability. Gut dysbiosis in cirrhosis and intervention with probiotics and synbiotics in a clinical setting is reviewed and evaluated. Recent studies have revealed the relationship between gut microbiota and host metabolism in chronic metabolic liver disease, especially, non-alcoholic fatty liver disease, alcoholic liver disease, and with the gut microbiota metabolic interactions in dysbiosis related metabolic diseases such as diabetes and obesity. Recently, our understanding of the relationship between the gut and liver and how this regulates systemic metabolic changes in liver cirrhosis has increased. The serum lipid levels of phospholipids, free fatty acids, polyunsaturated fatty acids, especially, eicosapentaenoic acid, arachidonic acid, and docosahexaenoic acid have significant correlations with specific fecal flora in liver cirrhosis. Many clinical and experimental reports support the relationship between fatty acid metabolism and gut-microbiota. Various blood metabolome such as cytokines, amino acids, and vitamins are correlated with gut microbiota in probioticstreated liver cirrhosis patients. The future evaluation of the gut-microbiota-liver metabolic network and the intervention of these relationships using probiotics, synbiotics, and prebiotics, with sufficient nutrition could aid the development of treatments and prevention for liver cirrhosis patients.

Linking uric acid metabolism to diabetic complications

Hyperuricemia have been thought to be caused by the ingestion of large amounts of purines, and prevention or treatment of hyperuricemia has intended to prevent gout. Xanthine dehydrogenase/xanthine oxidase(XDH/XO) is rate-limiting enzyme of uric acid generation, and allopurinol was developed as a uric acid(UA) generation inhibitor in the 1950 s and has been routinely used for gout prevention since then. Serum UA levels are an important risk factor of disease progression for various diseases, including those related to lifestyle. Recently, other UA generation inhibitors such as febuxostat and topiroxostat were launched. The emergence of these novel medications has promoted new research in the field. Lifestyle-related diseases, such as metabolic syndrome or type 2 diabetes mellitus, often have a common pathological foundation. As such, hyperuricemia is often present among these patients. Many in vitro and animal studies have implicated inflammation and oxidative stress in UA metabolism and vascular injury because XDH/XO act as one of the major source of reactive oxygen species Many studies on UA levels and associated diseases implicate involvement of UA generation in disease onset and/or progression. Interventional studies for UA generation, not UA excretion revealed XDH/XO can be the therapeutic target forvascular injury and renal dysfunction. In this review, the relationship between UA metabolism and diabetic complications is highlighted.

ATF4 regulates lipid metabolism and thermogenesis

Activating transcription factor 4 （ATF4） has been shown to play key roles in many physiological processes. There are no reports, however, demonstrating a direct link between ATF4 and lipid metabolism. We noticed that Atf4- deficient mice are lean, suggesting a possible role for ATF4 in regulating lipid metabolism. The goal of our current study is to investigate the involvement of ATF4 in lipid metabolism and elucidate the underlying mechanisms. Studies using Atf4-deficient mice revealed increased energy expenditure, as measured by oxygen consumption. These mice also showed increases in lipolysis, expression of uncoupling protein 2 （UCP2） and p-oxidation genes and decreases in expression of lipogenic genes in white adipose tissue （WAT）, suggesting increased utilization and decreased synthesis of fatty acids, respectively. Expression of UCP1, 2 and 3 was also increased in brown adipose tissue （BAT）, suggesting increased thermogenesis. The effect of ATF4 deletion on expression of UCPs in BAT suggests that increased thermogenesis may underlie increased energy expenditure. Thus, our study identifies a possible new function for ATF4 in regulating lipid metabolism and thermogenesis.

