scholarly journals Hyocholic acid species as novel biomarkers for metabolic disorders

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xiaojiao Zheng ◽  
Tianlu Chen ◽  
Aihua Zhao ◽  
Zhangchi Ning ◽  
Junliang Kuang ◽  
...  
Keyword(s):  
Metabolic Disorders ◽  
Gastric Bypass Surgery ◽  
Lower Serum ◽  
Obesity And Diabetes ◽  
Remission Of Diabetes ◽  
Novel Biomarkers ◽  
Prospective Cohorts ◽  
Human Blood And Urine ◽  
Hyocholic Acid ◽  
Separate Cohort

AbstractHyocholic acid (HCA) is a major bile acid (BA) species in the BA pool of pigs, a species known for its exceptional resistance to spontaneous development of diabetic phenotypes. HCA and its derivatives are also present in human blood and urine. We investigate whether human HCA profiles can predict the development of metabolic disorders. We find in the first cohort (n = 1107) that both obesity and diabetes are associated with lower serum concentrations of HCA species. A separate cohort study (n = 91) validates this finding and further reveals that individuals with pre-diabetes are associated with lower levels of HCA species in feces. Serum HCA levels increase in the patients after gastric bypass surgery (n = 38) and can predict the remission of diabetes two years after surgery. The results are replicated in two independent, prospective cohorts (n = 132 and n = 207), where serum HCA species are found to be strong predictors for metabolic disorders in 5 and 10 years, respectively. These findings underscore the association of HCA species with diabetes, and demonstrate the feasibility of using HCA profiles to assess the future risk of developing metabolic abnormalities.

scholarly journals Hyocholic acid species and the risk of type 2 diabetes

2018 ◽  
Author(s):  
Xiaojiao Zheng ◽  
Tianlu Chen ◽  
Runqiu Jiang ◽  
Aihua Zhao ◽  
Fengjie Huang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Mouse ◽  
Farnesoid X Receptor ◽  
Lower Serum ◽  
Obesity And Diabetes ◽  
Hyocholic Acid ◽  
G Protein Coupled ◽  
Unique Mechanism ◽  
Apparently Healthy

ABSTRACTHyocholic acid (HCA) and its derivatives are found in only trace amounts in human blood, but constitute approximately 76 % of the bile acid (BA) pool in the pig, a species known for its exceptional resistance to type 2 diabetes mellitus (T2DM). Here we show that HCA species play a crucial role in maintaining glucose homeostasis and preventing T2DM. We found that in two cohort studies (n=1,213), both obesity and diabetes were associated with lower serum concentrations of HCA species. Serum HCA levels in apparently healthy individuals (n=132) were found to be strong predictors for metabolic health 10 years later. Oral administration of HCA increased serum fasting GLP-1, to a greater extent than metformin, in healthy and diabetic mouse models. HCA upregulated GLP-1 secretion in intestinal enteroendocrine cells via simultaneously activating G-protein-coupled BA receptor, TGR5, and inhibiting farnesoid X receptor, a unique mechanism that is not found in other BA species.

The outer membrane protein Amuc_1100 of Akkermansia muciniphila promotes intestinal 5-HT biosynthesis and extracellular availability through TLR2 signalling

2021 ◽  
Author(s):  
Junchao Wang ◽  
Wenjuan Xu ◽  
Rongjuan Wang ◽  
Rongrong Cheng ◽  
Zhengquan Tang ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Outer Membrane ◽  
Outer Membrane Protein ◽  
Metabolic Disorders ◽  
Therapeutic Effects ◽  
Akkermansia Muciniphila ◽  
Intestinal Mucus ◽  
Obesity And Diabetes

Akkermansia muciniphila is a probiotic inhabiting host intestinal mucus layers and displays evident easing or therapeutic effects on host enteritis and metabolic disorders such as obesity and diabetes. The outer...

