glucagon-like-peptide-1 and Fatty-Liver

The principle pathological drivers of metabolic dysfunction-associated steatohepatitis (MASH) are obesity and associated insulin resistance, rendering them key therapeutic targets. As glucagon-like peptide 1 receptor agonists (GLP-1RAs) have been licensed for the treatment of diabetes and obesity, they were one of the first drug types to be evaluated in patients with MASH, and successful phase IIa and IIb studies have resulted in progression to phase III clinical trials. Alongside GLP-1RAs, newer combinations with glucagon agonists and/or glucose-dependent insulinotropic peptide (GIP) agonists have been explored in related patient groups, with evidence of improvements in weight, insulin resistance and non-invasive liver parameters. Whether GLP-1RAs have direct, independent effects on MASH or whether they impact on pathophysiology through improvements in weight, insulin resistance and glycaemic control remains a matter of debate. Combinations are being explored, although the potential improvement in efficacy will need to be weighed against the cumulative side-effect burden, potential drug-drug interactions and costs. There is also uncertainty regarding the optimal ratio of glucagon and GIP agonism to GLP-1 agonism in combination agents, and as to whether GIP agonism or antagonism is the optimal approach. Finally, there are also multiple hypothetical permutations combining gut hormone agonists with other emerging assets in the field. Given that the likely dominant mode of action of gut hormone agonists is upstream on weight, initial combinations might focus on agents which have been shown to have a more direct effect on fibrosis, which would include FGF21 and pan-PPAR agonists.

Topics: Animals; Clinical Trials as Topic; Fatty Liver; Fibrosis; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Molecular Targeted Therapy

Tirzepatide (Mounjaro™) is a single molecule that combines dual agonism of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors. Native GIP and GLP-1 are incretin hormones that stimulate insulin secretion and decrease glucagon secretion. GIP also plays a role in nutrient and energy metabolism, while GLP-1 also delays gastric emptying, supresses appetite and improves satiety. Eli Lilly is developing tirzepatide for the treatment of type 2 diabetes mellitus (T2DM), obesity, cardiovascular disorders in T2DM, heart failure, non-alcoholic steatohepatitis, obstructive sleep apnoea and for reducing mortality/morbidity in obesity. In May 2022, tirzepatide received its first approval in the USA to improve glycaemic control in adults with T2DM, as an adjunct to diet and exercise. Tirzepatide is in phase III development for heart failure, obesity and cardiovascular disorders in T2DM, and in phase II development for non-alcoholic steatohepatitis. This article summarizes the milestones in the development of tirzepatide leading to this first approval for T2DM.

Topics: Adult; Diabetes Mellitus, Type 2; Fatty Liver; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart Failure; Humans; Obesity

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western societies and a major cause of hepatic disease worldwide. Its more severe type, namely nonalcoholic steatohepatitis (NASH), may result in the development of cirrhosis and hepatocellular carcinoma. NAFLD, and especially NASH, are also associated with increased cardiovascular morbidity and mortality. Type 2 diabetes mellitus (T2DM) predisposes to NAFLD development and progression via insulin resistance and hyperglycemia. It has also been reported that the majority of T2DM patients have NAFLD/NASH, thus potentially further increasing their cardiometabolic risk. Current guidelines recommend to screen for NAFLD in all T2DM patients and vice-versa. Lifestyle remains the first-line therapeutic option for NAFLD/NASH. Among antidiabetic drugs, pioglitazone was shown to improve histological features of NASH. More recently, there is an increasing interest regarding the effects of newer anti-diabetic drugs, such as dipeptidyl peptidase 4 inhibitors (DPP-4i), sodium glucose cotransporter 2 inhibitors (SGLT2i), and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on NAFLD/NASH. The present narrative review considers the up-to-date data on the impact of DPP-4i, SGLT2i, and GLP-1 RAs on biochemical and/or histological markers of NAFLD/NASH. The potential clinical implications of these findings in daily practice are also discussed. Taking into consideration the global increasing prevalence of NAFLD/NASH, therapeutic options that can prevent or treat this disease will exert considerable benefits on human health.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Fatty Liver; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Non-alcoholic Fatty Liver Disease; Pioglitazone; Sodium-Glucose Transporter 2 Inhibitors

Nonalcoholic fatty liver disease (NAFLD) is prevalent in patients with obesity or type 2 diabetes. Nonalcoholic steatohepatitis (NASH), encompassing steatosis with inflammation, hepatocyte injury, and fibrosis, predisposes to cirrhosis, hepatocellular carcinoma, and even cardiovascular disease. In rodent models and humans with NAFLD/NASH, maladaptation of mitochondrial oxidative flux is a central feature of simple steatosis to NASH transition. Induction of hepatic tricarboxylic acid cycle closely mirrors the severity of oxidative stress and inflammation in NASH. Reactive oxygen species generation and inflammation are driven by upregulated, but inefficient oxidative flux and accumulating lipotoxic intermediates. Successful therapies for NASH (weight loss alone or with incretin therapy, or pioglitazone) likely attenuate mitochondrial oxidative flux and halt hepatocellular injury. Agents targeting mitochondrial dysfunction may provide a novel treatment strategy for NAFLD.

Topics: Animals; Fatty Liver; Glucagon-Like Peptide 1; Humans; Mitochondria; Non-alcoholic Fatty Liver Disease; Obesity; Pioglitazone; Thiazolidinediones

Insulin resistance and the metabolic syndrome are associated with fasting and postprandial dyslipidemia. This involves the hepatic and intestinal overproduction of very low density lipoproteins (VLDL) and chylomicron particles, respectively, which give rise to atherogenic remnants upon lipolysis in the circulation. Recently, the insulin secretagogue glucagon-like peptide-1 (GLP-1) has received attention not only as an anti-diabetic therapy for regulating glycaemia, but also as a regulator of lipid and lipoprotein metabolism. In fact, agents that raise endogenous bioactive levels of GLP-1 (dipeptidyl peptidase 4 inhibitors) and agents that directly stimulate GLP-1 receptors (GLP-1 receptor agonists) have been assessed in both preclinical and clinical trials for their ability to modulate plasma lipid parameters. Here we describe current evidence supporting a role for GLP-1 in preventing elevated intestinal chylomicron output and postprandial hypertriglyceridemia--an independent predictor of cardiovascular risk. Furthermore, we examine a role for GLP-1 in regulating fasting hepatic VLDL production and hindering the development of a potentially devastating comorbidity, hepatic steatosis. Possible mechanisms of action of GLP-1 are discussed including a reduction in intestinal absorption of dietary lipid and enhanced hepatic fatty acid oxidation or autophagy. Finally, we discuss the current controversy over whether these effects could occur via direct receptor stimulation or alternative, indirect pathways. We conclude that GLP- 1-based therapies appear promising in the management of diabetic dyslipidemia, and further studies are warranted to elucidate their mechanisms of action in both the intestine and liver.

Topics: Animals; Cardiovascular Diseases; Chylomicrons; Dyslipidemias; Fasting; Fatty Liver; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Intestinal Mucosa; Lipid Metabolism; Lipoproteins; Liver; Postprandial Period; Risk Factors; Triglycerides

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum that ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) and to cirrhosis. The recommended treatment for this disease includes measures that target obesity and insulin resistance. The present review summarizes the role of newer anti-diabetic agents in treatment of NAFLD.. PubMed, MEDLINE and Ovid databases were searched to identify human studies between January 1990 and January 2013 using specified key words. Original studies that enrolled patients with a diagnosis of NAFLD or NASH and involved use of newer classes of anti-diabetic agents for a duration of at least 3 months were included.. Out of the screened articles, four met eligibility criteria and were included in our review. The classes of newer anti-diabetic medications described were dipeptidyl peptidase IV inhibitors and glucagon-like peptide-1 analogues.. Liraglutide and Exenatide showed improvement in transaminases as well as histology in patients with NASH. Sitagliptin showed improvement in transaminases but limited studies are there to access its effect on histology. Further studies are needed to support use of newer anti-diabetic medications in patients with NAFLD.

Topics: Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Fatty Liver; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Liraglutide; Liver; Non-alcoholic Fatty Liver Disease; Peptides; Pyrazines; Sitagliptin Phosphate; Transaminases; Treatment Outcome; Triazoles; Venoms

Non-alcoholic fatty liver disease has reached epidemic proportions in type 2 diabetes (T2D). Glucagon-like peptide-1 analogues are licensed in T2D, yet little data exist on efficacy and safety in liver injury.. To assess the safety and efficacy of 26-week liraglutide on liver parameters in comparison with active-placebo.. Individual patient data meta-analysis was performed using patient-level data combined from six 26-week, phase-III, randomised controlled T2D trials, which comprise the 'Liraglutide Effect and Action in Diabetes' (LEAD) program. The LEAD-2 sub-study was analysed to assess the effect on CT-measured hepatic steatosis.. Of 4442 patients analysed, 2241 (50.8%) patients had an abnormal ALT at baseline [mean ALT 33.8(14.9) IU/L in females; 47.3(18.3) IU/L in males]. Liraglutide 1.8 mg reduced ALT in these patients vs. placebo (-8.20 vs. -5.01 IU/L; P = 0.003), and was dose-dependent (no significant differences vs. placebo with liraglutide 0.6 or 1.2 mg). This effect was lost after adjusting for liraglutide's reduction in weight (mean ALT difference vs. placebo -1.41 IU/L, P = 0.21) and HbA1c (+0.57 IU/L, P = 0.63). Adverse effects with 1.8 mg liraglutide were similar between patients with and without baseline abnormal ALT. In LEAD-2 sub-study, liraglutide 1.8 mg showed a trend towards improving hepatic steatosis vs. placebo (liver-to-spleen attenuation ratio +0.10 vs. 0.00; P = 0.07). This difference was reduced when correcting for changes in weight (+0.06, P = 0.25) and HbA(1c) (0.00, P = 0.93).. Twenty-six weeks' liraglutide 1.8 mg is safe, well tolerated and improves liver enzymes in patients with type 2 diabetes. This effect appears to be mediated by its action on weight loss and glycaemic control.

Topics: Alanine Transaminase; Blood Glucose; Diabetes Mellitus, Type 2; Fatty Liver; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Liraglutide; Liver; Liver Function Tests; Male; Non-alcoholic Fatty Liver Disease; Randomized Controlled Trials as Topic; Treatment Outcome; Weight Loss

Central nervous system (CNS) receives peripheral relevant information that are able to regulate individual's energy balance through metabolic, neural, and endocrine signals. Ingested nutrients come into contact with multiple sites in the gastrointestinal tract that have the potential to alter peptide and neural signaling. There is a strong relationship between CNS and those peripheral signals (as gastrointestinal hormones) in the control of food intake. The purpose of this review is to give updated information about the role of gut hormones as mediators of feeding behavior and of different nutrients in modulating gut hormones production. The role of gut hormones in the pathogenesis of emerging diseases as obesity and non-alcoholic fatty liver disease (NAFLD) is also discussed together with the possible role of these peripheral signals as targets of future therapeutic options.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Brain Stem; Cholecystokinin; Eating; Energy Intake; Energy Metabolism; Fatty Liver; Feeding Behavior; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Humans; Hunger; Hyperphagia; Non-alcoholic Fatty Liver Disease; Obesity; Peptide YY; Satiation

Nonalcoholic steatohepatitis (NASH) is a stage of nonalcoholic fatty liver disease (NAFLD), and in most patients, is associated with obesity and the metabolic syndrome. The current best treatment of NAFLD and NASH is weight reduction with the current options being life style modifications, with or without pharmaceuticals, and bariatric surgery. Bariatric surgery is an effective treatment option for individuals who are severely obese (body mass index ≥ 35 kg/m(2)), and provides for long-term weight loss and resolution of obesity-associated diseases in most patients. Regression and/or histologic improvement of NASH have been documented after bariatric surgery. We review the available literature reporting on the impact of the various bariatric surgery techniques on NASH.