Rational prescription of drugs within similar therapeutic or structural class for gastrointestinal disease treatment: Drug metabolism and its related interactions

AIM:To review and summarize drug metabolism and its related interactions in prescribing drugs within the similar therapeutic or structural class for gastrointestinal disease treatment so as to promote rational use of medicines in clinical practice.METHODS:Relevant literature was identified by performing MEDLINE/Pubmed searches covering the period from 1988 to 2006.RESULTS:Seven classes of drugs were chosen,including gastric proton pump inhibitors,histamine H2-receptor antagonists,benzamide-type gastroprokinetic agents,selective 5-HT3 receptor antagonists,fluoroquinolones,macrolide antibiotics and azole antifungals.They showed significant differences in metabolic profile(i.e.,the fraction of drug metabolized by cytochrome P450(CYP),CYP reaction phenotype,impact of CYP genotype on interindividual pharmacokinetics variability and CYP-mediated drug-drug interaction potential).Many events of severe adverse drug reactions and treatment failures were closely related to the ignorance of the above issues.CONCLUSION:Clinicians should acquaint themselves with what kind of drug has less interpatient variability in clearance and whether to perform CYP genotyping prior to initiation of therapy.The relevant CYP knowledgehelps clinicians to enhance the management of patients with gastrointestinal disease who may require treatment with polytherapeutic regimens.

AMPK-associated signaling to bridge the gap between fuel metabolism and hepatocyte viability

The adenosine monophosphate-activated protein kinase (AMPK) and p70 ribosomal S6 kinase-1 pathway may serve as a key signaling flow that regulates energy metabolism; thus, this pathway becomes an attractive target for the treatment of liver diseases that result from metabolic derangements. In addition, AMPK emerges as a kinase that controls the redox-state and mitochondrial function, whose activity may be modulated by antioxidants. A close link exists between fuel metabolism and mitochondrial biogenesis. The relationship between fuel metabolism and cell survival strongly implies the existence of a shared signaling network, by which hepatocytes respond to challenges of external stimuli. The AMPK pathway may belong to this network. A series of drugs and therapeutic candidates enable hepatocytes to protect mitochondria from radical stress and increase cell viability, which may be associated with the activation of AMPK, liver kinase B1, and other molecules or components. Consequently, the components downstream of AMPK may contribute to stabilizing mitochondrial membrane potential for hepatocyte survival. In this review, we discuss the role of the AMPK pathway in hepatic energy metabolism and hepatocyte viability. This information may help identify ways to prevent and/or treat hepatic diseases caused by the metabolic syndrome. Moreover, clinical drugs and experimental therapeutic candidates that directly or indirectly modulate the AMPK pathway in distinct manners are discussed here with particular emphasis on their effects on fuel metabolism and mitochondrial function.

Infant with cardiomyopathy: When to suspect inborn errors of metabolism?

Inborn errors of metabolism are identified in 5%-26% of infants and children with cardiomyopathy. Although fatty acid oxidation disorders, lysosomal and glycogen storage disorders and organic acidurias are well-known to be associated with cardiomyopathies, emerging reports suggest that mitochondrial dysfunction and congenital disorders of glycosylation may also account for a proportion of cardiomyopathies. This review article clarifies when primary care physicians and cardiologists should suspect inborn errors of metabolism in a patient with cardiomyopathy, and refer the patient to a metabolic specialist for a further metabolic work up, with specific discussions of "red flags" which should prompt additional evaluation.

Emerging roles of the intestine in control of cholesterol metabolism

The liver is considered the major “control center” for maintenance of whole body cholesterol homeostasis. This organ is the main site for de novo cholesterol synthesis, clears cholesterol-containing chylomicron remnants and low density lipoprotein particles from plasma and is the major contributor to high density lipoprotein (HDL; good cholesterol) formation. The liver has a central position in the classical definition of the reverse cholesterol transport pathway by taking up periphery-derived cholesterol from lipoprotein particles followed by conversion into bile acids or its direct secretion into bile for eventual removal via the feces. During the past couple of years, however, an additional important role of the intestine in maintenance of cholesterol homeostasis and regulation of plasma cholesterol levels has become apparent. Firstly, molecular mechanisms of cholesterol absorption have been elucidated and novel pharmacological compounds have been identified that interfere with the process and positively impact plasma cholesterol levels. Secondly, it is now evident that the intestine itself contributes to fecal neutral sterol loss as a cholesterol-secreting organ. Finally, very recent work has unequivocally demonstrated that the intestine contributes significantly to plasma HDL cholesterol levels. Thus, the intestine is a potential target for novel anti-atherosclerotic treatment strategies that, in addition to interference with cholesterol absorption, modulate direct cholesterol excretion and plasma HDL cholesterol levels.