Identification of entacapone as a chemical inhibitor of FTO mediating metabolic regulation through FOXO1

2019 ◽  
Vol 11 (488) ◽  
pp. eaau7116 ◽  
Author(s):  
Shiming Peng ◽  
Wen Xiao ◽  
Dapeng Ju ◽  
Baofa Sun ◽  
Nannan Hou ◽  
...  
Keyword(s):  
Metabolic Regulation ◽  
Metabolic Disorders ◽  
Fasting Blood Glucose ◽  
Reduced Body ◽  
Forkhead Box ◽  
Obesity And Diabetes ◽  
Approved Drugs ◽  
Blood Glucose Concentrations ◽  
Precise Molecular Mechanism

Recent studies have established the involvement of the fat mass and obesity-associated gene (FTO) in metabolic disorders such as obesity and diabetes. However, the precise molecular mechanism by which FTO regulates metabolism remains unknown. Here, we used a structure-based virtual screening of U.S. Food and Drug Administration–approved drugs to identify entacapone as a potential FTO inhibitor. Using structural and biochemical studies, we showed that entacapone directly bound to FTO and inhibited FTO activity in vitro. Furthermore, entacapone administration reduced body weight and lowered fasting blood glucose concentrations in diet-induced obese mice. We identified the transcription factor forkhead box protein O1 (FOXO1) mRNA as a direct substrate of FTO, and demonstrated that entacapone elicited its effects on gluconeogenesis in the liver and thermogenesis in adipose tissues in mice by acting on an FTO-FOXO1 regulatory axis.

scholarly journals The antagonist of CXCR1 and CXCR2 protects db/db mice from metabolic diseases through modulating inflammation

2019 ◽  
Vol 317 (6) ◽  
pp. E1205-E1217 ◽  
Author(s):  
Siyuan Cui ◽  
Lu Qiao ◽  
Shanshan Yu ◽  
Lili Men ◽  
Yu Li ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Immune Cell ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Signal Pathways ◽  
Therapeutic Effects ◽  
Obesity And Diabetes ◽  
Phosphorylated Akt

Interleukin-8 (IL-8, also named CXCL8) binds to its receptors (CXCR1 and CXCR2) with subsequent recruitment of neutrophils and enhancement of their infiltration into inflamed sites, which exaggerates inflammation in many diseases. Recent studies have proposed that metabolic disorders can be attenuated by counteracting certain inflammatory signal pathways. In this study, we examined whether intervention with G31P, an antagonist of CXCL8, could attenuate tissue inflammation and development of metabolic disorders in db/db mice. The db/m and db/db mice were subcutaneously injected with G31P or equivalent normal saline once a day for 6 wk. The physical and metabolic parameters, glucose tolerance, insulin sensitivity, hepatic lipid accumulation, and inflammation markers were measured. G31P improved hepatic insulin sensitivity by modulating expression of genes related to gluconeogenesis and phosphorylated Akt levels. The expressions of several genes encoding proteins involved in de novo lipogenesis were decreased in G31P-treated db/db mice. Meanwhile, immune cell infiltration and cytokine release were attenuated in db/db mice with G31P treatment. G31P also improved the ratio of proinflammatory M1 and anti-inflammatory M2 macrophages. Furthermore, G31P ameliorates metabolic disturbances via inhibition of CXCR1 and CXCR2 pathways in db/db mice. These data suggest that the selective inhibition of CXC chemokines may have therapeutic effects on symptoms associated with obesity and diabetes.

scholarly journals Metabolic signature of obesity-associated insulin resistance and type 2 diabetes

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Haya Al-Sulaiti ◽  
Ilhame Diboun ◽  
Maha V. Agha ◽  
Fatima F. S. Mohamed ◽  
Stephen Atkin ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Serum Samples ◽  
Metabolic Markers ◽  
Insulin Resistant ◽  
Increased Risk ◽  
Novel Biomarkers ◽  
Prospective Cohorts

Abstract Background Obesity is associated with an increased risk of insulin resistance and type 2 diabetes mellitus (T2DM). However, some obese individuals maintain their insulin sensitivity and exhibit a lower risk of associated comorbidities. The underlying metabolic pathways differentiating obese insulin sensitive (OIS) and obese insulin resistant (OIR) individuals remain unclear. Methods In this study, 107 subjects underwent untargeted metabolomics of serum samples using the Metabolon platform. Thirty-two subjects were lean controls whilst 75 subjects were obese including 20 OIS, 41 OIR, and 14 T2DM individuals. Results Our results showed that phospholipid metabolites including choline, glycerophosphoethanolamine and glycerophosphorylcholine were significantly altered from OIS when compared with OIR and T2DM individuals. Furthermore, our data confirmed changes in metabolic markers of liver disease, vascular disease and T2DM, such as 3-hydroxymyristate, dimethylarginine and 1,5-anhydroglucitol, respectively. Conclusion This pilot data has identified phospholipid metabolites as potential novel biomarkers of obesity-associated insulin sensitivity and confirmed the association of known metabolites with increased risk of obesity-associated insulin resistance, with possible diagnostic and therapeutic applications. Further studies are warranted to confirm these associations in prospective cohorts and to investigate their functionality.