Topics: Bariatric Surgery; Fatty Liver; Ghrelin; Glucagon-Like Peptide 1; Humans; Non-alcoholic Fatty Liver Disease; Obesity; Peptide YY; Weight Loss

Regulatory role of the brain in energy expenditure, appetite, glucose metabolism, and central effects of insulin has been prominently studied. Certain neurons in the hypothalamus increase or decrease appetite via orexigenes and anorexigenes, regulating energy balance and food intake. Hypothalamus is the site of afferent and efferent stimuli between special nuclei and beta- and alpha cells, and it regulates induction/inhibition of glucose output from the liver. Incretines, produced in intestine and in certain brain cells (brain-gut hormones), link to special receptors in the hypothalamus. Central role of insulin has been proved both in animals and in humans. Insulin gets across the blood-brain barrier, links to special hypothalamic receptors, regulating peripheral glucose metabolism. Central glucose sensing, via "glucose-excited" and "glucose-inhibited" cells have outstanding role. Former are active in hyperglycaemia, latter in hypoglycaemia, via influencing beta- and alpha cells, independently of traditional metabolic pathways. Evidence of brain insulin resistance needs centrally acting drugs, paradigm changes in therapy and prevention of metabolic syndrome, diabetes, cardiovascular and oncological diseases.

Topics: Animals; Appetite Depressants; Appetite Regulation; Blood Glucose; Brain; Ceramides; Cognition; Diabetes Mellitus, Type 2; Energy Metabolism; Fatty Liver; Glucagon-Like Peptide 1; Humans; Hypothalamus; Incretins; Insulin; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Metabolic Syndrome; Neuropeptides; Non-alcoholic Fatty Liver Disease; Oligopeptides; Orexins; Pyrrolidonecarboxylic Acid

As a signaling molecule with system endocrine function, UDCA improves insulin sensitivity by activating the nuclear farnezoid X-receptor; as a ligand for the TGR5/Gpbar-1 receptor, UDCA is able to stimulate the secretion of GLP-1. UDCA ameliorate of the anti-oxidative defenses in NAFLD, normalizes NAD+/NADH ratio, beta-oxidation. UDCA improves the liver biochemical and histological picture in NASH, also reduces hepatocytes apoptosis and restores adiponectin levels; in other studies, these data are not confirmed. In the experiment, UDCA prevents the development of steatosis in the liver. UDCA may increase efficiency in combination with statins, thiazolidinediones, vitamin E. Further controlled prospective trials are needed for research of the UDCA effect in NAFLD.

Topics: Cholagogues and Choleretics; Fatty Liver; Glucagon-Like Peptide 1; Humans; Non-alcoholic Fatty Liver Disease; Receptors, G-Protein-Coupled; Ursodeoxycholic Acid

Nonalcoholic fatty liver disease (NAFLD), first described in 1980, is now recognized as one of the most common causes of elevated liver enzymes and chronic liver disease in Western countries. The incidence of NAFLD in both adults and children is rising, in conjunction with the burgeoning epidemics of obesity and type 2 diabetes mellitus. NAFLD often coexists with other sequelae of the metabolic syndrome: central obesity, type 2 diabetes, hypertension, and hyperlipidemia. NAFLD encompasses a spectrum of pathologic liver diseases ranging from simple hepatic steatosis to a predominant lobular necro-inflammation, with or without centrilobular fibrosis (called nonalcoholic steatohepatitis or NASH). NASH can progress to cirrhosis, decompensated liver disease, and hepatocellular carcinoma. Though the natural history of NASH is still not clearly defined, it has been observed to progress to cirrhosis in 15%-220% of those affected. Insulin resistance is nearly universal in NASH and is thought to play an important role in its pathogenesis leading to dysregulated lipid metabolism. The prevalence of insulin resistance is reported in the general population to be approaching 45%, suggesting that NAFLD and NASH will contin nue to be an important public health concern. To date, NASH has proven to be a difficult disease to treat. Front-line therapy with lifestyle modifications resulting in weight loss through decreased caloric intake and moderate exercise is generally believed to be beneficial in patients with NASH, but is often difficult to maintain long term. Given that insulin resistance plays a dominant role in the pathogenesis, many studies have examined the use of insulin sensitizers: the biguanides (metformin), thiazolidinediones (pioglitazone, troglitazone, and rosiglitazone), glucagon-like peptide-1-receptor agonists, or incretins (exenatide)in NASH. This review will provide an overview of insulin resistance in NAFLD and provide a detailed summary on the clinical data regarding the use of insulin sensitizers in NASH.

Topics: Fatty Liver; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemic Agents; Insulin Resistance; Metformin; Prevalence; Thiazolidinediones; Triglycerides

The most frequent liver disorder in metabolic syndrome is the nonalcoholic fatty liver disease. Its pathogenesis is a complex, multifactorial process, characterized by insulin resistance and involvement of the endocrine system. Hypothyroidism may lead to nonalcoholic steatohepatitis via hyperlipidemia and obesity. Adult patients with growth hormone deficiency have a metabolic syndrome-like phenotype with obesity and many characteristic metabolic alterations. The chronic activation of the hypothalamic-pituitary-adrenal axis results in metabolic syndrome as well. Cushing's syndrome has also features of metabolic syndrome. Mild elevation of transaminase activities is commonly seen in patients with adrenal failure. Non-alcoholic steatosis is twice as common in postmenopusal as in premenopausal women and hormonal replacement therapy decreases the risk of steatosis. Insulin resistance, diabetes mellitus type 2, sleeping apnoe syndrome, cardiovascular disorders and non-alcoholic fatty liver disease are more frequent in polycystic ovary syndrome. Hypoandrogenism in males and hyperandrogenism in females may lead to fatty liver via obesity and insulin resistance. Adipokines (leptin, acylation stimulating protein, adiponectin) have a potential role in the pathogenesis of nonalcoholic fatty liver. The alterations of endocrine system must be considered in the background of cryptogenic liver diseases. The endocrine perspective may help the therapeutic approaches in the future.

Topics: Adipokines; Adrenal Glands; Adult; Androgens; Cushing Syndrome; Diabetes Mellitus, Type 2; Endocrine System; Estrogens; Fatty Liver; Female; Glucagon-Like Peptide 1; Gonadal Steroid Hormones; Humans; Hyperlipidemias; Hypothalamus; Hypothyroidism; Insulin; Insulin Resistance; Male; Metabolic Syndrome; Obesity; Pancreas; Pituitary Gland; Polycystic Ovary Syndrome; Postmenopause; Thyroid Gland

The prevalence of obesity and the metabolic syndrome (MS) is on the rise, and subsequently the hepatic manifestation of MS, nonalcoholic fatty liver disease (NAFLD), has become a common entity in clinical practice. Most patients with NAFLD face medical complications related to their underlying MS in other organ systems; however, a small but significant group of patients with the more aggressive form of fatty liver, nonalcoholic steatohepatitis (NASH), are at risk of developing cirrhosis and hepatocellular carcinoma. As patients are generally asymptomatic, often their disease goes unrecognized. This is particularly true for NASH, where liver biopsy is currently required to make the diagnosis. Once diagnosed, no one treatment has been shown to be universally efficacious and those that are of benefit are not without side effects. Effective treatment regimens directed at both decreasing insulin resistance as well as the processes leading to necroinflammation and hepatic fibrosis have been investigated and include lifestyle modification, surgical therapies, and pharmacotherapy. This review focuses on current and potential future therapies for NASH.

Topics: Animals; Antioxidants; Bariatric Surgery; Body Mass Index; Cannabinoids; Cholagogues and Choleretics; Comorbidity; Fatty Liver; Glucagon-Like Peptide 1; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Insulin Resistance; Lactones; Life Style; Metformin; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Thiazolidinediones; Treatment Outcome; Ursodeoxycholic Acid; Weight Loss

Gut microbiota modifiers may have beneficial effects of non-alcoholic fatty liver disease (NAFLD) but randomised controlled trials (RCT) are lacking in children.. To perform a double-blind RCT of VSL#3 vs. placebo in obese children with biopsy-proven NAFLD.. Of 48 randomised children, 44 (22 VSL#3 and 22 placebo) completed the study. The main outcome was the change in fatty liver severity at 4 months as detected by ultrasonography. Secondary outcomes were the changes in triglycerides, insulin resistance as detected by the homoeostasis model assessment (HOMA), alanine transaminase (ALT), body mass index (BMI), glucagon-like peptide 1 (GLP-1) and activated GLP-1 (aGLP-1). Ordinal and linear models with cluster confidence intervals were used to evaluate the efficacy of VSL#3 vs. placebo at 4 months.. At baseline, moderate and severe NAFLD were present in 64% and 36% of PLA children and in 55% and 45% of VSL#3 children. The probability that children supplemented with VSL#3 had none, light, moderate or severe FL at the end of the study was 21%, 70%, 9% and 0% respectively with corresponding values of 0%, 7%, 76% and 17% for the placebo group (P < 0.001). No between-group differences were detected in triglycerides, HOMA and ALT while BMI decreased and GLP-1 and aGLP1 increased in the VSL#3 group (P < 0.001 for all comparisons).. A 4-month supplement of VSL#3 significantly improves NAFLD in children. The VSL#3-dependent GLP-1 increase could be responsible for these beneficial effects. Trial identifier: NCT01650025 (www.clinicaltrial.gov).

Topics: Alanine Transaminase; Biopsy; Body Mass Index; Child; Dietary Supplements; Double-Blind Method; Fatty Liver; Female; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Male; Non-alcoholic Fatty Liver Disease; Obesity; Probiotics; Severity of Illness Index; Treatment Outcome; Ultrasonography

To evaluate the effects of six-month liraglutide treatment on body weight, visceral and subcutaneous fat and related markers in Japanese type 2 diabetic patients.. A total of 59 patients with type 2 diabetes were treated with liraglutide (0.3 mg/day for ≥1 week and then 0.6 mg/day for ≥1 week, gradually increasing the dose to 0.9 mg/day) for six months. Changes in body weight, body mass index (BMI), HbA1c, the fasting blood glucose level, visceral and subcutaneous fat areas, hepatic and renal CT values and the associated markers proinsulin, adiponectin and pentraxin (PTX) 3 were measured.. The study included one treatment-naïve patient, 10 patients who were switched from oral antidiabetic drugs and 35 patients who were switched from insulin therapy. At six months after treatment, the preprandial blood glucose levels were higher (148.8±40.5 mg/dL) than the baseline values (130.8±36.7, p<0.05); however, body weight, BMI and abdominal circumference were lower, and the liver/kidney CT ratio improved significantly from 1.64±0.44 at baseline to 1.78±0.42. An analysis of the patients who were not pretreated with insulin resistance ameliorators showed that six months of liraglutide treatment significantly decreased the subcutaneous but not visceral fat areas, significantly decreased the serum adiponectin levels and significantly increased the serum PTX3 levels.. In addition to its glucose-lowering effects, liraglutide exhibits weight loss promotion actions, reducing subcutaneous fat areas in particular. The weight and total fat area reduction properties of liraglutide are likely to be beneficial when this medication is used in combination with other oral antidiabetic drugs and insulin.