Molecular mechanism of carvedilol in attenuating the reversion to fetal energy metabolism during cardiac hypertrophy development

Objective: To explore the molecular regulation mechanism of carvedilol in attenuating the reversion back towards fetal energy metabolism during the development of cardiac hypertrophy induced by coarctation of abdominal aorta (CAA) in male Wistar rats. Methods: Hemodynamic and ventricular remodeling parameters, free fatty acid content in the serum were measured in the experimental animals at 16 weeks after the surgical CAA, the rats receiving carvedilol intervention (CAR) after CAA, and those with sham operation (SH). The expressions of muscle carnitine palmitoyltransferaseⅠ (M-CPTⅠ) and medium chain acyl-CoA dehydrogenase (MCAD) mRNA in the cardiac myocytes from every group were studied with RT-PCR. Results: Significant left ventricular hypertrophy were observed in the rats 16 weeks after coarctation operation (P<0.05), together with significant free fatty acids accumulation and downregulation of M-CPTⅠ and MCAD mRNA (P<0.05) in CAA group. Carvedilol at a dose of 30 mg/kg/d for 12 weeks inhibited the left ventricular hypertrophy induced by pressure overload and enhanced the gene expressions of rate-limiting enzyme (M-CPTⅠ) and key enzyme of fatty acid (MCAD) in the CAR group compared with CAA group (P<0.05). Conclusion: Pressure overload-induced hypertrophy in CAA rats causes the reversion back towards fetal enery metabolism, that is, downregulates the expressions of rate-limiting enzyme and key enzyme of fatty acid oxidation. The intervention therapy with carvedilol, a vasodilating alpha- and beta-adrenoreceptor antagonist, attenuates the reversion of the metabolic gene expression to fetal type through upregulating M-CPTⅠ and MCAD mRNA expressions. Thus, carvedilol may exert cardioprotective effects on heart failure by the mechanism of preserving the adult metabolic gene regulation.

Dietary silymarin ameliorating reproductive and lactation performance of sows via regulating body antioxidant and metabolism

Objective The experiment was conducted to explore the effects of silymarin on reproductive and lactation performance,serum antioxidants,and body metabolism of sows.Methods Sixty pregnant sows(85 d,Large×Landrace)with similar genetic background,body condition,and parity were randomly divided into three groups,and each group has 20 individually housed sows.The sows in the control group(CG)were fed with basal diet,and those in the experimental group A(EGA)and B(EGB)were fed with basal diet containing 250 and 500 mg/kg silymarin,respectively.The experiment lasted 46 days from day 85 of gestation to the end of lactation(weaning on day 17).The milk composition and serum biochemical para-meters were determined by a milk composition analyzer and a blood biochemical analyzer,respectively.Serum antioxidant indexes and plasma hormone levels were measured using the biochemical kits.The gas chromatograph was applied to detect the fecal short chain fatty acids.Results Compared with the CG,the total feed intake(TFI)and average daily feed intake(ADFI)were significantly increased(P<0.01),and the urea content in regular milk tended to increase(P=0.095)in the EG.The serum malondialdehyde(MDA)contents were decreased on day 90 of gestation and the day of farrowing(P<0.01),and the serum contents of total antioxidant capacity(T-AOC)tended to increase on day 17 of lactation(P=0.099)compared with the CG.Compared with the CG,the serum triglyceride(TG)concentrations in the EG tended to increase on day 90 of gestation(P=0.062),and the content of serum total protein(TP)and albumin(ALB)reduced on day 17 of lactation(P<0.01).Compared with the CG,plasm D-lactic acid content was decreased(P<0.05),and the plasma prostaglandin(PG)level tended to increase(P=0.088)in the EG on the day of farrowing and day 17 of lactation.Compared with the CG,fecal isobutyric acid concentration in the EG significantly decreased on the day of farrowing(P<0.05).Conclusion Adding 250-500 mg/kg silymarin to diets from the late gestation to the end of lactation could improve reproductive and lactation performance of sows via the regulation of nutrient metabolism and serum antioxidant.

