scholarly journals Neuropeptides in Obesity and Metabolic Disease

2018 ◽  
Vol 64 (1) ◽  
pp. 173-182 ◽  
Author(s):  
Agatha A van der Klaauw
Keyword(s):  
Neural Control ◽  
Energy Homeostasis ◽  
Energy State ◽  
Gut Hormones ◽  
Hormonal Control ◽  
Designer Drugs ◽  
Health Concern ◽  
Compensatory Mechanisms ◽  
Melanocortin 4 Receptor ◽  
Treatment Of Obesity

Abstract BACKGROUND The global rise in the prevalence of obesity and associated comorbidities such as type 2 diabetes, cardiovascular disease, and cancer represents a major public health concern. CONTENT Studies in rodents with the use of global and targeted gene disruption, and mapping of neurocircuitry by using optogenetics and designer receptors exclusively activated by designer drugs (DREADDs) have greatly advanced our understanding of the neural control of body weight. In conjunction with analytical chemistry techniques involving classical immunoassays and mass spectrometry, many neuropeptides that are key to energy homeostasis have been identified. The actions of neuropeptides are diverse, from paracrine modulation of local neurotransmission to hormonal control of distant target organs. SUMMARY Multiple hormones, such as the adipocyte-derived leptin, insulin, and gut hormones, and nutrients signal peripheral energy state to the central nervous system. Neurons in distinct areas of the hypothalamus and brainstem integrate and translate this information by both direct inhibitory/excitatory projections and anorexigenic or orexigenic neuropeptides into actions on food intake and energy expenditure. The importance of these neuropeptides in human energy balance is most powerfully illustrated by genetic forms of obesity that involve neuropeptides such as melanocortin-4-receptor (MC4R) deficiency. Drugs that mimic the actions of neuropeptides are being tested for the treatment of obesity. Successful therapeutic strategies in obesity will require in-depth knowledge of the neuronal circuits they are working in, the downstream targets, and potential compensatory mechanisms.

scholarly journals Dimorphic metabolic and endocrine disorders in mice lacking the constitutive androstane receptor

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Céline Lukowicz ◽  
Sandrine Ellero-Simatos ◽  
Marion Régnier ◽  
Fabiana Oliviero ◽  
Frédéric Lasserre ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Hepatic Steatosis ◽  
Energy Homeostasis ◽  
Metabolic Diseases ◽  
Constitutive Androstane Receptor ◽  
Developed Countries ◽  
Health Concern ◽  
Endocrine Disorders ◽  
Male Mice ◽  
Treatment Of Obesity

AbstractMetabolic diseases such as obesity, type II diabetes and hepatic steatosis are a public health concern in developed countries. The metabolic risk is gender‐dependent. The constitutive androstane receptor (CAR), which is at the crossroads between energy metabolism and endocrinology, has recently emerged as a promising therapeutic agent for the treatment of obesity and type 2 diabetes. In this study we sought to determine its role in the dimorphic regulation of energy homeostasis. We tracked male and female WT and CAR deficient (CAR−/−) mice for over a year. During aging, CAR−/− male mice developed hypercortisism, obesity, glucose intolerance, insulin insensitivity, dyslipidemia and hepatic steatosis. Remarkably, the latter modifications were absent, or minor, in female CAR−/− mice. When ovariectomized, CAR−/− female mice developed identical patterns of metabolic disorders as observed in male mice. These results highlight the importance of steroid hormones in the regulation of energy metabolism by CAR. They unveil a sexually dimorphic role of CAR in the maintenance of endocrine and metabolic homeostasis underscoring the importance of considering sex in treatment of metabolic diseases.

scholarly journals Appetite control

2005 ◽  
Vol 184 (2) ◽  
pp. 291-318 ◽  
Author(s):  
Katie Wynne ◽  
Sarah Stanley ◽  
Barbara McGowan ◽  
Steve Bloom
Keyword(s):  
Energy Homeostasis ◽  
Gut Hormones ◽  
The Body ◽  
Appetite Control ◽  
Homeostatic Process ◽  
The Past ◽  
Regulate Food Intake ◽  
Treatment Of Obesity ◽  
Physiological Systems