Topics: Adiponectin; Adiposity; Aged; Anthropometry; Asian People; Blood Glucose; Body Mass Index; Body Weight; C-Reactive Protein; Diabetes Mellitus, Type 2; Fasting; Fatty Liver; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Intra-Abdominal Fat; Japan; Kidney; Liraglutide; Liver; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Proinsulin; Serum Amyloid P-Component; Subcutaneous Fat; Tomography, X-Ray Computed

Sensitization to the adipokine leptin is a promising therapeutic strategy against obesity and its comorbidities and has been proposed to contribute to the lasting metabolic benefits of Roux-en-Y gastric bypass (RYGB) surgery. We formally tested this idea using Zucker fatty

Topics: Animals; Blood Glucose; Disease Models, Animal; Energy Metabolism; Fatty Liver; Gastric Bypass; Glucagon-Like Peptide 1; Glucose Tolerance Test; Homeostasis; Insulin; Obesity; Postoperative Period; Rats; Rats, Wistar; Rats, Zucker; Receptors, Leptin; Weight Loss

Topics: Animals; Diabetes Mellitus, Experimental; Fatty Liver; Glucagon-Like Peptide 1; Glucose; Hypoglycemic Agents; Insulin Secretion; Lipid Metabolism; Male; Mice, Inbred ICR; Mice, Obese; Molecular Docking Simulation; Peroxisome Proliferator-Activated Receptors; Receptors, G-Protein-Coupled

In liver transplantation (LT), organ shortage has led to the use of steatotic and non-steatotic grafts from donors after cardiocirculatory death (DCD). However, these grafts, especially those with steatosis, exhibit poor post-operative outcomes. To address this problem, we investigated the roles of gut-derived glucagon-like peptide 1 (GLP1) and dipeptidyl peptidase 4 (DPP4), the serine protease that cleaves it, in steatotic and non-steatotic LT from DCDs. Using Zucker rats, liver grafts from DCDs were cold stored and transplanted to recipients. GLP1 was administered to donors. The levels of GLP1 in intestine and of both GLP1 and DDP4 in circulation were unaltered following cardiocirculatory death (CD). In steatotic livers from DCD, increased GLP1 and decreased DPP4 were recorded, and administration of GLP1 caused a rise in hepatic GLP1 and a reduction in DDP4. This protected against inflammation, damage, and proliferation failure. Conversely, low GLP1 and high DDP4 were observed in non-steatotic livers from DCD. The exogenous GLP1 did not modify hepatic DDP4, and the accumulated GLP1 exerted harmful effects, increasing damage, inflammation, and regeneration failure. Herein, we show that there are differences in GLP1/DDP4 regulation depending on the type of liver implanted, suggesting that GLP1 can be used as a novel and effective therapy in steatotic grafts from DCDs but that it is not appropriate for non-steatotic DCDs.

Topics: Animals; Blotting, Western; Dipeptidyl Peptidase 4; Fatty Liver; Glucagon-Like Peptide 1; Immunohistochemistry; Lipid Peroxidation; Liver; Liver Transplantation; Male; Oxidative Stress; Peroxidase; Rats; Rats, Zucker

Non-alcoholic steatohepatitis (NASH) is a prevalent disease that is highly associated with the metabolic syndrome and type II diabetes. The development of in vivo models that reflect all nuances of the human NASH pathology is essential for drug discovery and development. We aimed to further characterise a dietary induced model of NASH both biochemically and histologically. In addition, we also investigated whether pioglitazone and liraglutide, drugs that have both been investigated as potential NASH treatments, could modulate the pathological changes induced by the NASH diet. Furthermore, to aid the translation of data from pre-clinical in vivo models, we aimed to adapt the NASH Clinical Research Network (CRN) histological score system for use in rodent studies.. Sprague Dawley rats were fed a high-fat diet (HFD) for 9 weeks, after which they were switched to a high fat, high cholesterol and cholate diet (HFCC) for 12 weeks. The rats were divided into treatment groups, receiving either 30 mg/kg pioglitazone p.o. SID or liraglutide s.c. 200 μg/kg BID or the respective vehicles. Serum levels of triglycerides (TG), cholesterol (Chol), LDL, HDL, AST and ALT, as well as body weight were assessed in all subjects. Upon termination, the liver was weighed and evaluated histologically using modified NASH-CRN criteria.. HFCC feeding induced severe hepatic injury and hepatomegaly as indicated by significant increases in AST, ALT and an increased liver weight. Additionally, HFCC feeding induced dyslipidaemia, significant increases in circulating cholesterol and LDL were observed. No obesogenic effect of the HFCC diet was observed, though the diet did induce insulin resistance. Histological analysis showed that the HFCC diet induced several NASH like features, though it did not induce the development of severe fibrosis. However, microgranulomas were often prevalent in addition to lobular inflammatory foci. Pioglitazone showed little efficacy upon both biochemical and histological features. However, liraglutide induced weight loss, improved glycaemic control, reduced ALT and AST and showed some beneficial effects upon steatosis and lobular inflammation.. Similar to previous reports we have shown that the atherogenic diet, HFCC, induces a phenotype akin to that seen in human NASH patients. Despite inducing all histological features of NASH, HFCC feeding does not promote the development of significant fibrosis within rodents. Pioglitazone and liraglutide have been investigated as potential NASH treatments. Within this model of NASH we have shown that pioglitazone has little efficacy, whereas liraglutide reduced the levels of circulating aminotransferases and had some beneficial effects upon NASH histological parameters.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Blood Glucose; Cholesterol; Diet, High-Fat; Disease Models, Animal; Fatty Liver; Glucagon-Like Peptide 1; Inflammation; Liraglutide; Liver; Male; Non-alcoholic Fatty Liver Disease; Pioglitazone; PPAR gamma; Rats; Rats, Sprague-Dawley; Rodentia; Triglycerides

The decrease in incretin effects is an important etiologic component of type 2 diabetes with unknown mechanisms. In an attempt to understand obesity-induced changes in liver oxygen homeostasis, we found that liver HIF-1α expression was increased mainly by soluble factors released from obese adipocytes, leading to decreased incretin effects. Deletion of hepatocyte HIF-1α protected obesity-induced glucose intolerance without changes in body weight, liver steatosis, or insulin resistance. In-depth mouse metabolic phenotyping revealed that obesity increased first-pass degradation of an incretin hormone GLP-1 with increased liver DPP4 expression and decreased sinusoidal blood flow rate, reducing active GLP-1 levels in peripheral circulation. Hepatocyte HIF-1α KO blocked these changes induced by obesity. Deletion of hepatocyte HIF-2α did not change liver DPP4 expression but improved hepatic steatosis. Our results identify a previously unknown pathway for obesity-induced impaired beta cell glucose response (incretin effects) and the development of glucose intolerance through inter-organ communications.

Topics: Adipose Tissue; Animals; Basic Helix-Loop-Helix Transcription Factors; Diet, High-Fat; Dipeptidyl Peptidase 4; Fatty Liver; Glucagon-Like Peptide 1; Glucose; Hepatitis; Hepatocytes; Insulin Resistance; Liver; Male; Mice, Knockout; Obesity

Activation of endoplasmic reticulum (ER) stress is involved in the development of nonalcoholic fatty liver disease. Glucagon-like peptide-1 (GLP-1) has been reported to reduce hepatic steatosis, but the underlying mechanism has not been fully elucidated. Here, we investigated whether exendin-4 (EX-4), a GLP-1 receptor analogue, improves hepatic steatosis through ER stress reduction. Furthermore, we explored which ER stress pathway is involved in this process, with a focus on the protein kinase RNA-like ER kinase (PERK)-nuclear factor erythroid-derived 2-related factor 2 (Nrf2) pathway. EX-4 treatment reduced hepatic lipid accumulation by suppressing the expression of lipogenic genes and restoring the expression of β-oxidation genes in palmitate-treated HepG2 cells and high fat diet (HFD)-fed mice. In addition, EX-4 treatment suppressed hepatic ER stress activation in HFD-fed mice and tunicamycin-treated mice. In particular, EX-4 treatment restored HFD- and tunicamycin-induced Nrf2 nuclear translocation to control levels. Inhibition of Nrf2 by siRNA enhanced phosphorylation of PERK and eukaryotic translation initiation factor 2α (eIF2α), as well as other substrates of the PERK pathway. Nrf2 knockdown also inhibited the protective effects of EX-4 against lipid accumulation, ER stress activation, and cell death in palmitate-treated HepG2 cells. EX-4 treatment prevents hepatic steatosis and improves cell survival by regulating hepatic lipid metabolism and reducing ER stress activation, and Nrf2 plays an essential role in the protective effect of GLP-1 on hepatic steatosis.

Topics: Animals; Cell Death; Cell Line; Cell Line, Tumor; Cell Survival; Endoplasmic Reticulum Stress; Exenatide; Fatty Liver; Glucagon-Like Peptide 1; Hep G2 Cells; Humans; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2

Obesity is a major health threat that affects men and women equally. Despite this fact, weight-loss potential of pharmacotherapies is typically first evaluated in male mouse models of diet-induced obesity (DIO). To address this disparity we herein determined whether a monomeric peptide with agonism at the receptors for glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon is equally efficient in correcting DIO, dyslipidemia, and glucose metabolism in DIO female mice as it has been previously established for DIO male mice.. Female C57BL/6J mice and a cohort of fatmass-matched C57BL/6J male mice were treated for 27 days via subcutaneous injections with either the GLP-1/GIP/glucagon triagonist or PBS. A second cohort of C57BL/6J male mice was included to match the females in the duration of the high-fat, high-sugar diet (HFD) exposure.. Our results show that GLP-1/GIP/glucagon triple agonism inhibits food intake and decreases body weight and body fat mass with comparable potency in male and female mice that have been matched for body fat mass. Treatment improved dyslipidemia in both sexes and reversed diet-induced steatohepatitis to a larger extent in female mice compared to male mice.. We herein show that a recently developed unimolecular peptide triagonist is equally efficient in both sexes, suggesting that this polypharmaceutical strategy might be a relevant alternative to bariatric surgery for the treatment of obesity and related metabolic disorders.

Topics: Adiposity; Animals; Diet, High-Fat; Dyslipidemias; Eating; Fatty Liver; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Male; Mice; Mice, Inbred C57BL; Obesity; Sex Factors

Nonalcoholic fatty liver is characterized by the abnormal accumulation of triglycerides within hepatocytes, resulting in a steatotic liver. Glucagon-like peptide 1 and its analog exendin-4 can ameliorate certain aspects of this syndrome by inducing weight loss and reducing hepatic triglyceride accumulation, but it is unclear whether these effects result from the effects of glucagon-like peptide 1 on the pancreas, or from direct action on the liver. This study investigated the direct action and putative cellular mechanism of exendin-4 on steatotic hepatocytes in culture. Steatosis was induced in cultured HepG2 human hepatoma cells by incubation in media supplemented with 2 mM each of linoleic acid and oleic acid. Steatotic hepatocytes were then pre-incubated in the protein kinase A inhibitor H89 for 30 min, then treated with exendin-4 over a period of 24 h. Cell viability and triglyceride content were characterized by a TUNEL assay and AdipoRed staining, respectively. Our results showed that steatotic cells maintained high levels of intracellular triglycerides (80%) compared to lean controls (25%). Exendin-4 treatment caused a significant reduction in intracellular triglyceride content after 12 h that persisted through 24 h, while protein kinase A inhibitors abolished the effects of exendin-4. The results demonstrate the exendin-4 induces a partial reduction in triglycerides in steatotic hepatocytes within 12 h via the GLP-1 receptor-mediated activation of protein kinase A. Thus, the reduction in hepatocyte triglyceride accumulation is likely driven primarily by downregulation of lipogenesis and upregulation of β-oxidation of free fatty acids.

