Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice.

Shutter, John R.; Graham, Melissa; Kinsey, Alfred C.; Scully, Sheila; Lüthy, Roland; Stark, Kevin L.

doi:10.1101/gad.11.5.593

Cited by 605 publications

(442 citation statements)

References 33 publications

Supporting

Mentioning

425

Contrasting

Unclassified

Order By: Relevance

“…The resulting phenotype is characterized by a single nonmodulated coat color and obesity. Investigations into the cause of the obesity phenotype identified AGRP by a match of its C-terminal cysteine spacing to that found in the agouti protein (8,17). …”

mentioning

confidence: 99%

High-Resolution NMR Structure of the Chemically-Synthesized Melanocortin Receptor Binding Domain AGRP(87−132) of the Agouti-Related Protein^,

et al. 2001

View full text Add to dashboard Cite

The agouti-related protein (AGRP) is an endogenous antagonist of the melanocortin receptors MC3R and MC4R found in the hypothalamus and exhibits potent orexigenic (appetite-stimulating) activity. The cysteine-rich C-terminal domain of this protein, corresponding to AGRP(87-132), contains five disulfide bonds and exhibits receptor binding affinity and antagonism equivalent to that of the full-length protein. The three-dimensional structure of this domain has been determined by 1 H NMR at 800 MHz. The first 34 residues of AGRP(87-132) are well-ordered and contain a three-stranded antiparallel sheet, where the last two strands form a hairpin. The relative spatial positioning of the disulfide cross-links demonstrates that the ordered region of AGRP(87-132) adopts the inhibitor cystine knot (ICK) fold previously identified for numerous invertebrate toxins. Interestingly, this may be the first example of a mammalian protein assigned to the ICK superfamily. The hairpin's turn region presents a triplet of residues (Arg-Phe-Phe) known to be essential for melanocortin receptor binding. The structure also suggests that AGRP possesses an additional melanocortin-receptor contact region within a loop formed by the first 16 residues of its C-terminal domain. This specific region shows little sequence homology to the corresponding region of the agouti protein, which is an MC1R antagonist involved in pigmentation. Consideration of these sequence differences, along with recent experiments on mutant and chimeric melanocortin receptors, allows us to postulate that this loop in the first 16 residues of its C-terminal domain confers AGRP's distinct selectivity for MC3R and MC4R.Obesity and associated disorders such as diabetes are now at epidemic levels in the United States and other developed countries (1, 2). An understanding at the molecular level of the normal processes governing energy homeostasis and weight regulation is therefore essential for developing a comprehensive understanding of these disorders and producing effective pharmaceutical treatments. Recent studies have demonstrated the key role played by brain melanocortin receptors (MCRs) in the regulation of energy homeostasis (3-6). Although MCRs are found in various tissues, these studies indicate that the specific receptors MC3R and MC4R are directly implicated in energy balance. All MCRs are G-protein-coupled receptors (GPCRs) that up-regulate the production of cAMP in the presence of small endogenous peptide agonists (7). These agonists are derived in vivo from the single pro-opiomelanocortin peptide (POMC) that is cleaved post-translationally to form the melanocortinstimulating hormones (MSHs) and the adrenocorticotropin hormone (ACTH). MCR function is also modulated by potent endogenous antagonists known as the agouti protein and the agouti-related protein (AGRP) that indeed may exert even greater control over MCR signaling than the peptide agonists (8-11). Relative to the small peptide agonists, these antagonists are larger in size and possess a five-dis...

show abstract

mentioning

confidence: 99%

High-Resolution NMR Structure of the Chemically-Synthesized Melanocortin Receptor Binding Domain AGRP(87−132) of the Agouti-Related Protein^,

et al. 2001

View full text Add to dashboard Cite

show abstract

“…90,91 A unique component of the melanocortin regulatory system is an endogenous MC4-R antagonist, agouti-related protein (AgRP). [92][93][94] Interestingly, AgRP is produced exclusively in the Arc in rodents, monkeys, and humans. 71,72,[93][94][95][96][97] Alpha-MSH-producing (Figure 2a, c) and AgRP-producing (Figure 3c, e) neurons are distributed and segregated in the medial and lateral regions of the Arc, respectively.…”

