scholarly journals Arcuate nucleus-dependent regulation of metabolism - pathways to obesity and diabetes mellitus

2021 ◽  
Author(s):  
Alexander Jais ◽  
Jens C Brüning
Keyword(s):  
Glucose Homeostasis ◽  
Arcuate Nucleus ◽  
Energy State ◽  
Energy Status ◽  
Integrative Physiology ◽  
Time Control ◽  
Obesity And Diabetes ◽  
Adiposity Signals ◽  
Treatment Of Obesity ◽  
Novel Therapeutic Strategies

Abstract The central nervous system (CNS) receives information from afferent neurons, circulating hormones and absorbed nutrients and integrates this information to orchestrate the actions of the neuroendocrine and autonomic nervous systems in maintaining systemic metabolic homeostasis. Particularly the arcuate nucleus of the hypothalamus (ARC) is of pivotal importance for primary sensing of adiposity signals, such as leptin and insulin, and circulating nutrients, such as glucose. Importantly, energy state-sensing neurons in the ARC not only regulate feeding but at the same time control multiple physiological functions, such as glucose homeostasis, blood pressure and innate immune responses. These findings have defined them as master regulators, which adapt integrative physiology to the energy state of the organism. The disruption of this fine-tuned control leads to an imbalance between energy intake and expenditure as well as deregulation of peripheral metabolism. Improving our understanding of the cellular, molecular and functional basis of this regulatory principle in the CNS could set the stage for developing novel therapeutic strategies for the treatment of obesity and metabolic syndrome. In this review, we summarize novel insights with a particular emphasis on ARC neurocircuitries regulating food intake and glucose homeostasis and sensing factors that inform the brain of the organismal energy status.

scholarly journals Bile Acid Signaling in Liver Metabolism and Diseases

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Tiangang Li ◽  
John Y. L. Chiang
Keyword(s):  
Bile Acid ◽  
Molecular Mechanisms ◽  
Acid Metabolism ◽  
Bile Acid Metabolism ◽  
Glucose And Lipid Metabolism ◽  
Obesity And Diabetes ◽  
Bile Acid Binding ◽  
Glucose And Lipid Homeostasis ◽  
Treatment Of Obesity ◽  
Novel Therapeutic Strategies

Obesity, diabetes, and metabolic syndromes are increasingly recognized as health concerns worldwide. Overnutrition and insulin resistance are the major causes of diabetic hyperglycemia and hyperlipidemia in humans. Studies in the past decade provide evidence that bile acids are not just biological detergents facilitating gut nutrient absorption, but also important metabolic regulators of glucose and lipid homeostasis. Pharmacological alteration of bile acid metabolism or bile acid signaling pathways such as using bile acid receptor agonists or bile acid binding resins may be a promising therapeutic strategy for the treatment of obesity and diabetes. On the other hand, bile acid signaling is complex, and the molecular mechanisms mediating the bile acid effects are still not completely understood. This paper will summarize recent advances in our understanding of bile acid signaling in regulation of glucose and lipid metabolism, and the potentials of developing novel therapeutic strategies that target bile acid metabolism for the treatment of metabolic disorders.

scholarly journals Hypothalamic WNT Signalling Is Impaired During Obesity and Reinstated by Leptin Treatment in Male Mice

Endocrinology ◽  
2013 ◽  
Vol 154 (12) ◽  
pp. 4737-4745 ◽  
Author(s):  
Jonas Benzler ◽  
Zane B. Andrews ◽  
Corinna Pracht ◽  
Sigrid Stöhr ◽  
Peter R. Shepherd ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Glucose Homeostasis ◽  
Wnt Pathway ◽  
Target Genes ◽  
Arcuate Nucleus ◽  
Glycogen Synthase ◽  
Active Form ◽  
Energy Status ◽  
Gsk 3Β ◽  
Deficient Mice

The WNT pathway has been well characterized in embryogenesis and tumorigenesis. In humans, specific polymorphisms in the T cell-specific transcription factor 7 and the WNT coreceptor, low-density lipoprotein receptor-related protein-6 (LRP-6), both prominent components of this pathway, correlate with a higher incidence of type 2 diabetes, suggesting that the WNT pathway might be involved in the control of adult glucose homeostasis. We previously demonstrated that glycogen-synthase-kinase-3β (GSK-3β), the key enzyme of the WNT pathway, is increased in the hypothalamus during obesity and exacerbates high-fat diet-induced weight gain as well as glucose intolerance. These data suggest that WNT action in the hypothalamus might be required for normal glucose homeostasis. Here we characterized whether WNT signaling in general is altered in the hypothalamus of adult obese mice relative to controls. First we identified expression of multiple components of this pathway in the murine arcuate nucleus by in situ hybridization. In this region mRNA of ligands and target genes of the WNT pathway were down-regulated in obese and glucose-intolerant leptin-deficient mice. Similarly, the number of cells immunoreactive for the phosphorylated (active) form of the WNT-coreceptor LRP-6 was also decreased in leptin-deficient mice. Leptin treatment normalized expression of the WNT-target genes Axin-2 and Cylin-D1 and increased the number of phospho-LRP-6-immunoreactive cells reaching levels of lean controls. Leptin also increased the levels of phosphorylated (inactive) GSK-3β in the arcuate nucleus, and this effect was colocalized to neuropeptide Y neurons, suggesting that inactivation of GSK-3β may contribute to the neuroendocrine control of energy homeostasis. Taken together our findings identify hypothalamic WNT signaling as an important novel pathway that integrates peripheral information of the body's energy status encoded by leptin.