Our understanding of the physiological systems that regulate food intake and body weight has increased immensely over the past decade. Brain centres, including the hypothalamus, brainstem and reward centres, signal via neuropeptides which regulate energy homeostasis. Insulin and hormones synthesized by adipose tissue reflect the long-term nutritional status of the body and are able to influence these circuits. Circulating gut hormones modulate these pathways acutely and result in appetite stimulation or satiety effects. This review discusses central neuronal networks and peripheral signals which contribute energy homeostasis, and how a loss of the homeostatic process may result in obesity. It also considers future therapeutic targets for the treatment of obesity.

scholarly journals Food demand and meal size in mice with single or combined disruption of melanocortin type 3 and 4 receptors

2010 ◽  
Vol 298 (6) ◽  
pp. R1667-R1674 ◽  
Author(s):  
Deniz Atalayer ◽  
Kimberly L. Robertson ◽  
Carrie Haskell-Luevano ◽  
Amy Andreasen ◽  
Neil E. Rowland
Keyword(s):  
Energy Homeostasis ◽  
Receptor Gene ◽  
Gut Hormones ◽  
Brain Regions ◽  
Meal Size ◽  
Food Demand ◽  
Double Knockout ◽  
Melanocortin 4 Receptor ◽  
Melanocortin 4 Receptor Gene ◽  
Anorectic Effect

Mice with homozygous genetic disruption of the melanocortin-4 receptor gene (MC4R−/−) are known to be hyperphagic and become obese, while those with disruption of the melanocortin-3 receptor gene (MC3R−/−) do not become markedly obese. The contribution of MC3R signaling in energy homeostasis remains little studied. In the present work, we compare MC3R−/− mice with wild-type (WT), MC4R−/−, and mice bearing disruption of both genes (double knockout, DKO) on select feeding and neuroanatomical dimensions. DKO mice were significantly more obese than MC4R−/−, whereas MC3R−/− weighed the same as WT. In a food demand protocol, DKO and MC4R−/− were hyperphagic at low unit costs for food, due primarily to increased meal size. However, at higher costs, their intake dropped below that of WT and MC3R−/−, indicating increased elasticity of food demand. To determine whether this higher elasticity was due to either the genotype or to the obese phenotype, the same food demand protocol was conducted in dietary obese C57BL6 mice. They showed similar elasticity to lean mice, suggesting that the effect is of genotypic origin. To assess whether the increased meal size in MC4R−/− and DKO might be due to reduced CCK signaling, we examined the acute anorectic effect of peripherally administered CCK and subsequently the induction of c-Fos immunoreactivity in select brain regions. The anorectic effect of CCK was comparable in MC4R−/− , DKO, and WT, but it was unexpectedly absent in MC3R−/−. CCK-induced c-Fos was lower in the paraventricular nucleus in MC3R−/− than the other genotypes. These data are discussed in terms of demand functions for food intake, MC receptors involved in feeding, and their relation to actions of gut hormones, such as CCK, and to obesity.

scholarly journals Agouti-related protein (83-132) is a competitive antagonist at the human melanocortin-4 receptor: no evidence for differential interactions with pro-opiomelanocortin-derived ligands

2004 ◽  
Vol 180 (1) ◽  
pp. 183-191 ◽  
Author(s):  
LE Pritchard ◽  
D Armstrong ◽  
N Davies ◽  
RL Oliver ◽  
CA Schmitz ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Intracellular Camp ◽  
Related Protein ◽  
Dissociation Kinetics ◽  
Competitive Antagonist ◽  
Melanocyte Stimulating Hormone ◽  
Natural Ligand ◽  
Melanocortin 4 Receptor ◽  
Significant Difference ◽  
Agouti Related Protein

