Acute intracerebroventricular administration of either carboxyl-terminal or amino-terminal fragments of agouti-related peptide produces a long-term decrease in energy expenditure in rats

Goto, Kyoko; Inui, Akio; Takimoto, Yoshiyuki; Yuzuriha, H; Asakawa, Akihiro; Kawamura, Y.; Tsuji, Hiroki; Takahara, Yukio; Takeyama, Chie; Katsuura, Goro; Kasuga, Masato

doi:10.3892/ijmm.12.3.379

Cited by 23 publications

(21 citation statements)

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“…Dietary fat intake can be reduced by injections of either enterostatin (33,34) or NPY (41) while Mu-opioid agonists will enhance fat intake (51). In this manuscript, we provide evidence for melanocortin signaling to affect dietary fat intake in a similar manner to that previously demonstrated within the hypothalamus (21,23,26,42). The importance of this CeA system and how it may interact with other systems within the amygdala or with the melanocortin network within the hypothalamus to affect fat intake remains to be evaluated.…”

Section: Perspectives and Significancesupporting

confidence: 64%

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Melanocortin activity in the amygdala controls appetite for dietary fat

Boghossian

Park

York

2010

American Journal of Physiology-Regulatory, Integrative and Comp

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The amygdala is rich in melanocortin 4 receptors. Because the reduction in dietary fat intake after enterostatin is injected in the central nucleus of the amygdala (CeA) is blocked by a melanocortin 4 receptor antagonist, we investigated the role of melanocortin activity in the CeA in regulating food intake and macronutrient choice. Sprague-Dawley rats, fitted with CeA cannulas, were fed either chow, a high-fat (HF) diet, or adapted to a two-choice HF or low-fat (LF) diet. Injections of the MC4R agonist melanotan II (MTII) in the CeA had a dose-dependent inhibitory effect on food intake that lasted for at least 24 h. This response was greater in rats fed a HF diet. The inverse agonist agouti-related protein (AgRP) and antagonist SHU-9119 increased food intake in a dose-dependent manner, with the hyperphagia lasting for 60 h. In rats adapted to a two-choice HF/LF diet, MTII decreased HF consumption but had no effect on LF consumption, resulting in a long-lasting decrease in total calorie intake (Ϫ35.5% after 24 h, P Ͻ 0.05). Total calorie intake increased in both AgRP-and SHU-9119-treated rats (32 and 109% after 24 h, respectively) as the result of increased intake of HF diet. There was no modification of LF consumption with AgRP treatment and a transient nonsignificant decrease with SHU-9119 treatment. Amygdala brain-derived neurotrophic factor expression was increased by AgRP in fed rats. These results identify the amygdala as a site of action for the melanocortin system to control food intake and dietary preferences.agouti-related protein; melanotan II; SHU-9119; brain derived neurotrophic factor, food intake FOR YEARS, HYPOTHALAMIC CENTERS have been considered as the major brain centers regulating food intake and/or macronutrient selection (45). The neural circuits involved in the regulation of feeding behavior are complex, and more recent studies implicate other parts of the brain in the regulation of ingestive behaviors. Areas such as the nucleus accumbens, the amygdala, the brain stem, and many others form together with the hypothalamic areas a complex circuitry regulating all levels of feeding behavior (6,8,55). Indeed, the paraventricular nucleus (PVN) is not essential for either neuropeptide Y (NPY)-induced feeding or the anorexic response to melanocortin activity (16) since both are evident in PVN-lesioned rats. Furthermore, the anorectic response to melanotan II (MTII) is evident in the dorsovagal complex of the brain stem (52,58).A number of neuropeptides and compounds are known to selectively affect macronutrient intake when administered centrally. For example, the orexigenic NPY (47, 48, 50) , norepinephrine (30, 50), or agouti-related protein (AgRP) (23) have been reported to induce specific selection of macronutrients. Enterostatin, a satiety factor secreted in the gastrointestinal tract and expressed also in the central nervous system, induces an immediate reduction in food intake and inhibits appetite specifically for dietary fat when injected peripherally or centrally (31,37,39).It has been hy...

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Section: Perspectives and Significancesupporting

confidence: 64%

“…The response to SHU-9119 was particularly pronounced in its magnitude and duration. This rapid-onset, long-lasting effect of AgRP has been described by others (21,23,26,42) after administration of AgRP in the third ventricle. Increased hypothalamic levels of AgRP (13,49) have been associated with an obesity phenotype.…”

Section: Discussionmentioning

confidence: 94%

Melanocortin activity in the amygdala controls appetite for dietary fat

Boghossian

Park

York

2010

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Recently, biological activity of synthetic AgRP and AgRP 54-82 has been reported. ICV injection of these synthetic peptides resulted in decreased energy expenditure and increased fat mass in rats [35]. The mechanism of action of amino-terminal AgRP fragments may involve binding to syndecan 3, providing an alternative explanation for the involvement of syndecan 3 in the regulation of energy balance.…”

Section: Discussionmentioning

confidence: 98%

Functional analysis of the Ala67Thr polymorphism in agouti related protein associated with anorexia nervosa and leanness