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.

Novel Non-invasive Approaches to the Treatment of Obesity: From Pharmacotherapy to Gene Therapy

2021 ◽  
Author(s):  
Angeliki M Angelidi ◽  
Matthew J Belanger ◽  
Alexander Kokkinos ◽  
Chrysi C Koliaki ◽  
Christos S Mantzoros
Keyword(s):  
Gene Therapy ◽  
Drug Targets ◽  
Energy Homeostasis ◽  
Treatment Options ◽  
Gastrointestinal Hormones ◽  
Interindividual Variation ◽  
Obesity Epidemic ◽  
Treatment Of Obesity ◽  
Underlying Mechanisms ◽  
Novel Therapeutic Strategies

Abstract Recent insights into the pathophysiologic underlying mechanisms of obesity have led to the discovery of several promising drug targets and novel therapeutic strategies to address the global obesity epidemic and its comorbidities. Current pharmacologic options for obesity management are largely limited in number and of modest efficacy/safety profile. Therefore, the need for safe and more efficacious new agents is urgent. Drugs which are currently under investigation modulate targets across a broad range of systems and tissues, including the central nervous system, gastrointestinal hormones, adipose tissue, kidney, liver, and skeletal muscle. Beyond pharmacotherapeutics, other potential antiobesity strategies are being explored, including novel drug delivery systems, vaccines, modulation of the gut microbiome, and gene therapy. The present review summarizes the pathophysiology of energy homeostasis, and highlights pathways being explored in the effort to develop novel antiobesity medications and interventions but does not cover devices and bariatric methods. Emerging pharmacologic agents and alternative approaches targeting these pathways and relevant research in both animals and humans are presented in detail. Special emphasis is given to treatment options at the end of the development pipeline and closer to the clinic, i.e., compounds that have a higher chance to be added to our therapeutic armamentarium in the near future. Ultimately, advancements in our understanding of the pathophysiology and interindividual variation of obesity may lead to multimodal and personalized approaches to obesity treatment that will result in safe, effective and sustainable weight loss until the root causes of the problem are identified and addressed.

scholarly journals CRISPR Knockdown of Kcnq3 Attenuates the M-current in NPY/AgRP Neurons

2020 ◽  
Author(s):  
Todd L. Stincic ◽  
Martha A. Bosch ◽  
Avery C. Hunker ◽  
Barbara Juarez ◽  
Ashley M. Connors ◽  
...  
Keyword(s):  
Arcuate Nucleus ◽  
Energy State ◽  
Input Resistance ◽  
Field Testing ◽  
Ingestive Behavior ◽  
Loss Of Function ◽  
Guide Rna ◽  
M Current ◽  
Subunit Mrna ◽  
Channel Expression

AbstractArcuate nucleus Neuropeptide Y/Agouti-related peptide (NPY/AgRP) neurons drive ingestive behavior in response to the internal and external environment of an organism. NPY/AgRP neurons are adjacent to the median eminence, a circumventricular organ, and circulating metabolic factors and hormones communicate the energy state of the animal via these neurons by altering the excitability of NPY/AgRP neurons, which produces an appropriate change in behavior to maintain homeostasis. One example of this plasticity is seen in the M-current, a subthreshold, non-inactivating K+ current that acts to modulate excitability. Fasting decreases while estradiol increases the M-current through regulation of subunit mRNA expression of Kcnq 2, 3, & 5. KCNQ2/3 heteromers are thought to mediate the majority of the M-current. Here we used a recently developed single adeno-associated viral (AAV) vector containing a recombinase-dependent Staphylococcus aureus Cas9 (SaCas9) and a single guide RNA against Kcnq3 to selectively delete Kcnq3 in NPY/AgRP neurons to produce a loss of function in the M-current. We found that this virus was effective at knocking down Kcnq3 but not Kcnq2 expression. With the reduced KCNQ3 channel expression NPY/AgRP neurons were more depolarized, exhibited a higher input resistance, and the rheobase current needed to induce firing was significantly reduced, indicative of increased excitability. Although the resulting decrease in the M-current did not overtly alter ingestive behavior, it did significantly reduce the locomotor activity as measured in open field testing. Therefore, the SaCas9-sgKcnq3 is efficient to knock down Kcnq3 expression thereby reducing the M-current and increasing the excitability of NPY/AgRP neurons.

scholarly journals Sucralose induced pancreatic toxicity in albino rats: Histomorphological evidence