Cell senescence,loss of splicing,and lipid metabolism in TDP-43-related neurodegenerative processes

In recent work,we have shown that cell senescence of mouse fibroblasts in vitro associates with a build-up of cryptic exons in selected mRNAs,whose level is usually controlled by the activity of TAR DNA binding protein of 43 kDa(Tdp-43)(Torres et al.,2022).In vivo,we also found traits of cell senescence in the motor neuron disease model achieved by overexpressing SOD-G93A,the SOD1 gene(harboring a single amino acid substitution of glycine to alanine at codon 93).

Exercise regulates cardiac metabolism: Sex does matter

Cardiac substrate utilization remains a critical focus for the research community.1 Research has acknowledged the role of metabolic flexibility in the development and progression of cardiac dysfunction during a variety of diseases and conditions.2,3 Under resting basal conditions,the heart relies on fatty acid metabolism as the primary energy source with glucose,lactate,ketone bodies,pyruvate,acetate,and branched-chain amino acids contributing as substrates depending on substrate availability,hormonal status,and myocardial conditioning.4 In addition to pathological states,physiological states,such as acute exercise,induce dynamic changes in substrate metabolism,including nearly a 10-fold increase in myocardial oxygen consumption.3,5 To meet the increased demand for energy during and after a bout of exercise,the heart muscle must exhibit metabolic flexibility and selectively utilize different substrates for adenosine triphosphate production.Moreover,metabolic substrate adaptations depend on the frequency,intensity,duration,and mode of exercise while multiple metabolic fluxes,such as the use,storage and mobilization of substrates must be coordinated to maintain energy homeostasis.1,2 Although many different processes of exercise-induced regulation and metabolic remodeling have been identified,35 the effect of exercise on cellular metabolism and the landscape of metabolic pathway regulation in response to both acute exercise and chronic exercise training remain unclear.

Altered Expression in Patients with Heart Failure of Circulating MicroRNAs Related to Lipoprotein Metabolism

Objective： This study aimed to investigate, for the first time, the expression of circulating miRNAs （microRNAs） related to lipoprotein metabolism in patients with HF （heart failure）. Medlods： Twenty patients with HF and 10 controls without HF were included. BNP （brain natxiuretic peptide）, a marker of HF severity, plasma lipid parameters and the expression of circulating miRNAs were determined. Key findings： Total, LDL-, non-HDL- and HDL-cholesterol, txiglycerides, and apo A-I did not differ between both groups, but apo B was lower in the HF group compared to controls （p = 0.007）. In respect to miRNAs, miR-33a, miR-144, miR-125, miR-30c, miR-122, miR-26a, miR-185, miR-758 and miR-106b were higher, from ten- to 25-fold, and miR-10b was lower about 4-fold, in HF group compared to controls. In HF patients a negative correlation between miR-26a and BNP, the marker of disease severity, was found （r = -0.552; p = 0.041）. Conclusions： Plasma levels of miRNAs involved in HDL and LDL metabolism regulation were strikingly changed in HF patients. The negative correlation between miR-26a and BNP values may suggest the possibility of the rise of a novel biomarker or therapeutic target in HF.

