scholarly journals Systemic LSD1 inhibition prevents aberrant remodeling of metabolism in obesity

2021 ◽  
Author(s):  
Bastian Ramms ◽  
Dennis P Pollow ◽  
Han Zhu ◽  
Chelsea Nora ◽  
Austin R Harrington ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Food Intake ◽  
Glycemic Control ◽  
Metabolic Reprogramming ◽  
Alcoholic Fatty Liver ◽  
Feeding Experiments ◽  
Lysine Specific Demethylase ◽  
Metabolic Remodeling ◽  
Treatment Of Obesity

The transition from lean to obese states involves systemic metabolic remodeling that impacts insulin sensitivity, lipid partitioning, inflammation, and glycemic control. Here, we have taken a pharmacological approach to test the role of a nutrient-regulated chromatin modifier, lysine-specific demethylase (LSD1), in obesity-associated metabolic reprogramming. We show that systemic administration of an LSD1 inhibitor (GSK-LSD1) reduces food intake and body weight, ameliorates non-alcoholic fatty liver disease (NAFLD), and improves insulin sensitivity and glycemic control in mouse models of obesity. GSK-LSD1 has little effect on systemic metabolism of lean mice, suggesting LSD1 has a context-dependent role in promoting maladaptive changes in obesity. Analysis of insulin target tissues identified white adipose tissue as the major site of insulin sensitization by GSK-LSD1, where it reduces adipocyte inflammation and lipolysis. We demonstrate that GSK-LSD1 reverses NAFLD in a non-hepatocyte-autonomous manner, suggesting an indirect mechanism via inhibition of adipocyte lipolysis and subsequent effects on lipid partitioning. Pair-feeding experiments further revealed that effects of GSK-LSD1 on hyperglycemia and NAFLD are not a consequence of reduced food intake and weight loss. These findings suggest that targeting LSD1 could be a strategy for treatment of obesity and its associated complications including type 2 diabetes and NAFLD.

scholarly journals Targeting Autophagy to Counteract Obesity-Associated Oxidative Stress

Antioxidants ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 102
Author(s):  
Federico Pietrocola ◽  
José Manuel Bravo-San Pedro
Keyword(s):  
Oxidative Stress ◽  
Oxygen Species ◽  
Alcoholic Fatty Liver ◽  
Redox Biology ◽  
Obesity Therapy ◽  
Treatment Of Obesity ◽  
Novel Therapeutic Strategies ◽  
Alcoholic Fatty Liver Disease ◽  
Shed Light

Reactive oxygen species (ROS) operate as key regulators of cellular homeostasis within a physiological range of concentrations, yet they turn into cytotoxic entities when their levels exceed a threshold limit. Accordingly, ROS are an important etiological cue for obesity, which in turn represents a major risk factor for multiple diseases, including diabetes, cardiovascular disorders, non-alcoholic fatty liver disease, and cancer. Therefore, the implementation of novel therapeutic strategies to improve the obese phenotype by targeting oxidative stress is of great interest for the scientific community. To this end, it is of high importance to shed light on the mechanisms through which cells curtail ROS production or limit their toxic effects, in order to harness them in anti-obesity therapy. In this review, we specifically discuss the role of autophagy in redox biology, focusing on its implication in the pathogenesis of obesity. Because autophagy is specifically triggered in response to redox imbalance as a quintessential cytoprotective mechanism, maneuvers based on the activation of autophagy hold promises of efficacy for the prevention and treatment of obesity and obesity-related morbidities.

Impact of PPAR-α induction on glucose homoeostasis in alcohol-fed mice

2013 ◽  
Vol 125 (11) ◽  
pp. 501-511 ◽  
Author(s):  
Valérie Lebrun ◽  
Olivier Molendi-Coste ◽  
Nicolas Lanthier ◽  
Christine Sempoux ◽  
Patrice D. Cani ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Insulin Sensitivity ◽  
Alcohol Consumption ◽  
Insulin Signalling ◽  
Liver Steatosis ◽  
Hepatic Insulin Resistance ◽  
Alcoholic Fatty Liver ◽  
Glucose Homoeostasis