Rijke

Jackson

Garner

et al. 2005

Biochemical Pharmacology

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AgRP is a neuropeptide that stimulates food intake through inhibition of central melanocortin receptors (MCRs). In humans, the nonconservative amino acid substitution Alanine (Ala) 67 Threonine (Thr) has been associated with Anorexia Nervosa and with leanness. In the present study, the cellular distribution, processing and in vitro and in vivo activities of Ala67 and Thr67 AgRP were investigated. Western blots of media and lysates of BHK cells stably transfected with Ala67 or Thr67 expression constructs showed identical AgRP bands. Both Ala67 and Thr67 AgRP colocalised with the Golgi apparatus, but not with the ER or lysosomes when expressed in Att20 D16V cells. Also, no differences were observed between the potencies of bacterially expressed Ala67 and Thr67 AgRP to stimulate MC4R in a reporter gene assay or inhibit food intake in rats. Taken together, no evidence was found for a functional defect of Thr67 AgRP related to MC4R interactions. #

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“…Control living slices were placed in nutrient medium consisting of 1 μl of phosphatebuffered saline and 2 ml of nutrient medium, while experimental slices were places in medium containing 1 μl of AGRP (AGRP-83-132, Phoenix Pharmaceuticals Inc., USA) (mouse-specific, dry sample dissolved in phosphatebuffered saline) to give a final concentration in the medium of 200 nM. Published data indicate that incubation in medium with this concentration for 3 h is sufficient for the physiological effect of AGRP to be apparent [12]. After incubation for 3 h, some of the midbrain explants were frozen on dry ice (n = 8), and ventral tegmental area tissue was dissected from these for preparation of samples for western blotting by the Laemmli method [15], ensuring that samples contained the same protein concentrations using the Bradford method [9].…”

mentioning

confidence: 99%

“…Because of this, the new protein was named agouti-related protein (AGRP). AGRP mRNA has been shown to be present only in neurons in the arcuate (or infundibular) nucleus of the hypothalamus in various mammals [7,12]. This encodes a propeptide from which a convertasedependent process forms several active protein fragments [11,19].…”

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confidence: 99%

The Role of AGRP in Regulating Dopaminergic Neurons in the Brain

Mikhrina

Романова

2015

Neurosci Behav Physi

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A new protein found in rodent brains has extensive structural similarity with agouti protein, which is expressed in the skin and produces a rusty coloration of the coat in rodents [16]. Because of this, the new protein was named agouti-related protein (AGRP). AGRP mRNA has been shown to be present only in neurons in the arcuate (or infundibular) nucleus of the hypothalamus in various mammals [7,12]. This encodes a propeptide from which a convertasedependent process forms several active protein fragments [11,19].AGRP in the brain has been shown to be an endogenous antagonist of melanocortin receptors types 3 and 4, and its functional significance is assessed in the literature as being related to the control of feeding behavior as an appetite-activating factor [10,11, 23]. However, increases in appetite are not always associated with increases in the AGRP balance in the brain. Thus, for example, obesity developing as a result of increased food intake is accompanied by a decrease in AGRP expression [1, 10], which does not correspond to its functional role as an appetite activator. In addition, the literature contains reports of studies demonstrating the role of AGRP as a melanocortin receptor agonist [22], as well as the suggestion that it acts via other, as yet unknown, types of receptor [20], which widens our understanding of the functional significance of this peptide.Immunohistochemical studies have demonstrated the presence of AGRP-immunoreactive processes in various parts of the brain [7, 13], which seems to provide evidence of the involvement of this peptide in regulating a variety of body functions.Analysis of published data, along with our own observations, provides evidence that AGRP-immunoreactive processes are detected in those areas of the brain containing dopaminergic neurons themselves (the arcuate nucleus of the hypothalamus, the zona incerta, the ventral tegmental area, the paraventricular nucleus of the hypothalamus, the periacqueductal gray matter) and their targets (the preoptic area, the paraventricular and supraoptic nuclei of the hypothalamus, etc.) [7]. However, the literature lacks any data on the possible involvement of AGRP in regulating the functional activity of dopaminergic brain neurons. Thus, the aim of the present work was to determine the possibility and nature of the influences of AGRP on dopaminergic brain neurons. We performed immunohistochemical studies to support the existence of structural interactions of AGRPand dopaminergic neurons, as well as in vitro experiments in which living slices of brain areas containing dopaminerImmunoreactive processes containing agouti-regulated protein (AGRP) were detected in various dopaminergic structures in the brains of rats and mice. Double immunolabeling demonstrated the presence of AGRP-immunoreactive processes around the bodies of dopaminergic neurons. In in vitro experiments, incubation of brain tissue from the ventral tegmental area and hypothalamus with AGRP(83-132) identified significant reductions in the optical density of tyrosine h...

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Acute intracerebroventricular administration of either carboxyl-terminal or amino-terminal fragments of agouti-related peptide produces a long-term decrease in energy expenditure in rats

Cited by 23 publications

References 0 publications

Melanocortin activity in the amygdala controls appetite for dietary fat

Melanocortin activity in the amygdala controls appetite for dietary fat

Functional analysis of the Ala67Thr polymorphism in agouti related protein associated with anorexia nervosa and leanness

The Role of AGRP in Regulating Dopaminergic Neurons in the Brain

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