Topics: Carcinoma, Hepatocellular; Cell Survival; Cyclic AMP-Dependent Protein Kinases; Exenatide; Fatty Liver; Glucagon-Like Peptide 1; Hep G2 Cells; Hepatocytes; Humans; Isoquinolines; Linoleic Acid; Lipogenesis; Liver Neoplasms; Oleic Acid; Pancreas; Peptides; Sulfonamides; Triglycerides; Venoms

Thyroid hormones (THs) as a therapeutic intervention to treat obesity has been tried but the effect of THs on body weight and the mechanistic details of which are far from clear. This study was designed to determine and elucidate the mechanistic details of metabolic action of THs in high-fat diet (HFD) fed Sprague Dawley (SD) rats. Rats were made surgically hypothyroid (thyroidectomy, Thx). Body weights and food and water intake profoundly decreased in HFD fed thyroidectomized group (HN Thx). Results showed that delayed insulin response, increased total cholesterol, high-density lipoprotein, and low-density lipoprotein in HN Thx. Unexpectedly, however, Thx reduced serum and hepatic triglyceride concentrations. Further studies revealed that Thx dramatically increased circulating GLP-1 as well as increased expressions of GLP-1 in small intestine. Diminished hepatic expressions of lipogenic genes, were observed in HN Thx group. Beta-catenin and glutamine synthetase, a known target of β-catenin, were up-regulated in the liver of HN Thx group. The expressions of gluconeogenic genes G6P and PCK were reduced in the liver of HN Thx group. The results may suggest that surgery-induced hypothyroidism increases GLP-1, the actions of which may in part be responsible for the reduction in water intake, appetite and hepatic steatosis.

Topics: Animals; Appetite Regulation; Diet, High-Fat; Dietary Fats; Eating; Fatty Liver; Glucagon-Like Peptide 1; Male; Rats; Rats, Sprague-Dawley; Thyroid Hormones; Thyroidectomy; Treatment Outcome

Perturbations in hepatic lipid and very-low-density lipoprotein (VLDL) metabolism are involved in the pathogenesis of obesity and hepatic insulin resistance. The objective of this study is to delineate the mechanism of subdiaphragmatic vagotomy in preventing obesity, hyperlipidemia, and insulin resistance.. By subjecting the complete subdiaphragmatic vagotomized mice to various nutritional conditions and investigating hepatic de novo lipogenesis pathway, we found that complete disruption of subdiaphragmatic vagal signaling resulted in a significant decrease of circulating VLDL-triglyceride compared with the mice obtained sham procedure. Vagotomy further prevented overproduction of VLDL-triglyceride induced by an acute fat load and a high-fat diet-induced obesity, hyperlipidemia, hepatic steatosis, and glucose intolerance. Mechanistic studies revealed that plasma glucagon-like peptide-1 was significantly raised in the vagotomized mice, which was associated with significant reductions in mRNA and protein expression of SREBP-1c (sterol regulatory element-binding protein 1c), SCD-1 (stearoyl-CoA desaturase-1), and FASN (fatty acid synthase), as well as enhanced hepatic insulin sensitivity. In vitro, treating mouse primary hepatocytes with a glucagon-like peptide-1 receptor agonist, exendin-4, for 48 hours inhibited free fatty acid, palmitic acid treatment induced de novo lipid synthesis, and VLDL secretion from hepatocytes.. Elevation of glucagon-like peptide-1 in vagotomized mice may prevent VLDL overproduction and insulin resistance induced by high-fat diet. These novel findings, for the first time, delineate an intrinsic gut-liver regulatory circuit that is mediated by glucagon-like peptide-1 in regulating hepatic energy metabolism.

Topics: Animals; Biomarkers; Blood Glucose; Cells, Cultured; Diet, High-Fat; Disease Models, Animal; Exenatide; Fatty Acid Synthase, Type I; Fatty Liver; Gene Expression Regulation; Glucagon-Like Peptide 1; Hepatocytes; Hyperlipidemias; Incretins; Insulin; Insulin Resistance; Intestinal Mucosa; Intestines; Lipoproteins, VLDL; Liver; Male; Mice, Inbred C57BL; Obesity; Peptides; RNA, Messenger; Signal Transduction; Stearoyl-CoA Desaturase; Sterol Regulatory Element Binding Protein 1; Time Factors; Triglycerides; Up-Regulation; Vagotomy; Vagus Nerve; Venoms

We have previously constructed an engineered anti-diabetic fusion protein using glucagon-like peptide-1 and the globular domain of adiponectin. Herein, we evaluated the therapeutic effects of this fusion protein (GAD) on high-fat diet (HFD)-fed ApoE(-/-) mice. The lipid-lowering effect of GAD was determined in C57BL/6 mice using a lipid tolerance test. The effects of GAD on HFD-induced glucose intolerance, atherosclerosis, and hepatic steatosis were evaluated in HFD-fed ApoE(-/-) mice using glucose tolerance test, histological examinations and real-time quantitative PCR. The anti-inflammation activity of GAD was assessed in vitro on macrophages. GAD improved lipid metabolism in C57BL/6 mice. GAD treatment alleviated glucose intolerance, reduced blood lipid level, and attenuated atherosclerotic lesion in HFD-fed ApoE(-/-) mice, which was associated with a repressed macrophage infiltration in the vessel wall. GAD treatment also blocked hepatic macrophage infiltration and prevented hepatic inflammation. GAD suppressed lipopolysaccharide-triggered inflammation responses on macrophages, which can be abolished by H89, an inhibitor of protein kinase A. These findings demonstrate that GAD is able to generate a variety of metabolic benefits in HFD-fed ApoE(-/-) mice and indicate that this engineered fusion protein is a promising lead structure for anti-atherosclerosis drug discovery.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Diet, High-Fat; Fatty Liver; Glucagon-Like Peptide 1; Glucose Intolerance; Lipids; Liver; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout

The release of Ca(2+) from the endoplasmic reticulum (ER) and subsequent replenishment of ER Ca(2+) by Ca(2+) entry through store-operated Ca(2+) channels (SOCE) play critical roles in the regulation of liver metabolism by adrenaline, glucagon and other hormones. Both ER Ca(2+) release and Ca(2+) entry are severely inhibited in steatotic hepatocytes. Exendin-4, a slowly-metabolised glucagon-like peptide-1 (GLP-1) analogue, is known to reduce liver glucose output and liver lipid, but the mechanisms involved are not well understood. The aim of this study was to determine whether exendin-4 alters intracellular Ca(2+) homeostasis in steatotic hepatocytes, and to evaluate the mechanisms involved. Exendin-4 completely reversed lipid-induced inhibition of SOCE in steatotic liver cells, but did not reverse lipid-induced inhibition of ER Ca(2+) release. The action of exendin-4 on Ca(2+) entry was rapid in onset and was mimicked by GLP-1 or dibutyryl cyclic AMP. In steatotic liver cells, exendin-4 caused a rapid decrease in lipid (half time 6.5min), inhibited the accumulation of lipid in liver cells incubated in the presence of palmitate plus the SOCE inhibitor BTP-2, and enhanced the formation of cyclic AMP. Hormone-stimulated accumulation of extracellular glucose in glycogen replete steatotic liver cells was inhibited compared to that in non-steatotic cells, and this effect of lipid was reversed by exendin-4. It is concluded that, in steatotic hepatocytes, exendin-4 reverses the lipid-induced inhibition of SOCE leading to restoration of hormone-regulated cytoplasmic Ca(2+) signalling. The mechanism may involve GLP-1 receptors, cyclic AMP, lipolysis, decreased diacylglycerol and decreased activity of protein kinase C.

Topics: Animals; Bucladesine; Calcium; Calcium Signaling; Cyclic AMP; Exenatide; Fatty Liver; Glucagon-Like Peptide 1; Hepatocytes; Hormones; Intracellular Space; Palmitic Acid; Peptides; Rats, Zucker; Venoms

Bariatric surgery not only elicits weight loss but also rapidly resolves diabetes. However, the mechanisms remain unclear. The present study investigates how diabetes and liver steatosis are improved after duodenal-jejunal bypass (DJB) compared with a glucagon-like peptide-1 (GLP-1) analog and correlations between bile acids and GLP-1 secretion.. We initially determined the effects of bile acids on GLP-1 in vitro and then assigned 12 male 16-week-old Otsuka Long-Evans Tokushima Fatty rats to groups that underwent DJB, a sham operation, or were treated with the GLP-1 receptor agonist, liraglutide (n = 4 each). Blood glucose, insulin, GLP-1, serum bile acids, liver steatosis, and the number of GLP-1 positive cells (L cells) in the small intestine and colon were investigated in the three groups at eight weeks postoperatively.. Levels of GLP-1mRNA were upregulated and GLP-1 secretion increased in cells incubated with bile acids in vitro. Weight gain was suppressed more in the DJB than in the sham group in vivo. Diabetes was more improved and GLP-1 levels were significantly higher in the DJB than in the sham group. Serum bile acids were significantly increased, the number of L cells in the ileum was upregulated compared with the sham group, and liver steatosis was significantly improved in the DJB compared with the other two groups.. Duodenal-jejunal bypass might improve diabetes and liver steatosis by enhancing GLP-1 secretion through increasing serum bile acids and the proliferation of L cells in the ileum, compared with liraglutide.

Topics: Animals; Bariatric Surgery; Bile Acids and Salts; Cell Proliferation; Cells, Cultured; Diabetes Mellitus; Enteroendocrine Cells; Fatty Liver; Glucagon-Like Peptide 1; Ileum; Male; Mice; Rats, Long-Evans; RNA, Messenger; Up-Regulation

Cardiovascular complications of obesity and diabetes are major health problems. Assessing their development, their link with ectopic fat deposition and their flexibility with therapeutic intervention is essential. The aim of this study was to longitudinally investigate cardiac alterations and ectopic fat accumulation associated with diet-induced obesity using multimodal cardiovascular magnetic resonance (CMR) in mice. The second objective was to monitor cardiac response to exendin-4 (GLP-1 receptor agonist).. Male C57BL6R mice subjected to a high fat (35 %) high sucrose (34 %) (HFHSD) or a standard diet (SD) during 4 months were explored every month with multimodal CMR to determine hepatic and myocardial triglyceride content (HTGC, MTGC) using proton MR spectroscopy, cardiac function with cine cardiac MR (CMR) and myocardial perfusion with arterial spin labeling CMR. Furthermore, mice treated with exendin-4 (30 μg/kg SC BID) after 4 months of diet were explored before and 14 days post-treatment with multimodal CMR.. HFHSD mice became significantly heavier (+33 %) and displayed glucose homeostasis impairment (1-month) as compared to SD mice, and developed early increase in HTGC (1 month, +59 %) and MTGC (2-month, +63 %). After 3 months, HFHSD mice developed cardiac dysfunction with significantly higher diastolic septum wall thickness (sWtnD) (1.28 ± 0.03 mm vs. 1.12 ± 0.03 mm) and lower cardiac index (0.45 ± 0.06 mL/min/g vs. 0.68 ± 0.07 mL/min/g, p = 0.02) compared to SD mice. A significantly lower cardiac perfusion was also observed (4 months:7.5 ± 0.8 mL/g/min vs. 10.0 ± 0.7 mL/g/min, p = 0.03). Cardiac function at 4 months was negatively correlated to both HTGC and MTGC (p < 0.05). 14-day treatment with Exendin-4 (Ex-4) dramatically reversed all these alterations in comparison with placebo-treated HFHSD. Ex-4 diminished myocardial triglyceride content (-57.8 ± 4.1 %), improved cardiac index (+38.9 ± 10.9 %) and restored myocardial perfusion (+52.8 ± 16.4 %) under isoflurane anesthesia. Interestingly, increased wall thickness and hepatic steatosis reductions were independent of weight loss and glycemia decrease in multivariate analysis (p < 0.05).. CMR longitudinal follow-up of cardiac consequences of obesity and diabetes showed early accumulation of ectopic fat in mice before the occurrence of microvascular and contractile dysfunction. This study also supports a cardioprotective effect of glucagon-like peptide-1 receptor agonist.