Alcohol consumption is a major cause of liver disease. It also associates with increased cardiovascular risk and Type 2 diabetes. ALD (alcoholic liver disease) and NAFLD (non-alcoholic fatty liver disease) share pathological features, pathogenic mechanisms and pattern of disease progression. In NAFLD, steatosis, lipotoxicity and liver inflammation participate to hepatic insulin resistance. The aim of the present study was to verify the effect of alcohol on hepatic insulin sensitivity and to evaluate the role of alcohol-induced steatosis and inflammation on glucose homoeostasis. C57BL/6J mice were fed for 20 days a modified Lieber–DeCarli diet in which the alcohol concentration was gradually increased up to 35% of daily caloric intake. OH (alcohol liquid diet)-fed mice had liver steatosis and inflammatory infiltration. In addition, these mice developed insulin resistance in the liver, but not in muscles, as demonstrated by euglycaemic–hyperinsulinaemic clamp and analysis of the insulin signalling cascade. Treatment with the PPAR-α (peroxisome-proliferator-activated receptor-α) agonist Wy14,643 protected against OH-induced steatosis and KC (Kupffer cell) activation and almost abolished OH-induced insulin resistance. As KC activation may modulate insulin sensitivity, we repeated the clamp studies in mice depleted in KC to decipher the role of macrophages. Depletion of KC using liposomes-encapsuled clodronate in OH-fed mice failed both to improve hepatic steatosis and to restore insulin sensitivity as assessed by clamp. Our study shows that chronic alcohol consumption induces steatosis, KC activation and hepatic insulin resistance in mice. PPAR-α agonist treatment that prevents steatosis and dampens hepatic inflammation also prevents alcohol-induced hepatic insulin resistance. However, KC depletion has little impact on OH-induced metabolic disturbances.

scholarly journals The Antiobesity Effects of Centrally Administered Neuromedin U and Neuromedin S Are Mediated Predominantly by the Neuromedin U Receptor 2 (NMUR2)

Endocrinology ◽  
2009 ◽  
Vol 150 (7) ◽  
pp. 3101-3109 ◽  
Author(s):  
Andrea Peier ◽  
Jennifer Kosinski ◽  
Kimberly Cox-York ◽  
Ying Qian ◽  
Kunal Desai ◽  
...  
Keyword(s):  
Food Intake ◽  
Energy Homeostasis ◽  
Central Administration ◽  
Diet Induced Obesity ◽  
Inhibit Food Intake ◽  
Selective Agonists ◽  
Treatment Of Obesity ◽  
The Brain ◽  
Deficient Mice

Neuromedin U (NMU) and neuromedin S (NMS) are structurally related neuropeptides that have been reported to modulate energy homeostasis. Pharmacological data have shown that NMU and NMS inhibit food intake when administered centrally and that NMU increases energy expenditure. Additionally, NMU-deficient mice develop obesity, whereas transgenic mice overexpressing NMU are lean and hypophagic. Two high-affinity NMU/NMS receptors, NMUR1 and NMUR2, have been identified. NMUR1 is predominantly expressed in the periphery, whereas NMUR2 is predominantly expressed in the brain, suggesting that the effects of centrally administered NMU and NMS are mediated by NMUR2. To evaluate the role of NMUR2 in the regulation of energy homeostasis, we characterized NMUR2-deficient (Nmur2−/−) mice. Nmur2−/− mice exhibited a modest resistance to diet-induced obesity that was at least in part due to reduced food intake. Acute central administration of NMU and NMS reduced food intake in wild-type but not in Nmur2−/− mice. The effects on activity and core temperature induced by centrally administered NMU were also absent in Nmur2−/− mice. Moreover, chronic central administration of NMU and NMS evoked significant reductions in body weight and sustained reductions in food intake in mice. In contrast, Nmur2−/− mice were largely resistant to these effects. Collectively, these data demonstrate that the anorectic and weight-reducing actions of centrally administered NMU and NMS are mediated predominantly by NMUR2, suggesting that NMUR2-selective agonists may be useful for the treatment of obesity.

scholarly journals Metabolic reprogramming via PPARα signaling in cardiac hypertrophy and failure: From metabolomics to epigenetics

