scholarly journals 60 YEARS OF POMC: Regulation of feeding and energy homeostasis by α-MSH

2016 ◽  
Vol 56 (4) ◽  
pp. T157-T174 ◽  
Author(s):  
Erica J P Anderson ◽  
Isin Çakir ◽  
Sheridan J Carrington ◽  
Roger D Cone ◽  
Masoud Ghamari-Langroudi ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Critical Role ◽  
Melanocortin System ◽  
Melanocyte Stimulating Hormone ◽  
Syndromic Obesity ◽  
Melanocortin Peptides ◽  
History Of ◽  
Glucocorticoid Production ◽  
The Brain ◽  
Biological Actions

The melanocortin peptides derived from pro-opiomelanocortin (POMC) were originally understood in terms of the biological actions of α-melanocyte-stimulating hormone (α-MSH) on pigmentation and adrenocorticotrophic hormone on adrenocortical glucocorticoid production. However, the discovery of POMC mRNA and melanocortin peptides in the CNS generated activities directed at understanding the direct biological actions of melanocortins in the brain. Ultimately, discovery of unique melanocortin receptors expressed in the CNS, the melanocortin-3 (MC3R) and melanocortin-4 (MC4R) receptors, led to the development of pharmacological tools and genetic models leading to the demonstration that the central melanocortin system plays a critical role in the regulation of energy homeostasis. Indeed, mutations in MC4R are now known to be the most common cause of early onset syndromic obesity, accounting for 2–5% of all cases. This review discusses the history of these discoveries, as well as the latest work attempting to understand the molecular and cellular basis of regulation of feeding and energy homeostasis by the predominant melanocortin peptide in the CNS, α-MSH.

The melanocortin system

2003 ◽  
Vol 284 (3) ◽  
pp. E468-E474 ◽  
Author(s):  
Ira Gantz ◽  
Tung M. Fong
Keyword(s):  
Sexual Function ◽  
Energy Homeostasis ◽  
Melanocortin Receptors ◽  
Experimental Basis ◽  
Melanocortin System ◽  
Genetic Studies ◽  
Melanocortin Peptides ◽  
Selective Agonists ◽  
Made In

The melanocortin system consists of melanocortin peptides derived from the proopiomelanocortin gene, five melanocortin receptors, two endogenous antagonists, and two ancillary proteins. This review provides an abbreviated account of the basic biochemistry, pharmacology, and physiology of the melanocortin system and highlights progress made in four areas. In particular, recent pharmacological and genetic studies have affirmed the role of melanocortins in pigmentation, inflammation, energy homeostasis, and sexual function. Development of selective agonists and antagonists is expected to further facilitate the investigation of these complex physiological functions and provide an experimental basis for new pharmacotherapies.

scholarly journals Depletion of Alpha-Melanocyte-Stimulating Hormone Induces Insatiable Appetite and Gains in Energy Reserves and Body Weight in Zebrafish

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 941
Author(s):  
Yang-Wen Hsieh ◽  
Yi-Wen Tsai ◽  
Hsin-Hung Lai ◽  
Chi-Yu Lai ◽  
Chiu-Ya Lin ◽  
...  
Keyword(s):  
Body Weight ◽  
Energy Homeostasis ◽  
Body Weight Gain ◽  
Genetically Engineered ◽  
Melanocortin Receptor ◽  
Synthetic Analog ◽  
Melanocortin System ◽  
Releasing Hormone ◽  
Melanocyte Stimulating Hormone ◽  
Stimulating Hormone