2014 ◽  
Vol 31 (02) ◽  
pp. 123-127 ◽  
Author(s):  
S. Gupta ◽  
S. Kalra ◽  
V. Bharihoke ◽  
D. Dhurandhar
Keyword(s):  
Lethal Dose ◽  
Nutrient Sensing ◽  
Albino Rats ◽  
Artificial Sweetener ◽  
Distilled Water ◽  
Obesity And Diabetes ◽  
Pancreatic Toxicity ◽  
Treatment Of Obesity ◽  
Wistar Albino Rats ◽  
And Control

AbstractIn the present world people have become conscious of the fact that sugar is one of the commonest culprits for gain in weight and blood sugar in diabetes. One of the artificial sweetener, sucralose is widely used by diabetics is still under strict scrutiny because of the contradictory feedbacks obtained from various studies, often discouraging its use. Therefore, there arises a need to check whether the use of sucralose is safe or not. The present study was designed to determine to evaluate and compare the histological changes of sucralose on the islets of pancreas in albino rats. Methods: The adult Wistar albino rats were given sucralose orally by gavage in the dose of 3gms/kg body weight/day dissolved in distilled water and only distilled water for 30 days to experimental and control groups respectively. The animals were weighed prior to and after the experiment. The animals were sacrificed on day 31. The pancreas was dissected and observed grossly. Tissue was processed; paraffin blocks were prepared and 8 micron thick sections were cut. Sections were stained with Haemotoxylin and Eosin and Gomori's stains. Results: Pancreatic toxicity was observed in the form of vaculation of islets, lymphocytic infilterate, degeneration of islets and acini of Pancreas. The commonly used non-lethal dose of sucralose induced damage to Pancreas is startling. Conclusion: The results obtained have wide implications for nutrient sensing and nutrition in the treatment of obesity and diabetes.

scholarly journals Early Overnutrition Results in Early-Onset Arcuate Leptin Resistance and Increased Sensitivity to High-Fat Diet

Endocrinology ◽  
2010 ◽  
Vol 151 (4) ◽  
pp. 1598-1610 ◽  
Author(s):  
Maria M. Glavas ◽  
Melissa A. Kirigiti ◽  
Xiao Q. Xiao ◽  
Pablo J. Enriori ◽  
Sarah K. Fisher ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
High Fat Diet ◽  
Arcuate Nucleus ◽  
Leptin Resistance ◽  
Signal Transducer ◽  
High Fat ◽  
Insulin Tolerance ◽  
Obesity And Diabetes ◽  
Transcription 3

Childhood obesity increases the risk of adult obesity and diabetes, suggesting that early overnutrition permanently programs altered energy and glucose homeostasis. In the present studies, we used a mouse model to investigate whether early overnutrition increases susceptibility to obesity and insulin resistance in response to a high-fat diet (HFD). Litters from Swiss Webster dams were culled to three [chronic postnatal overnutrition (CPO)] or 10 (control) pups and then weaned onto standard chow at postnatal day (P) 23. At 6 wk of age, a subset of mice was placed on HFD, and glucose and insulin tolerance were examined at 16–17 wk of age. Leptin sensitivity was determined by hypothalamic phosphorylated signal transducer and activator of transcription-3 immunoreactivity at P16 and adulthood after ip leptin. CPO mice exhibited accelerated body weight gain and hyperleptinemia during the preweaning period but only a slightly heavier body weight and normal glucose tolerance in adulthood on standard chow diet. Importantly, CPO mice exhibited significant leptin resistance in the arcuate nucleus, demonstrated by reduced activation of phospho-signal transducer and activator of transcription-3, as early as P16 and throughout life, despite normalized leptin levels. In response to HFD, CPO but not control mice displayed insulin resistance in response to an insulin tolerance test. In conclusion, CPO mice exhibited early and persistent leptin resistance in the arcuate nucleus and, in response to HFD, rapid development of obesity and insulin resistance. These studies suggest that early overnutrition can permanently alter energy homeostasis and significantly increase susceptibility to obesity and insulin resistance.

NAFTA

Eating NAFTA ◽  
2018 ◽  
pp. 89-116
Author(s):  
Alyshia Gálvez
Keyword(s):  
Economic Policy ◽  
Weight Gain ◽  
Free Trade ◽  
Population Level ◽  
The Body ◽  
Obesity And Diabetes ◽  
Production And Consumption ◽  
Treatment Of Obesity ◽  
Abrupt Rise

The fourth chapter, “NAFTA: Free Trade in the Body,” describes the magnitude and characteristics of Mexico’s so-called obesity and diabetes epidemic and the current hypotheses for the causes and treatment of obesity for individuals and at the population level. The chapter points out some of the lesser known hypotheses for the abrupt rise in obesity and diet-related chronic diseases in the last few decades. Far from linking the rise of obesity to increased appetites for snacks and sodas, some of these hypotheses focus on ways that the production and consumption of processed foods and beverages have increased people’s exposure to chemicals with metabolic and endocrinological properties that produce weight gain and alter organ function. The methodological and empirical challenges of understanding the effects of economic policy, like free trade agreements, on the body are explored.

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