Malfunction of the liver is a central factor in metabolic disease. Glucose production by liver is complex and controlled via indirect mechanisms; insulin regulates adipose tissue lipolysis, and free fatty acids in turn regulate liver glucose output. This latter concept is confirmed by studies in L-Akt-Foxo1 knockout mice. The adipocyte is a likely locus of hepatic insulin resistance. Also, kidneys play a role in regulating glucose production; denervated kidneys abrogate the effect of fat feeding to cause insulin resistance. Glucose itself is an important regulator of liver metabolism ("glucose effectiveness"); after entering liver, glucose is phosphorylated and can be exported as lactate. Using the dynamic glucose/lactate relationship, we have been able to estimate glucose effectiveness in intact animals and human subjects. Families have been identified with a glucokinase regulatory protein defect; modeling demonstrates elevated glucokinase activity. Insulin clearance by liver is highly variable among normal individuals, and is under environmental control: high fat diet reduces clearance by 30%. Liver insulin clearance is significantly lower in African American (AA) adults and children compared to European American participants, accounting for fasting hyperinsulinemia in AA. We hypothesize that reduced hepatic insulin clearance causes peripheral insulin resistance and increased Type 2 diabetes in AA. (C) 2019 Elsevier Inc. All rights reserved.
Skeletal muscle is recognized as a tissue with high metabolic capacity given its key roles in glucose and lipid metabolism. Although low muscle mass has been associated with metabolic disorders in adults, it is not clear if this body composition phenotype is related to metabolic health status earlier in life. In this review, we aim to clarify whether having low muscle mass is associated with increased risk of metabolic dysregulation in the pediatric population. Fifteen original articles investigating the relationship between body composition measures of muscle mass and single or clustered metabolic risk factors in children and adolescents were critically evaluated. Despite a growing body of evidence supporting low muscle mass as a risk factor for metabolic health in children and adolescents, conflicting associations were reported. Differences in body composition techniques, muscle mass indices, and clinical methods used to assess metabolic biomarkers may have contributed to a lack of a consistent conclusion. Moreover, most studies did not control for potential biological and lifestyle confounders. Future studies using precise, reproducible techniques to evaluate body composition and metabolic biomarkers are required to determine the implications of low muscle mass on metabolic health during childhood and adolescence. (C) 2019 Elsevier Inc. All rights reserved.
Moderate or low level hydrogen peroxides has been shown to play an important role in vascular smooth muscle cell (VSMC) function, in which the polymerase DNA-directed interacting protein 2 (Poldip2), functioned as a key regulator of NOX4 activity. In current study, we unexpectedly found that type 2 diabetes mellitus (T2DM) substantially suppresses the hepatic Poldip2 expression, and that the hepatic deficiency of Poldip2 may be correlated with dysregulation of hepatic cholesterol and plasma triglycerides. In cultured hepatocytes, we found that both insulin and leptin may inhibit hepatic expression of Poldip2 under high glucose concentration, but these suppressions were totally abolished under normoglycemic condition. POLDIP2 siRNA knockdown significantly impaired the H2O2 induction by insulin or leptin under normoglycemic condition, contributing the accumulation of cholesterol in cultured liver cells. The in vivo restoration of hepatic Poldip2 expression in T2DM mice remarkably rescued the moderate H2O2 generation in livers versus control mice, resulting in significant amelioration of hepatic cholesterol accumulation and plasma triglyceride levels. Importantly, the moderate induction of H2O2 in livers dramatically improved the hepatic PI3K-C-1/AKT signaling or dampened PI3K-C-2 gamma/AKT signaling through suppression of PTEN and PTP1B activities, thereby inhibiting the hepatic expression of HMGCR and SREBP2 for cholesterol synthesis. Moreover, the restitution of hepatic Poldip2 expression in diabetic mice significantly lowered the VLDL-cholesterol production rate, and substantially suppressed PEPCK and G6Pase expressions for gluconeogenesis, thus significantly improving the plasma insulin and glucose levels, and ITT and GTT outcomes in diabetic mice. Our findings suggest that hepatic dysregulation of Poldip2 may contribute to diabetic dyslipidemia and hyperglycemia. (C) 2019 Elsevier Inc. All rights reserved.