Topics: Adiposity; Animals; Blood Glucose; Coronary Circulation; Diabetes Mellitus; Diet, High-Fat; Dietary Sucrose; Disease Models, Animal; Exenatide; Fatty Liver; Glucagon-Like Peptide 1; Heart Diseases; Liver; Magnetic Resonance Imaging, Cine; Male; Mice, Inbred C57BL; Multimodal Imaging; Multivariate Analysis; Myocardial Contraction; Myocardial Perfusion Imaging; Myocardium; Obesity; Peptides; Predictive Value of Tests; Proton Magnetic Resonance Spectroscopy; Recovery of Function; Time Factors; Triglycerides; Venoms; Ventricular Function; Weight Gain

The incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gastrointestinal peptide hormones regulating postprandial insulin release from pancreatic β-cells. GLP-1 agonism is a treatment strategy in Type 2 diabetes and is evaluated in Non-alcoholic fatty liver disease (NAFLD). However, the role of incretins in its pathophysiology is insufficiently understood. Studies in mice suggest improvement of hepatic steatosis by GLP-1 agonism. We determined the secretion of incretins after oral glucose administration in non-diabetic NAFLD patients.. N=52 patients (n=16 NAFLD and n=36 Non-alcoholic steatohepatitis (NASH) patients) and n=50 matched healthy controls were included. Standardized oral glucose tolerance test was performed. Glucose, insulin, glucagon, GLP-1 and GIP plasma levels were measured sequentially for 120 minutes after glucose administration.. Glucose induced GLP-1 secretion was significantly decreased in patients compared to controls (p<0.001). In contrast, GIP secretion was unchanged. There was no difference in GLP-1 and GIP secretion between NAFLD and NASH subgroups. All patients were insulin resistant, however HOMA2-IR was highest in the NASH subgroup. Fasting and glucose-induced insulin secretion was higher in NAFLD and NASH compared to controls, while the glucose lowering effect was diminished. Concomitantly, fasting glucagon secretion was significantly elevated in NAFLD and NASH.. Glucose-induced GLP-1 secretion is deficient in patients with NAFLD and NASH. GIP secretion is contrarily preserved. Insulin resistance, with hyperinsulinemia and hyperglucagonemia, is present in all patients, and is more severe in NASH compared to NAFLD. These pathophysiologic findings endorse the current evaluation of GLP-1 agonism for the treatment of NAFLD.

Topics: Case-Control Studies; Fatty Liver; Female; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Non-alcoholic Fatty Liver Disease

The aims of the study were to evaluate (1) detection of cognitive function changing in rat with hepatosteatosis model and (2) evaluate the effect of GLP-1 analog (exenatide) on cognitive function in hepatosteatosis. In the study group, 30% fructose was given in nutrition water to perform hepatosteatosis for 8 weeks to 18 male rats. Six male rats were chosen as control group and had normal nutrition. Fructose nutrition group were stratified into 3 groups. In first group (n = 6), intracerebroventricular (ICV) infusion of exenatide (n = 6) was given. ICV infusion of NaCl (n = 6) was given to second group. And also, the third group had no treatment. And also, rats were evaluated for passive avoidance learning (PAL) and liver histopathology. Mean levels of latency time were statistically significantly decreased in rats with hepatosteatosis than those of normal rats (P < 0.00001). However, mean level of latency time in rats with hepatosteatosis treated with ICV exenatide was statistically significantly increased than that of rats treated with ICV NaCl (P < 0.001). Memory performance falls off in rats with hepatosteatosis feeding on fructose (decreased latency time). However, GLP-1 ameliorates cognitive functions (increased latency time) in rats with hepatosteatosis and releated metabolic syndrome.

Topics: Animals; Cognition; Disease Models, Animal; Exenatide; Fatty Liver; Glucagon-Like Peptide 1; Hypoglycemic Agents; Male; Peptides; Rats; Venoms

Although understanding the relation between psychotic behavior and immune abnormalities has been the focus of research for many years, it remains to be elucidated whether the changes in cytokine levels are part of etiology or a result of the stress associated with the disorder. In accordance with previous studies on changes in cytokine levels due to metabolic changes and psychosis, we hypothesized that fatty liver may potentiate apomorphine-induced stereotypy in a rodent model and that a synthetic glucagon-like peptide-1 analog exenatide would ameliorate this effect. In this study, 18 male Sprague Dawley albino mature rats were used. We induced hepatosteatosis in these rats by feeding them with 30% fructose dissolved in drinking water for 8 weeks. The animals were divided into three groups, namely, the normal group, the intracerebroventricular (ICV) exenatide group, and the ICV NaCl group. Apomorphine-induced stereotypic behavior test was performed in all groups and the liver was removed for histopathological examination after all the rats were euthanized. In the nonalcoholic fatty liver (NAFL) group, stereotypy scores were significantly increased compared with the control group rats (p < 0.00001). A significant decrease in stereotypy scores were observed in the ICV exenatide group with NAFL when compared with the ICV saline group with NAFL (p < 0.005). In addition, brain malondialdehyde and tumor necrosis factor-α levels decreased in the ICV exenatide group. The results of this study showed that fatty liver enhances the effect of apomorphine on stereotypy, which was reversed by exenatide possibly by antioxidant and anti-inflammatory effects.

Topics: Animals; Brain; Exenatide; Fatty Liver; Glucagon-Like Peptide 1; Liver; Male; Malondialdehyde; Peptides; Rats, Sprague-Dawley; Stereotyped Behavior; Tumor Necrosis Factor-alpha; Venoms

Simple hepatic steatosis is the early stage of non‑alcoholic fatty liver disease and is recognized as a benign process. Previous studies show that glucagon‑like peptide‑1 has great potential in improving hepatic steatosis. Recent data have revealed that inhibiting autophagy exacerbates lipid accumulation in hepatocytes. Therefore, the present study aimed to determine the effects of liraglutide (LG) on simple hepatic steatosis and the possible role of autophagy. Firstly, steatotic L‑02 cells were induced by incubating L‑02 cells with 1 mmol/l free fatty acid (FFA) mixture (oleic acid and palmitic acid at a molar ratio of 2:1) for 24 h. Intracellular lipid accumulation, cell viability, oxidative stress and apoptosis were evaluated. Secondly, steatotic L‑02 cells were treated with 10 or 100 nmol/l LG, 100 nmol/l LG plus 3‑methyladenine (3‑MA), or rapamycin for 24 h, and then lipid accumulation was measured. Next, the degree of lipid accumulation and the intensity of autophagy were assessed. Oil red O staining and triglyceride quantification demonstrated notable steatosis in L‑02 cells following exposure to 1 mmol/l FFA mixture for 24 h. There was no significant cytotoxicity, oxidative stress or apoptosis in steatotic L‑02 cells. Treatment with 100 nmol/l LG reduced lipid accumulation in steatotic L‑02 cells and increased the mRNA levels of microtubule‑associated protein 1 light chain 3B. Additionally, it enhanced the autophagic flux in steatotic L‑02 cells, as measured by western blot analysis and shown by electron microscopy. Additionally, 3‑MA weakened the ability of LG to improve hepatic steatosis and enhance autophagy. Our data indicate that LG reduces the lipid accumulation in steatotic L‑02 cells, and the activation of autophagy plays a significant role in this process.

Topics: Autophagy; Cell Line; Drug Evaluation, Preclinical; Fatty Acids, Nonesterified; Fatty Liver; Glucagon-Like Peptide 1; Humans; Lipid Metabolism; Liraglutide; Liver; Oxidative Stress

Liraglutide, a Glucagon-like peptide-1(GLP-1) analogue with 97% sequence identity to human GLP-1, increases insulin secretion and insulin sensitivity. Its effect on non-alcoholic fatty liver disease (NAFLD) remains poorly understood. In this study, we examined whether liraglutide can protect against inflammatory stress by inhibiting activation of c-Jun N-terminal protein kinase (JNK).. ApoE KO and adiponectin (Acrp30) knockdown mice fed a high-fat diet (HFD) were treated with liraglutide (1 mg/kg, twice daily) for 8 weeks. Liver tissue was procured for histological examination, real-time RT-PCR and Western blot analysis.. The results showed that the combination of HFD, Acrp30 knockdown and ApoE deficiency had additive effects on the development of insulin resistance (IR) and NAFLD. Administration of liraglutide prevented the development of HFD and hypoadiponectinaemia-induced IR and NAFLD in this model. Liraglutide also attenuated the expression of proinflammatory cytokines or transcription factor, including TNF-α and NF-κB(65) , and the expression of two lipogenesis-related genes, Acetyl-CoA Carboxylase (ACC) and fatty acid synthase (FAS). These changes were accompanied by elevated plasma of Acrp30, increased Acrp30 mRNA, AMP Kinase phosphorylation, and decreased mitogen-activated protein kinase 4 (MKK4) mRNA expression and JNK phosphorylation.. Our study also showed potent inhibitory effects of liraglutide on MKK4/JNK signalling which may be a mechanism for the observed improved insulin sensitivity and inflammatory stress induced by HFD and hypoadiponectinaemia.

Topics: Adiponectin; Analysis of Variance; Animals; Apolipoproteins E; Blotting, Western; Diet, High-Fat; Enzyme Activation; Fatty Liver; Gene Knockdown Techniques; Glucagon-Like Peptide 1; Histological Techniques; Insulin Resistance; JNK Mitogen-Activated Protein Kinases; Liraglutide; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction

Topics: Animals; Diet, High-Fat; Disease Models, Animal; Fatty Liver; Fibroblast Growth Factors; GATA4 Transcription Factor; Glucagon-Like Peptide 1; Gluconeogenesis; Glucose; Intestinal Mucosa; Liver; Mice; Mice, Knockout

Rodent obesity models have been shown to display impaired bile secretory functions. We have shown that glucagon-like peptide 1 (GLP-1) attenuates hepatic lipogenesis, and in the present study we investigated whether GLP-1 also improves high fat diet-associated cholestatic injury.. Wild type (WT) and dipeptidyl peptidase 4-deficient rats (DPP4-) with chronic elevated serum levels of active GLP-1 were fed regular chow and a Western diet for 2 months. Primary hepatocytes were used to assess GLP-1 effects on mRNA expression and transcription of genes encoding bile acid synthesis enzymes and transporters.. DPP4- exhibited attenuated liver injury as expressed by lower serum AST and ALT after 2 months of a Western diet. In addition, DPP4- had better insulin sensitivity, lower serum triglycerides, cholesterol and bile acids. Hepatic expression of cyp7A1, the rate limiting enzyme in conversion of cholesterol into bile acids, was strongly attenuated in DPP4- fed with a Western diet. Moreover, hepatic expression of bile transporter, ABCB11, was increased, facilitating a higher rate of bile secretion. Mechanistically, we showed that GLP-1 directly reduced basal and LXR-induced cyp7A1 mRNA expression and suppressed cyp7A1 transcription in transient transfection assays in primary hepatocytes. However, GLP-1 and its analog exendin 4 also induced mRNA expression of bile acid transporter ABCC3 in primary rat hepatocyte cultures.. Our data suggest that GLP-1 analogs may serve as a novel therapeutic drug to alleviate obesity-induced liver injury by reducing bile acid synthesis and improving liver bile secretory function.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Bile; Cholesterol 7-alpha-Hydroxylase; Diet; Dietary Fats; Dipeptidyl Peptidase 4; Fatty Liver; Gene Deletion; Gene Expression Regulation; Glucagon-Like Peptide 1; Hypolipidemic Agents; Male; Non-alcoholic Fatty Liver Disease; Rats; Rats, Inbred F344; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Valproic acid (VPA), as one of the most widely prescribed antiepileptic drugs (AED) for many types of epilepsy in adults and children, is associated with weight gain, alteration of adipocytokine homeostasis, insulin resistance and Non-Alcoholic Fatty Liver Disease (NAFLD). Retinol-binding protein 4 (RBP4) and Glucagon-like peptide-1 (GLP-1) are considered as important new targets in modern type 2 diabetes mellitus therapy linked to insulin resistance, NAFLD and visceral obesity acting via peripheral or central mechanisms. We herein demonstrate the lack of an influence of VPA treatment on RBP4 and GLP-1 in otherwise healthy patients. In summary, the absence of any relationship with RBP4 and GLP-1 concentrations does not suggest a role of these novel insulin resistance parameters as potential regulators of glucose and fat metabolism during VPA-therapy.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Child; Diabetes Mellitus, Type 2; Fatty Liver; Female; Glucagon-Like Peptide 1; Glucose; Homeostasis; Humans; Insulin Resistance; Liver; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Retinol-Binding Proteins, Plasma; Valproic Acid; Young Adult