The functions of anorexigenic neurons secreting proopiomelanocortin (POMC)/alpha-melanocyte-stimulating hormone (α-MSH) of the melanocortin system in the hypothalamus in vertebrates are energy homeostasis, food intake, and body weight regulation. However, the mechanisms remain elusive. This article reports on zebrafish that have been genetically engineered to produce α-MSH mutants, α-MSH−7aa and α-MSH−8aa, selectively lacking 7 and 8 amino acids within the α-MSH region, but retaining most of the other normal melanocortin-signaling (Pomc-derived) peptides. The α-MSH mutants exhibited hyperphagic phenotypes leading to body weight gain, as observed in human patients and mammalian models. The actions of several genes regulating appetite in zebrafish are similar to those in mammals when analyzed using gene expression analysis. These include four selected orexigenic genes: Promelanin-concentrating hormone (pmch), agouti-related protein 2 (agrp2), neuropeptide Y (npy), and hypothalamic hypocretin/orexin (hcrt). We also study five selected anorexigenic genes: Brain-derived neurotrophic factor (bdnf), single-minded homolog 1-a (sim1a), corticotropin-releasing hormone b (crhb), thyrotropin-releasing hormone (trh), and prohormone convertase 2 (pcsk2). The orexigenic actions of α-MSH mutants are rescued completely after hindbrain ventricle injection with a synthetic analog of α-MSH and a melanocortin receptor agonist, Melanotan II. We evaluate the adverse effects of MSH depletion on energy balance using the Alamar Blue metabolic rate assay. Our results show that α-MSH is a key regulator of POMC signaling in appetite regulation and energy expenditure, suggesting that it might be a potential therapeutic target for treating human obesity.

scholarly journals The central melanocortin system and human obesity

2020 ◽  
Author(s):  
Yongjie Yang ◽  
Yong Xu
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Energy Expenditure ◽  
Genetic Variants ◽  
Energy Homeostasis ◽  
Critical Role ◽  
Human Obesity ◽  
Melanocortin System ◽  
Prevalence Of Obesity

Abstract The prevalence of obesity and the associated comorbidities highlight the importance of understanding the regulation of energy homeostasis. The central melanocortin system plays a critical role in controlling body weight balance. Melanocortin neurons sense and integrate the neuronal and hormonal signals, and then send regulatory projections, releasing anorexigenic or orexigenic melanocortin neuropeptides, to downstream neurons to regulate the food intake and energy expenditure. This review summarizes the latest progress in our understanding of the role of the melanocortin pathway in energy homeostasis. We also review the advances in the identification of human genetic variants that cause obesity via mechanisms that affect the central melanocortin system, which have provided rational targets for treatment of genetically susceptible patients.

scholarly journals The leptin-dependent and -independent melanocortin signaling system: regulation of feeding and energy expenditure

2007 ◽  
Vol 193 (1) ◽  
pp. 1-9 ◽  
Author(s):  
Hiroyuki Shimizu ◽  
Kinji Inoue ◽  
Masatomo Mori
Keyword(s):  
Energy Expenditure ◽  
Energy Homeostasis ◽  
Leptin Receptor ◽  
Signaling System ◽  
Leptin Signaling ◽  
Melanocyte Stimulating Hormone ◽  
Hypothalamic Nuclei ◽  
Hypothalamic Arcuate Nucleus ◽  
Melanocortin Signaling ◽  
The Brain

The brain hypothalamus coordinates extra-hypothalamic regions to maintain energy homeostasis through the regulation of food intake and energy expenditure. A number of anorexigenic and orexigenic molecules in the hypothalamic nuclei participate in the control of energy homeostasis. Leptin and pro-opiomelanocortin (POMC)-derived α-melanocyte-stimulating hormone are key anorectic molecules, and the leptin receptor and POMC gene are both expressed in the hypothalamic arcuate nucleus. Although it has been considered that melanocortin signaling is localized downstream to leptin signaling, data have accumulated to support the concept of a leptin-independent melanocortin signaling system. We focus on and review the melanocortin signaling system that functions dependently or independently of leptin signaling in the regulation of energy homeostasis.

scholarly journals Determination of the melanocortin-4 receptor structure identifies Ca2+ as a cofactor for ligand binding