Background & aims: Hepatic alterations, such as in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are frequently associated with obesity. To investigate the molecular mechanisms of these alterations and to identify molecules that could be used as potential therapeutic targets, we investigated themodulation of hepatic indices of oxidative stress and inflammation in obese patients undergoing laparoscopic sleeve gastrectomy (LSG). Methods: Patients (n = 436) attending our obesity clinic underwent LSG for weight loss. We obtained a diagnostic intraoperative liver biopsy, and a sub-cohort (n = 120) agreed to a 1-year follow-up that included donation of blood samples and additional liver biopsies. Selected key molecules in blood and liver tissue were used to investigate the hepatic alterations in obesity, and their response to LSG. Results: One year post-surgery, the prevalence of diabetes, dyslipidemia and hypertension decreased significantly. LSG improved liver histology features in all patients. Improvement was greater in severe cases of NAFLD including those with steatohepatitis, bridging fibrosis or cirrhosis. Significant pre-surgery differences in plasma, and liver markers of oxidative stress and inflammation (including chemokine C-C motif ligand 2, paraoxonase-1, galectin-3, and sonic hedgehog) were observed between patients with, and those without, NASH; post-surgery indicated consistent improvements in these parameters. Conclusion: Our study shows that the histology and liver function of patients with morbid obesity are significantly improved after LSG via mechanisms that involve the reduction of oxidative stress and inflammatory processes. These data encourage the use of LSG as a therapeutic option to improve, or resolve, NAFLD. (C) 2019 Elsevier Inc. All rights reserved.
Objective: Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome. Steroid hormones and bile acids are potent regulators of hepatic carbohydrate and lipid metabolism. Steroid 5 beta-reductase (AKR1D1) is highly expressed in human liver where it inactivates steroid hormones and catalyzes a fundamental step in bile acid synthesis. Methods: Human liver biopsies were obtained from 34 obese patients and AKR1D1 mRNA expression levels were measured using qPCR. Genetic manipulation of AKR1D1 was performed in human HepG2 and Huh7 liver cell lines. Metabolic assessments were made using transcriptome analysis, western blotting, mass spectrometry, clinical biochemistry, and enzyme immunoassays. Results: In human liver biopsies, AKR1D1 expression decreased with advancing steatosis, fibrosis and inflammation. Expression was decreased in patients with type 2 diabetes. In human liver cell lines, AKR1D1 knockdown decreased primary bile acid biosynthesis and steroid hormone clearance. RNA-sequencing identified disruption of key metabolic pathways, including insulin action and fatty acid metabolism. AKR1D1 knockdown increased hepatocyte triglyceride accumulation, insulin sensitivity, and glycogen synthesis, through increased de novo lipogenesis and decreased beta-oxidation, fueling hepatocyte inflammation. Pharmacological manipulation of bile acid receptor activation prevented the induction of lipogenic and carbohydrate genes, suggesting that the observed metabolic phenotype is driven through bile acid rather than steroid hormone availability. Conclusions: Genetic manipulation of AKR1D1 regulates the metabolic phenotype of human hepatoma cell lines, driving steatosis and inflammation. Taken together, the observation that AKR1D1 mRNA is down-regulated with advancing NAFLD suggests that it may have a crucial role in the pathogenesis and progression of the disease. (C) 2019 The Author(s). Published by Elsevier Inc.