Lipid metabolism and m^(6)A RNA methylation are altered in lambs supplemented rumen-protected methionine and lysine in a low-protein diet

Background:Methionine or lysine has been reported to influence DNA methylation and fat metabolism,but their combined effects in N6-methyl-adenosine(m^(6)A)RNA methylation remain unclarified.The combined effects of rumen-protected methionine and lysine(RML)in a low-protein(LP)diet on lipid metabolism,m^(6)A RNA methylation,and fatty acid(FA)profiles in the liver and muscle of lambs were investigated.Sixty-three male lambs were divided into three treatment groups,three pens per group and seven lambs per pen.The lambs were fed a 14.5%crude protein(CP)diet(adequate protein[NP]),12.5%CP diet(LP),and a LP diet plus RML(LP+RML)for 60 d.Results:The results showed that the addition of RML in a LP diet tended to lower the concentrations of plasma leptin(P=0.07),triglyceride(P=0.05),and non-esterified FA(P=0.08).Feeding a LP diet increased the enzyme activity or m RNA expression of lipogenic enzymes and decreased lipolytic enzymes compared with the NP diet.This effect was reversed by supplementation of RML with a LP diet.The inclusion of RML in a LP diet affected the polyunsaturated fatty acids(PUFA),n-3 PUFA,and n-6 PUFA in the liver but not in the muscle,which might be linked with altered expression of FA desaturase-1(FADS1)and acetyl-Co A carboxylase(ACC).A LP diet supplemented with RML increased(P<0.05)total m^(6)A levels in the liver and muscle and were accompanied by decreased expression of fat mass and obesity-associated protein(FTO)and alk B homologue 5(ALKBH5).The m RNA expressions of methyltransferase-like 3(METTL3)and methyltransferase-like 14(METTL14)in the LP+RML diet group were lower than those in the other two groups.Supplementation of RML with a LP diet affected only liver YTH domain family(YTHDF2)proteins(P<0.05)and muscle YTHDF3(P=0.09),which can be explained by limited m^(6)Abinding proteins that were mediated in m RNA fate.Conclusions:Our findings showed that the inclusion of RML in a LP diet could alter fat deposition through modulations of lipogenesis and lipolysis in the liver and muscle.These changes in fat metabolism may be associated with the modification of m^(6)A RNA methylation.

Effect of Binge Drinking on Glucose Metabolism in Occasional Drinkers: An Experimental Study

Binge drinking is a major public health problem that affects all age groups. Its relation to the risk of impaired glucose metabolism and diabetes is unclear due to controversial findings in animal models and lack of studies in humans. We performed an experimental study on 10 adult volunteers (7M/3F) under the age of 40 who were occasional binge drinkers. In all participants, we performed a baseline two-hour euglycemic hyperinsulinemic clamp at 80 mU&bull;m&minus;2&bull;min&minus;1 at baseline for comparison with an age and sex matched control population of non-drinkers. On a second occasion, before and after ingestion of 78 g of alcohol (beer) in 2 hrs we also measured insulin sensitivity using a 15-minute short insulin tolerance test in drinkers. Blood glucose was also measured every 15 mins over 2 hours during alcohol ingestion. Volunteers were aged 27.6 ± 5.7 years, with a BMI of 23.1 ± 2.8 kg/m2, and ALAT of 24.7 ± 3.0 UI/L. Insulin sensitivity evaluated by the clamp technique was higher in occasional drinkers (M = 12.7 ± 3.4 mg&bull;kg&minus;1&bull;min&minus;1 vs. 8.0 ± 2.3 mg&bull;kg&minus;1&bull;min&minus;1 in non-drinkers, p = 0.011). Acute alcohol ingestion was associated with a non-significant trends towards improved glucose disappearance during short insulin tolerance test (KITT 2.53% ± 0.22%/min before vs. 3.11% ± 1.15%/min after;p = 0.122). Beer consumption induced a significant increase in capillary glycaemia of 78% (p = 0.001). Bingeing was associated with reduced insulin secretion (Homa-β 113.5 ± 22.7 vs. 155.4 ± 57.6;p = 0.047). Binge drinking may induce an increase in insulin sensitivity but acutely decrease insulin secretion.