Recent data suggest that gut microbiota contributes to the regulation of host lipid metabolism. We report how fermentable dietary fructo-oligosaccharides (FOS) control hepatic steatosis induced by n-3 PUFA depletion, which leads to hepatic alterations similar to those observed in non-alcoholic fatty liver disease patients.. C57Bl/6J mice fed an n-3 PUFA-depleted diet for 3 months were supplemented with FOS during the last 10 days of treatment. FOS-treated mice exhibited higher caecal Bifidobacterium spp. and lower Roseburia spp. content. Microarray analysis of hepatic mRNA revealed that FOS supplementation reduced hepatic triglyceride accumulation through a proliferator-activated receptor α-stimulation of fatty acid oxidation and lessened cholesterol accumulation by inhibiting sterol regulatory element binding protein 2-dependent cholesterol synthesis. Cultured precision-cut liver slices confirmed the inhibition of fatty acid oxidation. FOS effects were related to a decreased hepatic micro-RNA33 expression and to an increased colonic glucagon-like peptide 1 production.. The changes in gut microbiota composition by n-3 PUFA-depletion and prebiotics modulate hepatic steatosis by changing gene expression in the liver, a phenomenon that could implicate micro-RNA and gut-derived hormones. Our data underline the advantage of targeting the gut microbiota by colonic nutrients in the management of liver disease.

Topics: Animals; Bifidobacterium; Cholesterol; Dietary Supplements; Energy Intake; Fatty Acids, Omega-3; Fatty Liver; Gastrointestinal Tract; Gene Expression Regulation; Glucagon-Like Peptide 1; Lipid Metabolism; Liver; Male; Metagenome; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Oligosaccharides; Oxidative Stress; PPAR alpha; Prebiotics; Sterol Regulatory Element Binding Protein 1; Sterol Regulatory Element Binding Protein 2; Transcription Factors

Recent studies have provided new evidence that alterations in the composition of the gut microbiota--known as dysbiosis--participate in the development of obesity. The aim of the present study was to investigate the ability of chitin-glucan (CG) from a fungal source to modulate both the gut microbiota and glucose and lipid metabolism in high-fat (HF) diet-induced obese mice. Supplementation of the HF diet with fungal CG (10% w/w) induced caecal enlargement with prominent changes in gut microbiota: it restored the number of bacteria from clostridial cluster XIVa including Roseburia spp., which were decreased due to HF feeding. Furthermore, CG treatment significantly decreased HF-induced body weight gain, fat mass development, fasting hyperglycemia, glucose intolerance, hepatic triglyceride accumulation and hypercholesterolemia, independently of the caloric intake. All those parameters were negatively correlated with specific bacteria of clostridial cluster XIVa, i.e., Roseburia spp. (Pearson's correlations analysis). In contrast to prebiotics that more specifically target the bifidobacteria species, CG effects on obesity appear to be independent of the incretin glucagon-like peptide 1 (GLP-1) production, since portal GLP-1 and proglucagon (its precursor) expression were not modified by the dietary intervention. In conclusion, our findings support the view that chronic consumption of CG has potential beneficial effects with respect to the development of obesity and associated metabolic diabetes and hepatic steatosis, through a mechanism related to the restoration of the composition and/or the activity of gut bacteria, namely, bacteria from clostridial cluster XIVa.

Topics: Animals; Chitin; Diet, High-Fat; Dietary Fiber; Dietary Supplements; Fatty Liver; Gastrointestinal Tract; Glucagon-Like Peptide 1; Glucans; Glucose; Glucose Intolerance; Gram-Positive Bacteria; Hyperglycemia; Lipid Metabolism; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Proglucagon; Triglycerides; Weight Gain

The aims of this study were designed to determine whether liraglutide, a long-acting glucagon-like peptide, could reverse the adverse effects of a diet high in fat that also contained trans-fat and high-fructose corn syrup (ALIOS diet). Specifically, we examined whether treatment with liraglutide could reduce hepatic insulin resistance and steatosis as well as improve cardiac function. Male C57BL/6J mice were pair fed or fed ad libitum either standard chow or the ALIOS diet. After 8 wk the mice were further subdivided and received daily injections of either liraglutide or saline for 4 wk. Hyperinsulinemic-euglycemic clamp studies were performed after 6 wk, revealing hepatic insulin resistance. Glucose tolerance and insulin resistance tests were performed at 8 and 12 wk prior to and following liraglutide treatment. Liver pathology, cardiac measurements, blood chemistry, and RNA and protein analyses were performed. Clamp studies revealed hepatic insulin resistance after 6 wk of ALIOS diet. Liraglutide reduced visceral adiposity and liver weight (P < 0.001). As expected, liraglutide improved glucose and insulin tolerance. Liraglutide improved hypertension (P < 0.05) and reduced cardiac hypertrophy. Surprisingly, liver from liraglutide-treated mice had significantly higher levels of fatty acid binding protein, acyl-CoA oxidase II, very long-chain acyl-CoA dehydrogenase, and microsomal triglyceride transfer protein. We conclude that liraglutide reduces the harmful effects of an ALIOS diet by improving insulin sensitivity and by reducing lipid accumulation in liver through multiple mechanisms including, transport, and increase β-oxidation.

Topics: Adiposity; Animals; Cardiomegaly; Diet, High-Fat; Fatty Liver; Glucagon-Like Peptide 1; Glucose Tolerance Test; Hypertension; Insulin Resistance; Liraglutide; Liver; Male; Mice; Mice, Inbred C57BL

Free fatty acids provide an important energy source as nutrients, and act as signalling molecules in various cellular processes. Several G-protein-coupled receptors have been identified as free-fatty-acid receptors important in physiology as well as in several diseases. GPR120 (also known as O3FAR1) functions as a receptor for unsaturated long-chain free fatty acids and has a critical role in various physiological homeostasis mechanisms such as adipogenesis, regulation of appetite and food preference. Here we show that GPR120-deficient mice fed a high-fat diet develop obesity, glucose intolerance and fatty liver with decreased adipocyte differentiation and lipogenesis and enhanced hepatic lipogenesis. Insulin resistance in such mice is associated with reduced insulin signalling and enhanced inflammation in adipose tissue. In human, we show that GPR120 expression in adipose tissue is significantly higher in obese individuals than in lean controls. GPR120 exon sequencing in obese subjects reveals a deleterious non-synonymous mutation (p.R270H) that inhibits GPR120 signalling activity. Furthermore, the p.R270H variant increases the risk of obesity in European populations. Overall, this study demonstrates that the lipid sensor GPR120 has a key role in sensing dietary fat and, therefore, in the control of energy balance in both humans and rodents.

Topics: Adipocytes; Adipogenesis; Adipose Tissue; Animals; Calcium Signaling; Cell Differentiation; Diet, High-Fat; DNA Mutational Analysis; Energy Metabolism; Europe; Exons; Fatty Liver; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Humans; Insulin; Insulin Resistance; Lipogenesis; Liver; Macrophages; Mice; Mutation; Obesity; Receptors, G-Protein-Coupled; Signal Transduction; White People

Hepatic progenitor cells (HPCs) play a major role in liver repair and regeneration. We evaluated HPC involvement in pediatric nonalcoholic fatty liver disease (pNAFLD). Thirty biopsies of consecutive children and adolescents with untreated NAFLD (19 with nonalcoholic steatohepatitis [NASH] and 11 without NASH) were studied using immunohistochemistry and immunofluorescence. HPCs and HPC-expressing adipokines (e.g., adiponectin, resistin, and glucagon-like peptide 1 [GLP-1]) were counted and correlated with steatosis, inflammation, hepatocyte ballooning, fibrosis, and NAFLD activity score (NAS). The HPC compartment was expanded in pNAFLD, especially in children with NASH, and was independently associated with degree of fibrosis (r = 0.303; P = 0.033). NASH livers were also characterized by increased hepatocyte apoptosis, cell-cycle arrest, and an expanded pool of intermediate hepatocytes. Adiponectin expression in HPCs of pNAFLD patients was down-regulated with respect to the healthy liver, and this expression was inversely correlated with NAS score (r = -0.792; P < 0.001) and steatosis (r = -0.769; P < 0.001). Resistin expression in HPCs increased in pNAFLD and was related to degree of fibrosis (r = 0.432; P < 0.05). GLP-1 was overexpressed in HPCs of pNAFLD patients, and GLP-1 expression was related to degree of steatosis (r = 0.577; P < 0.05) and NAS (r = 0.594; P < 0.01).. HPC activation is involved in the response of the liver to oxidative stress in pNAFLD and is correlated with fibrosis and the progression toward NASH. HPCs express adiponectin, resistin, and GLP-1, which become available to resident liver cells and are strongly associated with the severity of NAFLD. These results may have important pathophysiological implications in the modulation of hepatic insulin resistance and the progression of liver injury.

Topics: Adiponectin; Adolescent; Apoptosis; Cell Count; Cell Cycle Checkpoints; Child; Fatty Liver; Female; Glucagon-Like Peptide 1; Hepatitis; Humans; Liver; Liver Cirrhosis; Male; Non-alcoholic Fatty Liver Disease; Resistin; Severity of Illness Index; Stem Cells

We previously showed that parenteral nutrition (PN) compared with formula feeding results in hepatic insulin resistance and steatosis in neonatal pigs. The current aim was to test whether the route of feeding (intravenous [IV] vs enteral) rather than other feeding modalities (diet, pattern) had contributed to the outcome.. Neonatal pigs were fed enterally or parenterally for 14 days with 1 of 4 feeding modalities as follows: (1) enteral polymeric formula intermittently (FORM), (2) enteral elemental diet (ED) intermittently (IEN), (3) enteral ED continuously (CEN), and (4) parenteral ED continuously (PN). Subgroups of pigs underwent IV glucose tolerance tests (IVGTT) and hyperinsulinemic-euglycemic clamps (CLAMP). Following CLAMP, pigs were euthanized and tissues collected for further analysis.. Insulin secretion during IVGTT was significantly higher and glucose infusion rates during CLAMP were lower in CEN and PN than in FORM and IEN. Endogenous glucose production rate was suppressed to zero in all groups during CLAMP. In the fed state, plasma glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide (GLP)-1, and GLP-2 were different between feeding modalities. Insulin receptor phosphorylation in liver and muscle was decreased in IEN, CEN, and PN compared with FORM. Liver weight was highest in PN. Steatosis and myeloperoxidase (MPO) activity tended to be highest in PN and CEN. Enterally fed groups had higher plasma GLP-2 and jejunum weight compared with PN.. PN and enteral nutrition (EN) when given continuously as an elemental diet reduces insulin sensitivity and the secretion of key gut incretins. The intermittent vs continuous pattern of EN produced the optimal effect on metabolic function.