Objective: Mineralocorticoid receptor activation of the epithelial sodium channel in endothelial cells (ECs) (EnNaC) is accompanied by aldosterone induced endothelial stiffening and impaired nitric oxide (NO)-mediated arterial relaxation. Recent data support enhanced activity of the alpha subunit of EnNaC (alpha EnNaC) mediates this aldosterone induced endothelial stiffening and associated endothelial NO synthase (eNOS) activation. There is mounting evidence that diet induced obesity diminishes expression and activation of AMP-activated protein kinase a (AMPK alpha), sirtuin 1 (Sirt1), which would be expected to lead to impaired downstream eNOS activation. Thereby, we posited that enhanced EnNaC activation contributes to diet induced obesity related increases in stiffness of the endothelium and diminished NO mediated vascular relaxation by increasing oxidative stress and related inhibition of AMPK alpha, Sirt1, and associated eNOS inactivation. Materials/Methods: Sixteen to twenty week-old alpha EnNaC knockout (alpha EnNaC(-/-)) and wild type littermate (EnNaC(+/+)) female mice were fed a mouse chow or an obesogenic western diet (WD) containing excess fat (46%) and fructose (17.5%) for 16 weeks. Sodium currents of ECs, endothelial stiffness and NO mediated aortic relaxation were examined along with indices of aortic oxidative stress, vascular remodeling and fibrosis. Results: Enhanced EnNaC activation-mediated WD-induced increases in sodium currents in isolated lung ECs, increased endothelial stiffness and impaired aortic endothelium-dependent relaxation to acetylcholine (10(-9)-10(-4) mol/L). These abnormalities occurred in conjunction with WD-mediated aortic tissue oxidative stress, inflammation, and decreased activation of AMPK alpha, Sirt1, and downstream eNOS were substantially mitigated in alpha EnNaC(-/-) mice. Importantly, alpha EnNaC(-/-) prevented WD induced increases in endothelial stiffness and related impairment of endothelium-dependent relaxation as well as aortic fibrosis and remodeling. However, EnNaC signaling was not involved in diet-induced abnormal expression of adipokines and CYP11b2 in abdominal aortic perivascular adipose tissue. Conclusion: These data suggest that endothelial specific EnNaC activation mediates WD-induced endothelial stiffness, impaired eNOS activation, aortic fibrosis and remodeling through increased aortic oxidative stress and increased inflammation related to a reduction of AMPK alpha and Sirt 1 mediated eNOS phosphorylation/activation and NO production. (C) 2019 Elsevier Inc. All rights reserved.
Background and purpose: TGR5 plays an important role in many physiological processes. However, the functions of TGR5 in the regulation of the glucose metabolism and insulin sensitivity in the skeletal muscles have not been fully elucidated. We synthesized MN6 as a potent and selective TGR5 agonist. Here, the effect of MN6 on insulin resistance in skeletal muscles was evaluated in diet-induced obese (DIO) mice and C2C12 myotubes, and the underlying mechanisms were explored. Methods: The activation of MN6 on human and mouse TGR5 was evaluated by a cAMP assay in HEK293 cell lines stable expressing hTGR5/CRE or mTGR5/CRE cells. GLP-1 secretion was measured in NCI-H716 cells and CD1 mice. The acute and chronic effects of MN6 on regulating metabolic abnormalities were observed in ob/ob and DIO mice. 2-deoxyglucose uptake was examined in isolated skeletal muscles. Akt phosphorylation, glucose uptake and glycogen synthesis were examined to assess the effects of MN6 on palmitate-induced insulin resistance in C2C12 myotubes. Results: MN6 potently activated human and mouse TGR5 with EC50 values of 15.9 and 17.9 nmol/L, respectively, and stimulated GLP-1 secretion in NCI-H716 cells and CD1 mice. A single oral dose of MN6 significantly decreased the blood glucose levels in ob/ob mice. Treatment with MN6 for 15 days reduced the fasting blood glucose and HbA1c levels in ob/ob mice. MN6 improved glucose and insulin tolerance and enhanced the insulin-stimulated glucose uptake of skeletal muscles in DIO mice. The palmitate-induced impairment of insulin-stimulated Akt phosphorylation, glucose uptake and glycogen synthesis in C2C12 myotubes could be prevented by MN6. The effect of MN6 on palmitate-impaired insulin-stimulated Akt phosphorylation was abolished by siRNA-mediated knockdown of TGR5 or by the inhibition of adenylate cyclase or protein kinase A, suggesting that this effect is dependent on the activation of TGR5 and the cAMP/PKA pathway. Conclusions: Our study identified that a TGR5 agonist could ameliorate insulin resistance by the cAMP/PKA pathway in skeletal muscles; this uncovered a new effect of the TGR5 agonist on regulating the glucose metabolism and insulin sensitivity in skeletal muscles and further strengthened its potential value for the treatment of type 2 diabetes. (C) 2019 Elsevier Inc. All rights reserved.