2017 ◽  
Vol 313 (3) ◽  
pp. H584-H596 ◽  
Author(s):  
Junco Shibayama Warren ◽  
Shin-ichi Oka ◽  
Daniela Zablocki ◽  
Junichi Sadoshima
Keyword(s):  
Cardiac Hypertrophy ◽  
Current Knowledge ◽  
Critical Role ◽  
Cardiac Metabolism ◽  
Metabolic Reprogramming ◽  
Metabolic Phenotype ◽  
Global Changes ◽  
Peroxisome Proliferator ◽  
Metabolic Remodeling

Studies using omics-based approaches have advanced our knowledge of metabolic remodeling in cardiac hypertrophy and failure. Metabolomic analysis of the failing heart has revealed global changes in mitochondrial substrate metabolism. Peroxisome proliferator-activated receptor-α (PPARα) plays a critical role in synergistic regulation of cardiac metabolism through transcriptional control. Metabolic reprogramming via PPARα signaling in heart failure ultimately propagates into myocardial energetics. However, emerging evidence suggests that the expression level of PPARα per se does not always explain the energetic state in the heart. The transcriptional activities of PPARα are dynamic, yet highly coordinated. An additional level of complexity in the PPARα regulatory mechanism arises from its ability to interact with various partners, which ultimately determines the metabolic phenotype of the diseased heart. This review summarizes our current knowledge of the PPARα regulatory mechanisms in cardiac metabolism and the possible role of PPARα in epigenetic modifications in the diseased heart. In addition, we discuss how metabolomics can contribute to a better understanding of the role of PPARα in the progression of cardiac hypertrophy and failure.

scholarly journals Glucose-6 Phosphate, a Central Hub for Liver Carbohydrate Metabolism

Metabolites ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 282 ◽  
Author(s):  
Fabienne Rajas ◽  
Amandine Gautier-Stein ◽  
Gilles Mithieux
Keyword(s):  
Glucose Metabolism ◽  
Metabolic Diseases ◽  
De Novo ◽  
Glycogen Synthesis ◽  
Metabolic Reprogramming ◽  
De Novo Lipogenesis ◽  
Type I ◽  
Alcoholic Fatty Liver ◽  
Hexosamine Pathway

Cells efficiently adjust their metabolism according to the abundance of nutrients and energy. The ability to switch cellular metabolism between anabolic and catabolic processes is critical for cell growth. Glucose-6 phosphate is the first intermediate of glucose metabolism and plays a central role in the energy metabolism of the liver. It acts as a hub to metabolically connect glycolysis, the pentose phosphate pathway, glycogen synthesis, de novo lipogenesis, and the hexosamine pathway. In this review, we describe the metabolic fate of glucose-6 phosphate in a healthy liver and the metabolic reprogramming occurring in two pathologies characterized by a deregulation of glucose homeostasis, namely type 2 diabetes, which is characterized by fasting hyperglycemia; and glycogen storage disease type I, where patients develop severe hypoglycemia during short fasting periods. In these two conditions, dysfunction of glucose metabolism results in non-alcoholic fatty liver disease, which may possibly lead to the development of hepatic tumors. Moreover, we also emphasize the role of the transcription factor carbohydrate response element-binding protein (ChREBP), known to link glucose and lipid metabolisms. In this regard, comparing these two metabolic diseases is a fruitful approach to better understand the key role of glucose-6 phosphate in liver metabolism in health and disease.

scholarly journals Gs-coupled GPCR signalling in AgRP neurons triggers sustained increase in food intake

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Ken-ichiro Nakajima ◽  
Zhenzhong Cui ◽  
Chia Li ◽  
Jaroslawna Meister ◽  
Yinghong Cui ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Potential Role ◽  
G Protein Coupled Receptors ◽  
Signalling Cascades ◽  
Treatment Of Obesity ◽  
G Protein Coupled ◽  
Stimulation Of ◽  
Sustained Increase

Abstract Agouti-related peptide (AgRP) neurons of the hypothalamus play a key role in regulating food intake and body weight, by releasing three different orexigenic molecules: AgRP; GABA; and neuropeptide Y. AgRP neurons express various G protein-coupled receptors (GPCRs) with different coupling properties, including Gs-linked GPCRs. At present, the potential role of Gs-coupled GPCRs in regulating the activity of AgRP neurons remains unknown. Here we show that the activation of Gs-coupled receptors expressed by AgRP neurons leads to a robust and sustained increase in food intake. We also provide detailed mechanistic data linking the stimulation of this class of receptors to the observed feeding phenotype. Moreover, we show that this pathway is clearly distinct from other GPCR signalling cascades that are operative in AgRP neurons. Our data suggest that drugs able to inhibit this signalling pathway may become useful for the treatment of obesity.