Topics: Administration, Intravenous; Animals; Animals, Newborn; Blood Glucose; Endpoint Determination; Enteral Nutrition; Fatty Liver; Female; Food, Formulated; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Incretins; Inflammation; Insulin; Insulin Resistance; Insulin Secretion; Intestine, Small; Liver; Metabolic Diseases; Nonlinear Dynamics; Organ Size; Parenteral Nutrition; Swine

GATA4, a zinc finger domain transcription factor, is critical for jejunal identity. Mice with an intestine-specific GATA4 deficiency (GATA4iKO) are resistant to diet-induced obesity and insulin resistance. Although they have decreased intestinal lipid absorption, hepatic de novo lipogenesis is inhibited. Here, we investigated dietary lipid-dependent and independent effects on the development of steatosis and fibrosis in GATA4iKO mice.. GATA4iKO and control mice were fed a Western-type diet (WTD) or a methionine and choline-deficient diet (MCDD) for 20 and 3 weeks, respectively. Functional effects of GATA4iKO on diet-induced liver steatosis were investigated.. WTD-but not MCDD-fed GATA4iKO mice showed lower hepatic concentrations of triglycerides, free fatty acids, and thiobarbituric acid reactive species and had reduced expression of lipogenic as well as fibrotic genes compared with controls. Reduced nuclear sterol regulatory element-binding protein-1c protein levels were accompanied by lower lipogenic gene expression. Oil red O and Sirius Red staining of liver sections confirmed the observed reduction in hepatic lipid accumulation and fibrosis. Immunohistochemical staining revealed an increased number of jejunal glucagon-like peptide 1 (GLP-1) positive cells in GATA4iKO mice. Consequently, we found enhanced phosphorylation of hepatic AMP-activated protein kinase and acetyl-CoA carboxylase alpha.. Our results provide strong indications for a protective effect of intestinal GATA4 deficiency on the development of hepatic steatosis and fibrosis via GLP-1, thereby blocking hepatic de novo lipogenesis.

Topics: AMP-Activated Protein Kinase Kinases; Animals; Choline Deficiency; Diet; Disease Models, Animal; Fatty Acids, Nonesterified; Fatty Liver; GATA4 Transcription Factor; Glucagon-Like Peptide 1; Jejunum; Lipid Metabolism; Liver Cirrhosis; Male; Methionine; Mice; Mice, Knockout; Protein Kinases; Sterol Regulatory Element Binding Protein 1; Thiobarbituric Acid Reactive Substances; Triglycerides

BACKGROUND. Liraglutide leading to improve not only glycaemic control but also liver inflammation in non-alcoholic fatty liver disease (NAFLD) patients. AIMS. The aim of this study is to elucidate the effectiveness of liraglutide in NAFLD patients with type 2 diabetes mellitus (T2DM) compared to sitagliptin and pioglitazone. METHODS. We retrospectively enrolled 82 Japanese NAFLD patients with T2DM and divided into three groups (liraglutide: N = 26, sitagliptin; N = 36, pioglitazone; N = 20). We compared the baseline characteristics, changes of laboratory data and body weight. RESULTS. At the end of follow-up, ALT, fast blood glucose, and HbA1c level significantly improved among the three groups. AST to platelet ratio significantly decreased in liraglutide group and pioglitazone group. The body weight significantly decreased in liraglutide group (81.8 kg to 78.0 kg, P < 0.01). On the other hands, the body weight significantly increased in pioglitazone group and did not change in sitagliptin group. Multivariate regression analysis indicated that administration of liraglutide as an independent factor of body weight reduction for more than 5% (OR 9.04; 95% CI 1.12-73.1, P = 0.04). CONCLUSIONS. Administration of liraglutide improved T2DM but also improvement of liver inflammation, alteration of liver fibrosis, and reduction of body weight.

Topics: Adult; Alanine Transaminase; Blood Glucose; Body Weight; Comorbidity; Diabetes Mellitus, Type 2; Drug Evaluation; Drug Therapy, Combination; Fatty Liver; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Inflammation; Liraglutide; Liver Cirrhosis; Logistic Models; Male; Middle Aged; Multivariate Analysis; Non-alcoholic Fatty Liver Disease; Odds Ratio; Pioglitazone; Platelet Count; Pyrazines; Retrospective Studies; Sitagliptin Phosphate; Thiazolidinediones; Treatment Outcome; Triazoles

In addition to improve glucose intolerance, recent studies suggest that glucagon-like peptide-1 (GLP-1) receptor agonism also decreases triglyceride (TG) levels. The aim of this study was to evaluate the effect of GLP-1 receptor agonism on very-low-density lipoprotein (VLDL)-TG production and liver TG metabolism.. The GLP-1 peptide analogues CNTO3649 and exendin-4 were continuously administered subcutaneously to high fat diet-fed APOE*3-Leiden transgenic mice. After 4 weeks, hepatic VLDL production, lipid content, and expression profiles of selected genes involved in lipid metabolism were determined.. CNTO3649 and exendin-4 reduced fasting plasma glucose (up to -30% and -28% respectively) and insulin (-43% and -65% respectively). In addition, these agents reduced VLDL-TG production (-36% and -54% respectively) and VLDL-apoB production (-36% and -43% respectively), indicating reduced production of VLDL particles rather than reduced lipidation of apoB. Moreover, they markedly decreased hepatic content of TG (-39% and -55% respectively), cholesterol (-30% and -55% respectively), and phospholipids (-23% and -36% respectively), accompanied by down-regulation of expression of genes involved in hepatic lipogenesis (Srebp-1c, Fasn, Dgat1) and apoB synthesis (Apob).. GLP-1 receptor agonism reduces VLDL production and hepatic steatosis in addition to an improvement of glycemic control. These data suggest that GLP-receptor agonists could reduce hepatic steatosis and ameliorate dyslipidemia in patients with type 2 diabetes mellitus.

Topics: Animals; Apolipoprotein E3; Apolipoproteins B; Blood Glucose; Diabetes Mellitus, Type 2; Dyslipidemias; Exenatide; Fatty Liver; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Insulin; Lipogenesis; Liver; Male; Mice; Mice, Transgenic; Peptides; Receptors, Glucagon; Venoms

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are effective for obese patients with type 2 diabetes mellitus (T2DM) because they concomitantly target obesity and dysglycaemia. Considering the high prevalence of non-alcoholic fatty liver disease (NAFLD) in patients with T2DM, we determined the impact of 6 months' GLP-1 RA therapy on intrahepatic lipid (IHL) in obese, T2DM patients with hepatic steatosis, and evaluated the inter-relationship between changes in IHL with those in glycosylated haemoglobin (HbA(1)c), body weight, and volume of abdominal visceral and subcutaneous adipose tissue (VAT and SAT). We prospectively studied 25 (12 male) patients, age 50±10 years, BMI 38.4±5.6 kg/m(2) (mean ± SD) with baseline IHL of 28.2% (16.5 to 43.1%) and HbA(1)c of 9.6% (7.9 to 10.7%) (median and interquartile range). Patients treated with metformin and sulphonylureas/DPP-IV inhibitors were given 6 months GLP-1 RA (exenatide, n = 19; liraglutide, n = 6). IHL was quantified by liver proton magnetic resonance spectroscopy ((1)H MRS) and VAT and SAT by whole body magnetic resonance imaging (MRI). Treatment was associated with mean weight loss of 5.0 kg (95% CI 3.5,6.5 kg), mean HbA(1c) reduction of 1·6% (17 mmol/mol) (0·8,2·4%) and a 42% relative reduction in IHL (-59.3, -16.5%). The relative reduction in IHL correlated with that in HbA(1)c (ρ = 0.49; p = 0.01) but was not significantly correlated with that in total body weight, VAT or SAT. The greatest IHL reduction occurred in individuals with highest pre-treatment levels. Mechanistic studies are needed to determine potential direct effects of GLP-1 RA on human liver lipid metabolism.

Topics: Adiposity; Adult; Blood Glucose; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Fatty Liver; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Liraglutide; Liver; Male; Middle Aged; Obesity; Peptides; Prospective Studies; Venoms; Weight Loss

The metabolic syndrome, a disease arising from the world-wide epidemic of obesity, is manifested as severe insulin resistance, hyperlipidaemia, hepatic steatosis and diabetes. Previously we reported that GLP-1(9-36)amide, derived from the gluco-incretin hormone, glucagon-like peptide-1 (GLP-1), suppresses gluconeogenesis in isolated hepatocytes. The aims of this study were to determine the effects of GLP-1(9-36)amide in diet-induced obese mice that model the development of the metabolic syndrome.. Mice rendered obese by feeding a very high fat diet were administered GLP-1(9-36)amide via subcutaneous osmopumps for 8 weeks. Body weight, energy intake, plasma insulin and glucose levels (insulin-resistance), and hepatic steatosis were assessed.. Eight-week infusions of GLP-1(9-36)amide inhibited weight gain, increased energy intake, prevented the development of fasting hyperinsulinaemia and hyperglycaemia, and curtailed the accumulation of liver triglycerides. The peptide had no effects in mice fed a normal chow diet. Notably, energy intake in the obese mice receiving GLP-1(9-36)amide was 20% greater than obese mice receiving vehicle control.. GLP-1(9-36)amide exerts insulin-like actions in the presence of insulin resistance and prevents the development of metabolic syndrome. Curtailment of weight gain in the face of increased caloric intake suggests that GLP-1(9-36)amide increases energy expenditure. These findings suggest the possibility of the use of GLP-1(9-36)amide, or a peptide mimetic derived there from, for the treatment of obesity, insulin resistance and the metabolic syndrome.

Topics: Animals; Body Weight; Dietary Fats; Energy Intake; Fatty Liver; Glucagon-Like Peptide 1; Insulin; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Obese; Receptors, Glucagon; Weight Gain

Glucagon-like peptide-1 (GLP-1), a gut-derived peptide degraded by dipeptidyl peptidase-4 (DPP4), stimulates insulin secretion in response to nutrients, yet its direct effect on the liver is controversial. We investigated the effects of GLP-1 on hepatic fat and glucose metabolism and elucidated its mechanism of action.. Hepatic fat metabolism, including lipogenic enzymes and signal transduction regulators, was assessed in livers of DPP4-deficient rats (DPP4-) with chronically elevated GLP-1 and in GLP-1-treated primary hepatocytes. The effect of chronic elevated GLP-1 on insulin sensitivity was measured using the hyperinsulinemic-euglycemic clamp.. Normal and high fat diet fed DPP4-rats displayed reduced hepatic triglycerides, accompanied by down-regulation of lipogenesis enzymes and parallel up-regulation of carnitine palmitoyltransferase-1, a key enzyme in fatty acid β-oxidation. In vitro studies demonstrated that these effects were directly induced by GLP-1. Mechanistically, GLP-1 increased cAMP in hepatocytes, resulting in the phosphorylation of cAMP-activated protein kinase (AMPK), a suppressor of lipogenesis. Indeed, hepatocytes expressing a dominant negative Ad-DN-AMPK displayed attenuated GLP-1 effects on AMPK phosphorylation and its downstream lipogenic targets. Importantly, normoglycemic DPP4-rats did not display improved hepatic insulin sensitivity in vivo, suggesting a direct effect of GLP-1 on fat metabolism. Finally, DPP4-rats expressed lower levels of hepatic proinflammatory and profibrotic cytokines in response to nutrient stimuli.. GLP-1 suppresses hepatic lipogenesis via activation of the AMPK pathway. GLP-1 inhibitory effects on hepatic fat accumulation and nutrient-induced hepatic proinflammatory response suggest GLP-1 analogs as novel therapies for non-alcoholic fatty liver diseases.