Background: Perturbed endoplasmic reticulum (ER) homeostasis and increased levels of G0/G1 Switch Gene 2 (G0S2) have been documented in animal models with fatty liver disease. In this study, we investigated whether G0S2 is regulated by branch of the unfolded protein response (UPR) and contributes to ER stress-induced hepatic steatosis. Methods: We first analyzed G0S2 expression and the state of the three canonical UPR branches in several hepatic steatosis models, tunicamycin-treated C57BL/6J mice and HepG2 cells, where ER homeostasis was perturbed. We pretreated HepG2 cells with tauroursodeoxycholic acid (TUDCA) to validate whether G0S2 was the downstream target of ER stress. Loss or gain function analysis was conducted to identify which UPR branch specifically linked to G0S2 transcription. The transcription mechanism was estimated by luciferase reporter assay and ChIP assay. Results: Here we showed that the activation of ER stress was accompanied by elevation of G0S2 expression in the occurrence of fatty liver disease. Furthermore, G0S2 was found to be a novel target gene of activating transcription factor 4(ATF4). We also localized one conserved ATF4-binding sequence in the 5' regulatory region of G0S2, which was responsible for transcriptional activating G0S2 by ATF4. Conclusion: G0S2 is regulated by the PERK-eIF2 alpha-ATF4 branch of the UPR and mediates ER stress-induced hepatic steatosis. (C) 2019 Elsevier Inc. All rights reserved.
Hypoglycaemia is common in both type 1 and type 2 diabetes and has both acute and long-term consequences. Therefore, a key to proper glucose-lowering therapy in diabetes is to avoid or prevent hypoglycaemia. Incretin therapy (DPP-4 inhibitors and GLP-1 receptor agonists) offers an advantage in this respect, because it reduces glucose with a low risk of hypoglycaemia, both in monotherapy and in combination with other therapies. The reason for this low risk of hypoglycaemia is the glucose dependency of action of incretin therapy and the sustainment of glucose counter-regulatory hormone responses to hypoglycaemia, in particular the glucagon response. Incretin therapy is also associated with a low risk of hypoglycaemia in patient groups which are especially vulnerable and susceptible for hypoglycaemia, e.g., subjects with renal impairment, elderly subjects and subjects with on-going insulin therapy. This review summarizes how incretin therapy may meet the challenges of hypoglycaemia and suggests that incretin therapy is a therapy of choice to avoid hypoglycaemia, both in the general diabetes population and in subjects with increased risk or vulnerability for hypoglycaemia. (C) 2019 Elsevier Inc. All rights reserved.
Background: Psoriasis is a chronic inflammatory skin disease characterized by an abnormal T-cell-mediated immune response, and is associated with metabolic syndrome (MetS) and components thereof. However, few prospective studies have investigated the associations between MetS and its components, on the one hand, and the risk of psoriasis, on the other. Therefore, we investigated the association between the presence of MetS and its components and the prospective risk of psoriasis development. Methods: In total, 9,718,591 adults (2,595,878 in the MetS group and 7,122,713 in the comparison group) were evaluated using data from the Korean National Health Insurance Service (2009 to 2017). Results: MetS was positively associated with an increased risk of psoriasis over an 8-year follow-up period after adjusting for age, sex, smoking status, alcohol consumption, physical activity, household income, and body mass index (hazard ratio 1.05, 95% confidence interval 1.04-1.06). The risk of psoriasis tended to increase as the number of MetS components increased, and this trend was significant in obese subjects (P for trend <0.001). Conclusion: Psoriasis was significantly and positively associated with MetS and several components thereof; MetS severity and obesity affected these associations over 8 years of follow-up, suggesting that MetS is a risk factor for the development of psoriasis. (C) 2019 Elsevier Inc. All rights reserved.