Interactions between pro-opiomelanocortin (POMC)-derived peptides, agouti-related protein (AGRP) and the melanocortin-4 receptor (MC4-R) are central to energy homeostasis. In this study we have undertaken comprehensive pharmacological analysis of these interactions using a CHOK1 cell line stably transfected with human MC4-R. Our main objectives were (1) to compare the relative affinities and potencies of POMC-derived peptides endogenously secreted within the hypothalamus, (2) to investigate the potency of AGRP(83-132) antagonism with respect to each POMC-derived peptide and (3) to determine whether AGRP(83-132) and POMC-derived peptides act allosterically or orthosterically. We have found that beta melanocyte-stimulating hormone (betaMSH), desacetyl alpha MSH (da-alphaMSH) and adrenocorticotrophic hormone all have very similar affinities and potencies at the MC4-R compared with the presumed natural ligand, alphaMSH. Moreover, even MSH precursors, such as beta lipotrophic hormone, showed significant binding and functional activity. Therefore, many POMC-derived peptides could have important roles in appetite regulation and it seems unlikely that alphaMSH is the sole physiological ligand. We have shown that AGRP(83-132) acts as a competitive antagonist. There was no significant difference in the potency of inhibition by AGRP(83-132) or agouti(87-132) at the MC4-R, regardless of which POMC peptide was used as an agonist. Furthermore, we have found that AGRP(83-132) has no effect on the dissociation kinetics of radiolabelled Nle4,D-Phe7 MSH from the MC4-R, indicating an absence of allosteric effects. This provides strong pharmacological evidence that AGRP(83-132) acts orthosterically at the MC4-R to inhibit Gs-coupled accumulation of intracellular cAMP.

scholarly journals Insulin blunts the response of glucose-excited neurons in the ventrolateral-ventromedial hypothalamic nucleus to decreased glucose

2009 ◽  
Vol 296 (5) ◽  
pp. E1101-E1109 ◽  
Author(s):  
Victoria E. Cotero ◽  
Vanessa H. Routh
Keyword(s):  
Energy Homeostasis ◽  
Ventromedial Hypothalamus ◽  
Glucose Sensing ◽  
Hypothalamic Nucleus ◽  
Compensatory Mechanisms ◽  
Glucose Levels ◽  
Compound C ◽  
Obesity And Diabetes ◽  
Extracellular Glucose ◽  
Pi3k Signaling Pathway

Insulin signaling is dysfunctional in obesity and diabetes. Moreover, central glucose-sensing mechanisms are impaired in these diseases. This is associated with abnormalities in hypothalamic glucose-sensing neurons. Glucose-sensing neurons reside in key areas of the brain involved in glucose and energy homeostasis, such as the ventromedial hypothalamus (VMH). Our results indicate that insulin opens the KATP channel on VMH GE neurons in 5, 2.5, and 0.1 mM glucose. Furthermore, insulin reduced the sensitivity of VMH GE neurons to a decrease in extracellular glucose level from 2.5 to 0.1 mM. This change in the glucose sensitivity in the presence of insulin was reversed by the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin (10 nM) but not by the mitogen-activated kinase (MAPK) inhibitor PD-98059 (PD; 50 μM). Finally, neither the AMPK inhibitor compound C nor the AMPK activator AICAR altered the activity of VMH GE neurons. These data suggest that insulin attenuates the ability of VMH GE neurons to sense decreased glucose via the PI3K signaling pathway. Furthermore, these data are consistent with the role of insulin as a satiety factor. That is, in the presence of insulin, glucose levels must decline further before GE neurons respond. Thus, the set point for detection of glucose deficit and initiation of compensatory mechanisms would be lowered.