Interaction between peroxisomes and mitochondria in fatty acid metabolism

Peroxisomes and mitochondria are ubiquitously found organelles. They both are dynamic structures able to divide, to fuse and to undergo autophagic processes. Their activities are dependent on proteins that are, for most (mitochondria) or all (peroxisome) of them, synthesized in the cytosol from the nuclear genome. Nevertheless, the membrane structures and the DNA content differ between these two organelles. Mitochondria possess a small circular genome while peroxisomes don’t. The control of their dynamic is dependent on specific factors even if some of those are able to affect both. These two organelles are metabolically connected: they are both involved in lipid metabolism. They are both able to beta oxidize fatty acids and are implicated in ROS production. However, their precise function in these metabolic pathways and their physiological functions are different. While mitochondrial metabolism is closely related to energy production, peroxisome does not seem to be associated with energy production but with the production of bioactive molecules and in detoxification processes.

The mTORC1 complex in pre-osteoblasts regulates whole-body energy metabolism independently of osteocalcin

Overnutrition causes hyperactivation of mTORC1-dependent negative feedback loops leading to the downregulation of insulin signaling and development of insulin resistance.In osteoblasts(OBs),insulin signaling plays a crucial role in the control of systemic glucose homeostasis.We utilized mice with conditional deletion of Rptor to investigate how the loss of mTORC1 function in OB affects glucose metabolism under normal and overnutrition dietary states.Compared to the controls,chow-fed Rptorob−/−mice had substantially less fat mass and exhibited adipocyte hyperplasia.Remarkably,upon feeding with high-fat diet,mice with pre-and post-natal deletion of Rptor in OBs were protected from diet-induced obesity and exhibited improved glucose metabolism with lower fasting glucose and insulin levels,increased glucose tolerance and insulin sensitivity.This leanness and resistance to weight gain was not attributable to changes in food intake,physical activity or lipid absorption but instead was due to increased energy expenditure and greater whole-body substrate flexibility.RNA-seq revealed an increase in glycolysis and skeletal insulin signaling pathways,which correlated with the potentiation of insulin signaling and increased insulin-dependent glucose uptake in Rptorknockout osteoblasts.Collectively,these findings point to a critical role for the mTORC1 complex in the skeletal regulation of wholebody glucose metabolism and the skeletal development of insulin resistance.

IMMUNOCHEMICAL IDENTIFICATION AND LOCALIZATION OF CYTOCHROME P-450HSjISOZYME, AN ENZYME RELATED TO NITROSAMINE METABOLISM, IN HUMAN GASTRIC MUCOSA AND GASTRIC CARCINOMA

Monoclonal antibody (MAb) to rat liver cyto-chrome P-450j isozyme, an activating enzyme specific to nitrosamine metabolism, was used coupled with immunoblotting, densitometer scanning of SDS-PAGE gels and immunohistochemical technique. The trace P-450HSj isozyme (Mr. 51.5 Kd) was found in human gastric mucosa. It was similar to P-450j in molecular weight, catalytic and immunochemical properties. The concentrations of P-450HSj in mucosa of lesser curvature were higher than those in greater curvature. This might be one of the important reasons that lesser curvature is the commonest area for gastric carcinoma. But there was possibly less P-450HSj in gastric mucosa with cancer. Im-munohistochemically, P-450HSj was discovered in the cytoplasm of some glandular epithelial cells, especially in the glands with hyperplastic and intestinal metaplastic changes adjacent to carcinoma. It was also found in some normal glands and in tumor cells of high-differentiated adenocarcinoma, but not in those of low-differentiated ones. Following subjects are discussed: (1) the method of detecting trace P-450HSj, (2) the rule of distribution of P-450HSj, and (3) the relationship between the isozyme and the occurrence of gastric cancer caused by nitrosa-mines.