scholarly journals ACE2 Pathway Regulates Thermogenesis and Energy Metabolism

2021 ◽  
Author(s):  
Xi Cao ◽  
Tingting Shi ◽  
Chuanhai Zhang ◽  
Wanzhu Jin ◽  
Lini Song ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Energy Expenditure ◽  
Brown Adipose Tissue ◽  
Knockout Mice ◽  
Metabolic Disorders ◽  
Energy Homeostasis ◽  
Cold Stimulation ◽  
Obesity And Diabetes ◽  
Brown Adipose ◽  
Pka Pathway

Identification of key regulators of energy homeostasis holds important therapeutic promise for metabolic disorders, such as obesity and diabetes. ACE2 cleaves angiotensin II (Ang II) to generate Ang-(1-7) which acts mainly through the Mas receptor. Here, we identify ACE2 pathway as a critical regulator in the maintenance of thermogenesis and energy expenditure. We found that ACE2 is highly expressed in brown adipose tissue (BAT) and that cold stimulation increases ACE2 and Ang-(1-7) levels in BAT and serum. ACE2 knockout mice (ACE2-/y), Mas knockout mice (Mas-/-), and the mice transplanted with brown adipose tissue from Mas-/- mice displayed impaired thermogenesis. In contrast, impaired thermogenesis of db/db obese diabetic mice and high-fat diet-induced obese mice were ameliorated by overexpression of ACE2 or continuous infusion of Ang-(1-7). Activation of ACE2 pathway was associated with improvement of metabolic parameters, including blood glucose, lipids and energy expenditure in multiple animal models. Consistently, ACE2 pathway remarkably enhanced the browning of white adipose tissue. Mechanistically, we showed that ACE2 pathway activated Akt/FoxO1 and PKA pathway, leading to induction of UCP1 and activation of mitochondrial function. Our data propose that adaptive thermogenesis requires regulation of ACE2 pathway and highlight novel therapeutic targets for the treatment of metabolic disorders.

scholarly journals Circulating syndecan-1 is reduced in pregnancies with poor fetal growth and its secretion regulated by matrix metalloproteinases and the mitochondria

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Damanpreet Garcha ◽  
Susan P. Walker ◽  
Teresa M. MacDonald ◽  
Jon Hyett ◽  
Jessica Jellins ◽  
...  
Keyword(s):  
Electron Transport ◽  
Matrix Metalloproteinases ◽  
Fetal Growth ◽  
Electron Transport Chain ◽  
Growth Restriction ◽  
Mitochondrial Electron Transport Chain ◽  
Transport Chain ◽  
Novel Biomarkers ◽  
Prospective Cohorts ◽  
Control Study

AbstractFetal growth restriction is a leading cause of stillbirth that often remains undetected during pregnancy. Identifying novel biomarkers may improve detection of pregnancies at risk. This study aimed to assess syndecan-1 as a biomarker for small for gestational age (SGA) or fetal growth restricted (FGR) pregnancies and determine its molecular regulation. Circulating maternal syndecan-1 was measured in several cohorts; a large prospective cohort collected around 36 weeks’ gestation (n = 1206), a case control study from the Manchester Antenatal Vascular service (285 women sampled at 24–34 weeks’ gestation); two prospective cohorts collected on the day of delivery (36 + 3–41 + 3 weeks’ gestation, n = 562 and n = 405 respectively) and a cohort who delivered for preterm FGR (< 34 weeks). Circulating syndecan-1 was consistently reduced in women destined to deliver growth restricted infants and those delivering for preterm disease. Syndecan-1 secretion was reduced by hypoxia, and its loss impaired proliferation. Matrix metalloproteinases and mitochondrial electron transport chain inhibitors significantly reduced syndecan-1 secretion, an effect that was rescued by coadministration of succinate, a mitochondrial electron transport chain activator. In conclusion, circulating syndecan-1 is reduced among cases of term and preterm growth restriction and has potential for inclusion in multi-marker algorithms to improve detection of poorly grown fetuses.

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