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 Pharmacological treatment of obesity

2006 ◽  
Vol 50 (2) ◽  
pp. 377-389 ◽  
Author(s):  
Marcio C. Mancini ◽  
Alfredo Halpern
Keyword(s):  
Insulin Resistance ◽  
Pharmacological Treatment ◽  
Energy Homeostasis ◽  
Extensive Review ◽  
Obesity Management ◽  
Physiological Mechanisms ◽  
Triggering Factor ◽  
Treatment Of Obesity ◽  
Obesity Drugs ◽  
Cannabinoid Agonist

This review offers an overview of physiological agents, current therapeutics, as well as medications, which have been extensively used and those agents not currently available or non-classically considered anti-obesity drugs. As obesity - particularly that of central distribution - represents an important triggering factor for insulin resistance, its pharmacological treatment is relevant in the context of metabolic syndrome control. The authors present an extensive review on the criteria for anti-obesity management efficacy, on physiological mechanisms that regulate central and/or peripheral energy homeostasis (nutrients, monoamines, and peptides), on beta-phenethylamine pharmacological derivative agents (fenfluramine, dexfenfluramine, phentermine and sibutramine), tricyclic derivatives (mazindol), phenylpropanolamine derivatives (ephedrin, phenylpropanolamine), phenylpropanolamine oxytrifluorphenyl derivative (fluoxetine), a naftilamine derivative (sertraline) and a lipstatine derivative (orlistat). An analysis of all clinical trials - over ten-week long - is also presented for medications used in the management of obesity, as well as data about future medications, such as a the inverse cannabinoid agonist, rimonabant.

scholarly journals AMPK as a mediator of hormonal signalling

2009 ◽  
Vol 44 (2) ◽  
pp. 87-97 ◽  
Author(s):  
Chung Thong Lim ◽  
Blerina Kola ◽  
Márta Korbonits
Keyword(s):  
Protein Synthesis ◽  
Fatty Acid ◽  
Metabolic Disorders ◽  
Energy Homeostasis ◽  
Metabolic Effects ◽  
Whole Body ◽  
Acid Oxidation ◽  
Treatment Of Obesity ◽  
Amp Activated Protein Kinase ◽  
Hormonal Signalling

AMP-activated protein kinase (AMPK) is a key molecular player in energy homeostasis at both cellular and whole-body levels. AMPK has been shown to mediate the metabolic effects of hormones such as leptin, ghrelin, adiponectin, glucocorticoids and insulin as well as cannabinoids. Generally, activated AMPK stimulates catabolic pathways (glycolysis, fatty acid oxidation and mitochondrial biogenesis) and inhibits anabolic pathways (gluconeogenesis, glycogen, fatty acid and protein synthesis), and has a direct appetite-regulating effect in the hypothalamus. Drugs that activate AMPK, namely metformin and thiazolidinediones, are often used to treat metabolic disorders. Thus, AMPK is now recognised as a potential target for the treatment of obesity and associated co-morbidities.

A Review of Past and Present Weight Loss Strategies and the Potential Role of Bariatric Arterial Embolization

2020 ◽  
Vol 04 (02) ◽  
pp. 195-205
Author(s):  
Varun R. Danda ◽  
Christopher R. Bailey ◽  
Clifford R. Weiss
Keyword(s):  
Weight Loss ◽  
Treatment Options ◽  
Arterial Embolization ◽  
Health Concern ◽  
Lifestyle Modifications ◽  
Obesity Epidemic ◽  
Cost Treatment ◽  
Clinically Significant ◽  
Treatment Of Obesity ◽  
Bariatric Embolization

AbstractThe obesity epidemic is a growing public health concern that has a severe effect on the health care system with significant morbidity, mortality, and cost. Treatment options for obesity include lifestyle modifications, pharmacotherapy, and bariatric surgery. Newer, less-invasive therapies including endoscopic bariatric procedures have been developed in recent years to fill the treatment gap that exists between noninvasive approaches and surgery. Bariatric artery embolization (BAE) is a novel minimally invasive endovascular procedure that has been developed to treat obesity. Recent evidence has suggested that bariatric embolization is well tolerated and can induce clinically significant weight loss through a hormonally mediated mechanism. This article will review existing preclinical and clinical data, and explore future directions of the endovascular treatment of obesity.

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