Topics: AMP-Activated Protein Kinases; Animals; Base Sequence; Cells, Cultured; Cyclic AMP; Cytokines; Dipeptidyl Peptidase 4; DNA Primers; Enzyme Activation; Fatty Liver; Glucagon-Like Peptide 1; Hepatocytes; Inflammation Mediators; Lipids; Lipogenesis; Liver; Male; Metabolic Networks and Pathways; Rats; Rats, Inbred F344; Rats, Transgenic; RNA, Messenger

The metabolic syndrome is an obesity-associated disease manifested as severe insulin resistance, hyperlipidemia, hepatic steatosis, and diabetes. Previously we proposed that a nonapeptide, FIAWLVKGRamide, GLP-1(28-36)amide, derived from the gluco-incretin hormone, glucagon-like peptide-1 (GLP-1), might have insulin-like actions. Recently, we reported that the nonapeptide appears to enter hepatocytes, target to mitochondria, and suppress glucose production and reactive oxygen species. Therefore, the effects of GLP-1(28-36)amide were examined in diet-induced obese, insulin-resistant mice as a model for the development of human metabolic syndrome.. Three- to 11-week infusions of GLP-1(28-36)amide were administered via osmopumps to mice fed a very high fat diet (VHFD) and to control mice on a normal low fat diet (LFD). Body weight, DXA, energy intake, plasma insulin and glucose, and liver triglyceride levels were assessed. GLP-1(28-36)amide inhibited weight gain, accumulation of liver triglycerides, and improved insulin sensitivity by attenuating the development of fasting hyperglycemia and hyperinsulinemia in mice fed VHFD. GLP-1(28-36)amide had no observable effects in control LFD mice. Surprisingly, the energy intake of peptide-infused obese mice is 25-70% greater than in obese mice receiving vehicle alone, yet did not gain excess weight.. GLP-1(28-36)amide exerts insulin-like actions selectively in conditions of obesity and insulin resistance. The peptide curtails weight gain in diet-induced obese mice in the face of an increase in energy intake suggesting increased energy expenditure. These findings suggest utility of GLP-1(28-36)amide, or a peptide mimetic derived there from, for the treatment of insulin resistance and the metabolic syndrome.

Topics: Animals; Diabetes Mellitus, Type 2; Dietary Fats; Eating; Fatty Liver; Glucagon-Like Peptide 1; Hyperglycemia; Hyperinsulinism; Insulin Resistance; Liver; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Obesity; Peptide Fragments; Triglycerides; Weight Gain

Nonalcoholic fatty liver disease (NAFLD) is a known outcome of hepatosteatosis. Free fatty acids (FFA) induce the unfolded protein response (UPR) or endoplasmic reticulum (ER) stress that may induce apoptosis. Recent data indicate ER stress to be a major player in the progression of fatty liver to more aggressive lesions. Autophagy on the other hand has been demonstrated to be protective against ER stress-induced cell death. We hypothesized that exendin-4 (GLP-1 analog) treatment of fat loaded hepatocytes can reduce steatosis by autophagy which leads to reduced ER stress-related hepatocyte apoptosis.. Primary human hepatocytes were loaded with saturated, cis- and trans-unsaturated fatty acids (palmitic, oleic and elaidic acid respectively). Steatosis, induced with all three fatty acids, was significantly resolved after exendin-4 treatment. Exendin-4 sustained levels of GRP78 expression in fat-loaded cells when compared to untreated fat-loaded cells alone. In contrast, CHOP (C/EBP homologous protein); the penultimate protein that leads to ER stress-related cell death was significantly decreased by exendin-4 in hepatocytes loaded with fatty acids. Finally, exendin-4 in fat loaded hepatocytes clearly promoted gene products associated with macroautophagy as measured by enhanced production of both Beclin-1 and LC3B-II, markers for autophagy; and visualized by transmission electron microscopy (TEM). Similar observations were made in mouse liver lysates after mice were fed with high fat high fructose diet and treated with a long acting GLP-1 receptor agonist, liraglutide.. GLP-1 proteins appear to protect hepatocytes from fatty acid-related death by prohibition of a dysfunctional ER stress response; and reduce fatty acid accumulation, by activation of both macro-and chaperone-mediated autophagy. These findings provide a novel role for GLP-1 proteins in halting the progression of more aggressive lesions from underlying steatosis in humans afflicted with NAFLD.

Topics: Adipocytes; Animals; Apoptosis; Autophagy; Diet, High-Fat; Dietary Carbohydrates; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Exenatide; Fatty Liver; Fructose; Glucagon-Like Peptide 1; Hepatocytes; Humans; Life Style; Male; Mice; Mice, Inbred C57BL; Obesity; Peptides; Survival Analysis; Unfolded Protein Response; Venoms

Although a high-fat diet (HFD) is recognized as an important contributor to obesity, human research is limited by confounders such as income, whereas animal research has typically examined diet during specific developmental periods rather than throughout the lifespan. We hypothesized that the use of an HFD in short-term studies as has been commonly done in animals does not adequately reflect the lifelong dietary patterns seen frequently in humans with consequent metabolic disturbances. We examined the impact of HFD from weaning until 39 weeks (middle age) on the metabolism of male rats. At 7, 26, and 39 weeks, glucose tolerance tests were performed, a subset of animals was euthanized, and serum and tissues were collected. After 4 weeks, preceding increased body weight, HFD animals had increased intra-abdominal fat, triglycerides, and hyperglycemia. Hyperinsulinemia was insufficient to maintain normoglycemia, and beta cell mass and glucagon-like peptide 1 decreased over time in HFD and control animals. Despite lacking significant lipid abnormalities, nonalcoholic fatty liver disease was evident by 39 weeks. Our HFD model demonstrated that significant metabolic abnormalities may go undetected by current standard screening such as weighing and biochemistry.

Topics: Adiposity; Animals; Blood Glucose; Body Weight; Diet, High-Fat; Dietary Fats; Disease Models, Animal; Fatty Liver; Glucagon-Like Peptide 1; Glucose Tolerance Test; Glycemic Index; Hyperglycemia; Hyperinsulinism; Insulin; Intra-Abdominal Fat; Male; Non-alcoholic Fatty Liver Disease; Obesity; Rats; Rats, Wistar; Triglycerides

Glucagon-like peptide 1 (GLP-1) is a naturally occurring peptide secreted by the L cells of the small intestine. GLP-1 functions as an incretin and stimulates glucose-mediated insulin production by pancreatic beta cells. In this study, we demonstrate that exendin-4/GLP-1 has a cognate receptor on human hepatocytes and that exendin-4 has a direct effect on the reduction of hepatic steatosis in the absence of insulin. Both glucagon-like peptide 1 receptor (GLP/R) messenger RNA and protein were detected on primary human hepatocytes, and receptor was internalized in the presence of GLP-1. Exendin-4 increased the phosphorylation of 3-phosphoinositide-dependent kinase-1 (PDK-1), AKT, and protein kinase C zeta (PKC-zeta) in HepG2 and Huh7 cells. Small interfering RNA against GLP-1R abolished the effects on PDK-1 and PKC-zeta. Treatment with exendin-4 quantitatively reduced triglyceride stores compared with control-treated cells.. This is the first report that the G protein-coupled receptor GLP-1R is present on human hepatocytes. Furthermore, it appears that exendin-4 has the same beneficial effects in vitro as those seen in our previously published in vivo study in ob/ob mice, directly reducing hepatocyte steatosis. Future use for human nonalcoholic fatty liver disease, either in combination with dietary manipulation or other pharmacotherapy, may be a significant advance in treatment of this common form of liver disease.

Topics: 3-Phosphoinositide-Dependent Protein Kinases; Exenatide; Fatty Liver; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hepatocytes; Humans; Insulin; Peptides; Protein Kinase C; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Receptors, Glucagon; Signal Transduction; Venoms

The control of glucose metabolism is a complex process, and dysregulation at any level can cause impaired glucose tolerance and insulin resistance. These two defects are well-known characteristics associated with obesity and onset of type 2 diabetes. Here we introduce the N-terminal dipeptidase, DPP2, as a novel regulator of the glucose metabolism. We generated mice with a neurogenin 3 (NGN3)-specific DPP2 knockdown (kd) to explore a possible role of DPP2 in maintaining metabolic homeostasis. These mice spontaneously developed hyperinsulinemia, glucose intolerance, and insulin resistance by 4 months of age. In addition, we observed an increase in food intake in DPP2 kd mice, which was associated with a significant increase in adipose tissue mass and enhanced liver steatosis but no difference in body weight. In accordance with these findings, the mutant mice had a higher rate of respiratory exchange than the control littermates. This phenotype was exacerbated with age and when challenged with a high-fat diet. We report, for the first time, that DPP2 enzyme activity is essential for preventing hyperinsulinemia and maintaining glucose homeostasis. Interestingly, the phenotype of NGN3-DPP2 kd mice is opposite that of DPP4 knockout mice with regard to glucose metabolism, namely the former have normal glucagon-like peptide 1 levels but present with glucose intolerance, whereas the latter have increased glucagon-like peptide 1, which is accompanied by augmented glucose tolerance.

Topics: Adipose Tissue; Animals; Basic Helix-Loop-Helix Transcription Factors; Blood Glucose; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Eating; Fasting; Fatty Liver; Female; Fluorescent Antibody Technique; Glucagon-Like Peptide 1; Glucose Intolerance; Insulin; Insulin Resistance; Male; Mice; Mice, Knockout; Mice, Transgenic; Nerve Tissue Proteins; Obesity

Nonalcoholic fatty liver disease (NAFLD) represents a burgeoning problem in hepatology, and is associated with insulin resistance. Exendin-4 is a peptide agonist of the glucagon-like peptide (GLP) receptor that promotes insulin secretion. The aim of this study was to determine whether administration of Exendin-4 would reverse hepatic steatosis in ob/ob mice. Ob/ob mice, or their lean littermates, were treated with Exendin-4 [10 microg/kg or 20 microg/kg] for 60 days. Serum was collected for measurement of insulin, adiponectin, fasting glucose, lipids, and aminotransferase concentrations. Liver tissue was procured for histological examination, real-time RT-PCR analysis and assay for oxidative stress. Rat hepatocytes were isolated and treated with GLP-1. Ob/ob mice sustained a reduction in the net weight gained during Exendin-4 treatment. Serum glucose and hepatic steatosis was significantly reduced in Exendin-4 treated ob/ob mice. Exendin-4 improved insulin sensitivity in ob/ob mice, as calculated by the homeostasis model assessment. The measurement of thiobarbituric reactive substances as a marker of oxidative stress was significantly reduced in ob/ob-treated mice with Exendin-4. Finally, GLP-1-treated hepatocytes resulted in a significant increase in cAMP production as well as reduction in mRNA expression of stearoyl-CoA desaturase 1 and genes associated with fatty acid synthesis; the converse was true for genes associated with fatty acid oxidation. In conclusion, Exendin-4 appears to effectively reverse hepatic steatosis in ob/ob mice by improving insulin sensitivity. Our data suggest that GLP-1 proteins in liver have a novel direct effect on hepatocyte fat metabolism.

Topics: Adipose Tissue; Alanine Transaminase; Animals; Blood Glucose; Cyclic AMP; Exenatide; Fatty Liver; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Insulin Resistance; Lipid Peroxidation; Liver; Male; Mice; Mice, Obese; Peptides; PPAR alpha; Receptors, Glucagon; RNA, Messenger; Stearoyl-CoA Desaturase; Sterol Regulatory Element Binding Protein 1; Venoms; Weight Gain