Introduction: Metabolic and hormonal signals have been shown to be associated with brain activity in the context of ingestive behaviour. However, this has mostly been seen in studies using external administration of hormones or glucose. We therefore studied endocrine-brain interaction in a physiological setting with hormone levels determined by metabolic conditions such as normal food intake vs. prolonged fasting. Methods: 24 healthy, normal weight men participated in two sessions, one involving a 38-hour fasting period and one a non-fasting control condition with standardized meals. Functional magnetic resonance imaging was performed at the end of the experiment with participants being required to rate pictures of food. Brain activation was compared between conditions in predefined regions of interest (ROIs). Multiple blood samples were taken to determine levels of insulin, C-peptide, cortisol, ACTH, glucose and adiponectin. These were used as a predictor variable in a regression analysis on brain activations in the different ROIs. Results: Food pictures were rated as more desirable in the fasting condition. Univariate analysis of ROI activations revealedmainly effects of food rating and no significant effects of the metabolic state. Multiple regression analysis revealed associations between orbitofrontal cortex activation and blood glucose in the non-fasting condition. In the fasting condition adiponectin was associated with the signal from the caudate nucleus and insulin and C-peptide were associated with functional activity of orbitofrontal regions. Discussion: Associations of endocrine signals and functional neural regions could be demonstrated in a realistic setting without external administration of hormones. As the current approach was correlational, further studies need to address the causal role of hormonal signals. (C) 2019 Elsevier Inc. All rights reserved.
Background: Glucocorticoid (GC) excess increases lipolysis, circulating free fatty acid concentrations and lipid oxidation rates in humans. In vitro and animal studies have shown that GCs increase adipocyte ATGL and HSL mRNA contents and HSL phosphorylations, but the effects of GC on in vivo lipase signaling in humans are uncertain. Our study was designed to test how GC administration affects ATGL and HSL related signals in human adipose tissue. Material and methods: Nine healthy young men underwent 5 days administration of 37.5 mg prednisolone/d in a randomized, double-blinded, placebo-controlled crossover design. At the end of each 5 d period the subjects were studied after an overnight fast for 6.5 h including a basal period and a 21/2 h hyperinsulinemic euglycemic clamp. Adipose tissue biopsies were sampled from the abdominal subcutaneous adipose tissue at the end of the basal period and the clamp. Results: GC treatment increased serum FFA concentrations and comparative gene identification-58 (CGI-58) mRNA - an ATGL activator - and decreased G0/G1 switch 2 gene (G0S2) mRNA - an ATGL inhibitor - in adipose tissue biopsies. In addition, pro-lipolytic ser(563) HSL phosphorylations and protein kinase A (PKA) phosphorylation of PLIN1 (Perilipin-1) increased. The transcripts of ANGPTL4 (Angiopoietin-like 4) mRNA - a regulator of circulating triglycerides - were elevated by GC; as were CIDE (Cell-death Inducing DNA fragmentation factor-a-like Effector)-A and CIDE-C mRNA transcripts indicative of concurrent stimulation of lipolysis and lipogenesis. Finally GCs reduced insulin receptor phosphorylation, and Akt protein levels. Conclusions: High dose GC administration to humans leads to pro-lipolytic alterations of CGI-58, G0S2 and ANGPTL4 mRNA transcripts, increases PKA signaling to lipolysis and inhibits the insulin signal in adipose tissue. The increased CIDE-A and CIDE-C mRNA levels suggest concomitant stimulation of lipolysis and lipid storage. (C) 2019 Elsevier Inc. All rights reserved.