Obesity, diabetes, and neoplasia in yellow
 A
 vy
 /‐ mice: ectopic expression of the
 agouti
 gene

Yen, Terence T.; Gill, Anne; Frigeri, Luciano G.; Barsh, Gregory S.; Wolff, George L.

doi:10.1096/fasebj.8.8.8181666

Cited by 299 publications

(190 citation statements)

References 51 publications

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“…It has been well established that A y /a mice are moderately hyperphagic with mature-onset obesity (5,45). On the other hand, ob/ob mice are voraciously hyperphagic with early-onset obesity (17,43).…”

Section: Discussionmentioning

confidence: 99%

Hyperleptinemia in A^y/a mice upregulates arcuate cocaine- and amphetamine-regulated transcript expression

Tsuruta

Yoshimatsu

Hidaka

et al. 2002

American Journal of Physiology-Endocrinology and Metabolism

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Sakata. Hyperleptinemia in A y /a mice upregulates arcuate cocaine-and amphetamine-regulated transcript expression. Am J Physiol Endocrinol Metab 282: E967-E973, 2002; 10.1152/ajpendo.00292.2001.-The effects of leptin on cocaine-and amphetamine-regulated transcript (CART) and agouti-related protein (AGRP) expression in the hypothalamic arcuate nucleus of obese A y /a mice were investigated. CART mRNA expression was upregulated by 41% and AGRP mRNA downregulated by 78% in hyperleptinemic A y /a mice relative to levels in lean a/a mice. The mRNA expression of these neuropeptides in either young nonobese A y /a mice or rats treated with SHU-9119, a synthetic melanocortin-4 receptor (MC4R) antagonist, did not differ significantly from that in the corresponding controls. After a 72-h fast, which decreased the concentration of serum leptin, CART and AGRP mRNA expression decreased and increased, respectively, in A y /a mice. The expression levels of these neuropeptides in leptin-deficient A y /a ob/ob double mutants were comparable to those in a/a ob/ob mice. Leptin thus modulates both CART and AGRP mRNA expression in obese A y /a mice, whereas leptin signals are blocked at the MCR4R level. Taken together, the present findings indicate that differential expression of these neuropeptides in A y /a and ob/ob mice results in dissimilar progression toward obesity. leptin; lethal yellow mice; agouti-related protein; arcuate nucleus LEPTIN HAS BEEN SHOWN TO INDUCE anorectic effects in rodents, at least in part, by signaling through the melanocortin-4 receptor (MC4R) (36). Agouti protein has a potent antagonistic effect on hypothalamic MC4R (7, 30), and rodents become hyperphagic when signaling is interrupted (19,31). Lethal yellow (A y /a) mice display ectopic overexpression of agouti protein in the brain, which results in defective proopiomelanocortin (POMC)/MC4R signaling and, upon maturation, obesity (7,16,30,44). Because these obese mice are both hyperleptinemic and insensitive to exogenous leptin treatment (16, 44), they are thought to be in a "leptin-resistant state." However, it has been reported that the major effects of POMC-and leptin-induced signals on body weight are independent and additive in A y /a ob/ob doubly mutant mice (3). In addition, full leptin responsiveness is restored in A y /a ob/ob mice (3). These findings indicate that defective signaling through MC4R does not necessarily impair leptin action completely. It is quite likely that leptin continues to act, at least in part, on some hypothalamic neuropeptides in A y /a mice.Cocaine-and amphetamine-regulated transcript (CART) was originally identified as a hypothalamic neuropeptide upregulated by cocaine and amphetamine treatment (6). Central administration of CART induces c-fos expression in several hypothalamic nuclei related with feeding control (11,42). Recombinant CART fragments decreased food intake in rodents (1, 29, 42), whereas anti-CART antibodies increased it (24). Asnicar et al. (2) have recently demonstrated that absence of CART results i...

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Section: Discussionmentioning

confidence: 99%

Hyperleptinemia in A^y/a mice upregulates arcuate cocaine- and amphetamine-regulated transcript expression

Tsuruta

Yoshimatsu

Hidaka

et al. 2002

American Journal of Physiology-Endocrinology and Metabolism

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“…A QTL located close to the PrP gene is associated with resistance to gastrointestinal nematode infection (marker ILST059 [86], see Fig. 1).…”

Section: Gastrointestinal Nematodesmentioning

confidence: 99%

“…GNAS1 is thought to be an imprinted gene [54,58]. While the ASIP gene encodes a paracrinesignaling molecule that causes hair follicle melanocytes to synthesize the yellow pigment, phaeomelanin, pleiotropic effects of this gene are known to include adult-onset obesity [86]. This is of particular interest following the observation that there is a relationship between PrP genotype and coat colour (which would most likely be under the control of the Agouti locus) in Soay and Shetland sheep 6 .…”

Section: Growth and Obesity Traitsmentioning

confidence: 99%

The evidence of associations between prion protein genotype and production, reproduction, and health traits in sheep

Sweeney

Hanrahan

2008

Vet. Res.

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“…This signal is provided by periodic changes of the agouti protein (ASIP) in the skin (9). The agouti lethal yellow mutation (A y /a) in the mouse results from the ectopic expression of the agouti protein in tissues outside of the skin, including the brain (16). The resulting phenotype is characterized by a single nonmodulated coat color and obesity.…”

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

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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...

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Obesity, diabetes, and neoplasia in yellow A ^vy /‐ mice: ectopic expression of the agouti gene

Cited by 299 publications

References 51 publications

Hyperleptinemia in A^y/a mice upregulates arcuate cocaine- and amphetamine-regulated transcript expression

Hyperleptinemia in A^y/a mice upregulates arcuate cocaine- and amphetamine-regulated transcript expression

The evidence of associations between prion protein genotype and production, reproduction, and health traits in sheep

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

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Obesity, diabetes, and neoplasia in yellow A vy /‐ mice: ectopic expression of the agouti gene

Cited by 299 publications

References 51 publications

Hyperleptinemia in Ay/a mice upregulates arcuate cocaine- and amphetamine-regulated transcript expression

Hyperleptinemia in Ay/a mice upregulates arcuate cocaine- and amphetamine-regulated transcript expression

The evidence of associations between prion protein genotype and production, reproduction, and health traits in sheep

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

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Product

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Obesity, diabetes, and neoplasia in yellow A ^vy /‐ mice: ectopic expression of the agouti gene

Hyperleptinemia in A^y/a mice upregulates arcuate cocaine- and amphetamine-regulated transcript expression

Hyperleptinemia in A^y/a mice upregulates arcuate cocaine- and amphetamine-regulated transcript expression

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