mentioning

confidence: 99%

Body weight is regulated by the brain: a link between feeding and emotion

2005

View full text Add to dashboard Cite

Regulated energy homeostasis is fundamental for maintaining life. Unfortunately, this critical process is affected in a high number of mentally ill patients. Eating disorders such as anorexia nervosa are prevalent in modern societies. Impaired appetite and weight loss are common in patients with depression. In addition, the use of neuroleptics frequently produces obesity and diabetes mellitus. However, the neural mechanisms underlying the pathophysiology of these behavioral and metabolic conditions are largely unknown. In this review, we first concentrate on the established brain machinery of food intake and body weight, especially on the melanocortin and neuropeptide Y (NPY) systems as illustration. These systems play a critical role in receiving and processing critical peripheral metabolic cues such as leptin and ghrelin. It is also notable that both systems modulate emotion and motivated behavior as well. Secondly, we discuss the significance and potential promise of multidisciplinary molecular and neuroanatomic techniques that will likely increase the understanding of brain circuitries coordinating energy homeostasis and emotion. Finally, we introduce several lines of evidence suggesting a link between the melanocortin/NPY systems and several neurotransmitter systems on which many of the psychotropic agents exert their influence. Maintaining energy homeostasis is fundamental for survival. However, obesity due to over-nutrition is an increasing worldwide public health problem. 1 In psychiatric practice, on the other hand, impaired appetite is one of the crucial issues. Anorexia and weight loss are common, for example, in patients suffering from depression. Eating disorders are medically intractable and life threatening. In addition, the so-called 'atypical' antipsychotic agents, currently and widely used to treat psychoses, often induce hyperphagia, obesity, and diabetes mellitus. [2][3][4] In the past decade, fortunately, there has been remarkable progress in understanding the molecular mechanisms of food intake and body weight. This is due in large part to increased research activity towards combating the rising incidences of obesity and associated metabolic disorders. As a result, it is now established that the central nervous system (CNS) senses and processes peripheral metabolic cues including leptin 5 and ghrelin, 6,7 resulting in coordinated energy homeostasis. However, the pathophysiology of the disequilibrium between energy intake and expenditure in psychiatric disorders remains largely unknown. Nevertheless, evidence suggests that several CNS systems regulating energy balance may be dysregulated in patients with mental illnesses, for example, eating disorders, and drug addiction. [8][9][10][11][12][13][14] In the current review, we will illustrate the neuroanatomic and molecular genetic aspects of the melanocortin and neuropeptide Y (NPY) systems residing in the CNS downstream of leptin and ghrelin, to discuss the neural bases of feeding, metabolism, and emotion. Additionally, we point the reader to...

show abstract

“…A AGRP (inicialmente chamada de ART, ou transcrito relacionado a agouti) foi recentemente clonada em virtude de sua homologia com a proteína agouti do camundongo (150). A AGRP tem 132 aminoácidos, um a mais que a proteína agouti (151).…”

Section: G Proteína Relacionada a Agouti (Agrp)unclassified

Aspectos fisiológicos do balanço energético

Mancini

Halpern

2002

Arq Bras Endocrinol Metab

View full text Add to dashboard Cite

RESUMOconhecidos. Nesta revisão, abordamos os nutrientes, monoaminas e peptídeos que podem levar a redução da ingestão e, em alguns casos, aumentar a ingestão de alimentos. Vários desses mecanismos podem levar ao desenvolvimento de novas abordagens no tratamento da obesidade ou na elucidação do mecanismo de ação de agentes farmacológicos. NUTRIENTES Agentes de Ação Periférica a. Análogos e metabólitos da hexoseA teoria glicostática (1) propõe que taxas de utilização de glicose podem ser sinais para iniciar ou ultimar a ingestão alimentar.Glicose. Uma diminuição no nível de glicose pode preceder e iniciar a alimentação em animais e humanos (2,3). Infusões periféricas de glicose diminuem a ingestão alimentar em animais experimentais, sendo o nervo vago a conexão entre os glicorreceptores periféricos e o cérebro. Quando glicose é infundida na circulação portal, a descarga de aferentes vagais é reduzida à medida que a concentração de glicose aumenta (4). A infusão de glicose ou arginina diminui a taxa de transmissão aferente e aumenta a transmissão simpática eferente ao tecido adiposo marrom (5).

show abstract

Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice.

Cited by 605 publications

References 33 publications

High-Resolution NMR Structure of the Chemically-Synthesized Melanocortin Receptor Binding Domain AGRP(87−132) of the Agouti-Related Protein^,

High-Resolution NMR Structure of the Chemically-Synthesized Melanocortin Receptor Binding Domain AGRP(87−132) of the Agouti-Related Protein^,

Body weight is regulated by the brain: a link between feeding and emotion

Aspectos fisiológicos do balanço energético

Contact Info

Product

Resources

About

Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice.

Cited by 605 publications

References 33 publications

High-Resolution NMR Structure of the Chemically-Synthesized Melanocortin Receptor Binding Domain AGRP(87−132) of the Agouti-Related Protein,

High-Resolution NMR Structure of the Chemically-Synthesized Melanocortin Receptor Binding Domain AGRP(87−132) of the Agouti-Related Protein,

Body weight is regulated by the brain: a link between feeding and emotion

Aspectos fisiológicos do balanço energético

Contact Info

Product

Resources

About

High-Resolution NMR Structure of the Chemically-Synthesized Melanocortin Receptor Binding Domain AGRP(87−132) of the Agouti-Related Protein^,

High-Resolution NMR Structure of the Chemically-Synthesized Melanocortin Receptor Binding Domain AGRP(87−132) of the Agouti-Related Protein^,