Science ◽  
2020 ◽  
Vol 368 (6489) ◽  
pp. 428-433 ◽  
Author(s):  
Jing Yu ◽  
Luis E. Gimenez ◽  
Ciria C. Hernandez ◽  
Yiran Wu ◽  
Ariel H. Wein ◽  
...  
Keyword(s):  
G Protein ◽  
Energy Homeostasis ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Peptide Ligand ◽  
Melanocyte Stimulating Hormone ◽  
Melanocortin 4 Receptor ◽  
Syndromic Obesity ◽  
G Protein Coupled

The melanocortin-4 receptor (MC4R) is involved in energy homeostasis and is an important drug target for syndromic obesity. We report the structure of the antagonist SHU9119-bound human MC4R at 2.8-angstrom resolution. Ca2+ is identified as a cofactor that is complexed with residues from both the receptor and peptide ligand. Extracellular Ca2+ increases the affinity and potency of the endogenous agonist α-melanocyte–stimulating hormone at the MC4R by 37- and 600-fold, respectively. The ability of the MC4R crystallized construct to couple to ion channel Kir7.1, while lacking cyclic adenosine monophosphate stimulation, highlights a heterotrimeric GTP-binding protein (G protein)–independent mechanism for this signaling modality. MC4R is revealed as a structurally divergent G protein–coupled receptor (GPCR), with more similarity to lipidic GPCRs than to the homologous peptidic GPCRs.

scholarly journals Obesity Affects the Microbiota–Gut–Brain Axis and the Regulation Thereof by Endocannabinoids and Related Mediators

2020 ◽  
Vol 21 (5) ◽  
pp. 1554 ◽  
Author(s):  
Nicola Forte ◽  
Alba Clara Fernández-Rilo ◽  
Letizia Palomba ◽  
Vincenzo Di Marzo ◽  
Luigia Cristino
Keyword(s):  
Intestinal Microbiota ◽  
Energy Homeostasis ◽  
Critical Role ◽  
Hypothalamic Area ◽  
Peripheral Tissues ◽  
Regulatory Circuits ◽  
Bidirectional Communication ◽  
Factor Α ◽  
Fat Diets ◽  
The Brain

The hypothalamus regulates energy homeostasis by integrating environmental and internal signals to produce behavioral responses to start or stop eating. Many satiation signals are mediated by microbiota-derived metabolites coming from the gastrointestinal tract and acting also in the brain through a complex bidirectional communication system, the microbiota–gut–brain axis. In recent years, the intestinal microbiota has emerged as a critical regulator of hypothalamic appetite-related neuronal networks. Obesogenic high-fat diets (HFDs) enhance endocannabinoid levels, both in the brain and peripheral tissues. HFDs change the gut microbiota composition by altering the Firmicutes:Bacteroidetes ratio and causing endotoxemia mainly by rising the levels of lipopolysaccharide (LPS), the most potent immunogenic component of Gram-negative bacteria. Endotoxemia induces the collapse of the gut and brain barriers, interleukin 1β (IL1β)- and tumor necrosis factor α (TNFα)-mediated neuroinflammatory responses and gliosis, which alter the appetite-regulatory circuits of the brain mediobasal hypothalamic area delimited by the median eminence. This review summarizes the emerging state-of-the-art evidence on the function of the “expanded endocannabinoid (eCB) system” or endocannabinoidome at the crossroads between intestinal microbiota, gut-brain communication and host metabolism; and highlights the critical role of this intersection in the onset of obesity.

scholarly journals Sulfide catabolism ameliorates hypoxic brain injury

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Eizo Marutani ◽  
Masanobu Morita ◽  
Shuichi Hirai ◽  
Shinichi Kai ◽  
Robert M. H. Grange ◽  
...  
Keyword(s):  
Brain Injury ◽  
Mitochondrial Respiration ◽  
Energy Homeostasis ◽  
Critical Role ◽  
Ground Squirrels ◽  
Mammalian Brain ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Sulfide:Quinone Oxidoreductase ◽  
The Brain