scholarly journals A constitutive active allele of the transcription factor Msn2 mimicking low PKA activity dictates metabolic remodeling in yeast

2018 ◽  
Vol 29 (23) ◽  
pp. 2848-2862 ◽  
Author(s):  
Vera Pfanzagl ◽  
Wolfram Görner ◽  
Martin Radolf ◽  
Alexandra Parich ◽  
Rainer Schuhmacher ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Signature ◽  
Metabolic Reprogramming ◽  
Diauxic Shift ◽  
Environmental Stress Response ◽  
Metabolic Switch ◽  
Metabolic Remodeling ◽  
Active Allele ◽  
Limited Degree

In yeast, protein kinase A (PKA) adjusts transcriptional profiles, metabolic rates, and cell growth in accord with carbon source availability. PKA affects gene expression mostly via the transcription factors Msn2 and Msn4, two key regulators of the environmental stress response. Here we analyze the role of the PKA-Msn2 signaling module using an Msn2 allele that harbors serine-to-alanine substitutions at six functionally important PKA motifs (Msn2A6) . Expression of Msn2A6 mimics low PKA activity, entails a transcription profile similar to that of respiring cells, and prevents formation of colonies on glucose-containing medium. Furthermore, Msn2A6 leads to high oxygen consumption and hence high respiratory activity. Substantially increased intracellular concentrations of several carbon metabolites, such as trehalose, point to a metabolic adjustment similar to diauxic shift. This partial metabolic switch is the likely cause for the slow-growth phenotype in the presence of glucose. Consistently, Msn2A6 expression does not interfere with growth on ethanol and tolerated is to a limited degree in deletion mutant strains with a gene expression signature corresponding to nonfermentative growth. We propose that the lethality observed in mutants with hampered PKA activity resides in metabolic reprogramming that is initiated by Msn2 hyperactivity.

Eat, run, and…shiver? From the exercise – diet and energy balance symposium at CSEP 2005

2007 ◽  
Vol 32 (3) ◽  
pp. 503-504
Author(s):  
Éric Doucet
Keyword(s):  
Weight Loss ◽  
Energy Balance ◽  
Food Intake ◽  
Exercise Physiology ◽  
Canadian Society ◽  
Short Introduction ◽  
Novel Proteins ◽  
Treatment Of Obesity ◽  
Successful Weight Loss

This short introduction includes a brief description of papers that were prepared following the “Symposium on Exercise – Diet and Energy Balance”, which was presented at the Canadian Society for Exercise Physiology annual meeting in the autumn of 2005. Briefly, these three papers discuss findings related to (i) the emerging role of exercise in the treatment of obesity and its co-morbidities, (ii) the role of novel proteins secreted by fat, and (iii) the control of appetite and food intake after successful weight loss.

scholarly journals Surgical treatment of obesity

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 617 ◽  
Author(s):  
Vance L. Albaugh ◽  
Naji N. Abumrad
Keyword(s):  
Bariatric Surgery ◽  
Chronic Diseases ◽  
Metabolic Surgery ◽  
Future Research ◽  
Obesity Prevalence ◽  
Alcoholic Fatty Liver ◽  
Beneficial Effects ◽  
Treatment Of Obesity

Obesity prevalence continues to increase worldwide, as do the numerous chronic diseases associated with obesity, including diabetes, non-alcoholic fatty liver disease, dyslipidemia, and hypertension. The prevalence of bariatric surgery also continues to increase and remains the most effective and sustainable treatment for obesity. Over the last several years, numerous prospective and longitudinal studies have demonstrated the benefits of bariatric surgery on weight loss, mortality, and other chronic diseases. Even though the mechanisms underlying many of these beneficial effects remain poorly understood, surgical management of obesity continues to increase given its unmatched efficacy. In this commentary, we discuss recent clinical advancements as well as several areas needed for future research, including indications for bariatric and metabolic surgery, determination of responders and non-responders, metabolic surgery in non-obese individuals, and the evolving role of bariatric surgery in adolescents.

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