AbstractThe mammalian brain is highly vulnerable to oxygen deprivation, yet the mechanism underlying the brain’s sensitivity to hypoxia is incompletely understood. Hypoxia induces accumulation of hydrogen sulfide, a gas that inhibits mitochondrial respiration. Here, we show that, in mice, rats, and naturally hypoxia-tolerant ground squirrels, the sensitivity of the brain to hypoxia is inversely related to the levels of sulfide:quinone oxidoreductase (SQOR) and the capacity to catabolize sulfide. Silencing SQOR increased the sensitivity of the brain to hypoxia, whereas neuron-specific SQOR expression prevented hypoxia-induced sulfide accumulation, bioenergetic failure, and ischemic brain injury. Excluding SQOR from mitochondria increased sensitivity to hypoxia not only in the brain but also in heart and liver. Pharmacological scavenging of sulfide maintained mitochondrial respiration in hypoxic neurons and made mice resistant to hypoxia. These results illuminate the critical role of sulfide catabolism in energy homeostasis during hypoxia and identify a therapeutic target for ischemic brain injury.

Chips with Everything

2017 ◽  
Author(s):  
David Segal
Keyword(s):  
Quantum Computing ◽  
Integrated Circuits ◽  
Critical Role ◽  
Moore’S Law ◽  
Moore's Law ◽  
Silicon Chips ◽  
History Of ◽  
Future Potential ◽  
Digital Computers ◽  
Dna Computer

Chapter 3 highlights the critical role materials have in the development of digital computers. It traces developments from the cat’s whisker to valves through to relays and transistors. Accounts are given for transistors and the manufacture of integrated circuits (silicon chips) by use of photolithography. Future potential computing techniques, namely quantum computing and the DNA computer, are covered. The history of computability and Moore’s Law are discussed.

scholarly journals L2HGDH Missense Variant in a Cat with L-2-Hydroxyglutaric Aciduria

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 682
Author(s):  
Matthias Christen ◽  
Nils Janzen ◽  
Anne Fraser ◽  
Adrian C. Sewell ◽  
Vidhya Jagannathan ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Genetic Defect ◽  
Clinical Signs ◽  
Missense Variant ◽  
Microcytic Anemia ◽  
Abnormal Behavior ◽  
Functional Candidate Gene ◽  
History Of ◽  
The Brain ◽  
Hydroxyglutaric Acid

A 7-month-old, spayed female, domestic longhair cat with L-2-hydroxyglutaric aciduria (L-2-HGA) was investigated. The aim of this study was to investigate the clinical signs, metabolic changes and underlying genetic defect. The owner of the cat reported a 4-month history of multiple paroxysmal seizure-like episodes, characterized by running around the house, often in circles, with abnormal behavior, bumping into obstacles, salivating and often urinating. The episodes were followed by a period of disorientation and inappetence. Neurological examination revealed an absent bilateral menace response. Routine blood work revealed mild microcytic anemia but biochemistry, ammonia, lactate and pre- and post-prandial bile acids were unremarkable. MRI of the brain identified multifocal, bilaterally symmetrical and T2-weighted hyperintensities within the prosencephalon, mesencephalon and metencephalon, primarily affecting the grey matter. Urinary organic acids identified highly increased levels of L-2-hydroxyglutaric acid. The cat was treated with the anticonvulsants levetiracetam and phenobarbitone and has been seizure-free for 16 months. We sequenced the genome of the affected cat and compared the data to 48 control genomes. L2HGDH, coding for L-2-hydroxyglutarate dehydrogenase, was investigated as the top functional candidate gene. This search revealed a single private protein-changing variant in the affected cat. The identified homozygous variant, XM_023255678.1:c.1301A>G, is predicted to result in an amino acid change in the L2HGDH protein, XP_023111446.1:p.His434Arg. The available clinical and biochemical data together with current knowledge about L2HGDH variants and their functional impact in humans and dogs allow us to classify the p.His434Arg variant as a causative variant for the observed neurological signs in this cat.

Sign in / Sign up

Export Citation Format

Share Document