PVN infusion of GLP-1-(7—36) amide suppresses feeding but does not induce aversion or alter locomotion in rats

McMahon, Lance Richard; Wellman, Paul J.

doi:10.1152/ajpregu.1998.274.1.r23

Cited by 127 publications

(137 citation statements)

References 28 publications

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“…The dose-response relationships for locomotor activity and food intake were highly correlated with exenatide treatment, although a higher dose was required to produce statistically significant changes in activity than to reduce food intake. Acutely, peripherally administered exenatide potently inhibited 60 min food intake in fasted mice with an ED 50 of B2 mg/kg, consistent with previous reports. 31 In rats, the potency of exenatide to reduce food intake following i.p.…”

Section: Discussionsupporting

confidence: 91%

“…The half-maximal effective dose (ED 50 ) for food intake suppression was 2.3 mg/kg70.11 log units, with a maximal suppression of 70%. Similar ED 50 values were observed at the 30 and 120 min time points (1.2 and 2.5 mg/ kg, respectively, data not shown). At 2.4 mg/kg (approximate ED 50 ), exenatide significantly decreased cumulative food intake compared to vehicle at the 120, 180, 240 and 300 min time points (Figure 1b).…”

Section: Resultssupporting

confidence: 81%

“…21,[32][33][34] However, site-specific administration of GLP-1 in the CNS shows this effect to be mediated by distinct GLP-1 receptor populations that are separable from those mediating food intake effects. 49,50 In summary, the current data demonstrate for the first time the ability of peripherally administered exenatide to reduce body weight gain and improve metabolic profile in normal rodents consuming an HF diet, a model that parallels the genetic variability and environmental conditions contributing to human obesity, and supports a role for exenatide in metabolic pathways mediating food intake and body weight.…”

Section: Discussionsupporting

confidence: 53%

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Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures

Mack¹,

Moore²,

Jodka³

et al. 2006

Int J Obes

127

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Background: Exenatide (exendin-4) is an incretin mimetic currently marketed as an antidiabetic agent for patients with type 2 diabetes. In preclinical models, a reduction in body weight has also been shown in low-fat-fed, leptin receptor-deficient rodents. Objective: To more closely model the polygenic and environmental state of human obesity, we characterized the effect of exenatide on food intake and body weight in high-fat-fed, normal (those with an intact leptin signaling system) rodents. As glucagon-like peptide-1 receptor agonism has been found to elicit behaviors associated with visceral illness in rodents, we also examined the effect of peripheral exenatide on kaolin consumption and locomotor activity. Methods and results: High-fat-fed C57BL/6 mice and Sprague-Dawley rats were treated with exenatide (3, 10 and 30 mg/kg/ day) for 4 weeks via subcutaneously implanted osmotic pumps. Food intake and body weight were assessed weekly. At 4 weeks, body composition and plasma metabolic profiles were measured. Kaolin consumption and locomotor activity were measured in fasted Sprague-Dawley rats following a single intraperitoneal injection of exenatide (0.1-10 mg/kg). Exenatide treatment in mice and rats dose-dependently decreased food intake and body weight; significant reductions in body weight gain were observed throughout treatment at 10 and 30 mg/kg/day (Po0.05). Decreased body weight gain was associated with a significant decrease in fat mass (Po0.05) with sparing of lean tissue. Plasma cholesterol, triglycerides and insulin were also significantly reduced (Po0.05). Exenatide at 10 mg/kg significantly reduced food intake (Po0.05) but failed to induce kaolin intake. In general, locomotor activity was reduced at doses of exenatide that decreased food intake, although a slightly higher dose was required to produce significant changes in activity. Conclusion: Systemic exenatide reduces body weight gain in normal, high-fat-fed rodents, a model that parallels human genetic variation and food consumption patterns, and may play a role in metabolic pathways mediating food intake.

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Section: Discussionsupporting

confidence: 91%

Section: Resultssupporting

confidence: 81%

Section: Discussionsupporting

confidence: 53%

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Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures

Mack¹,

Moore²,

Jodka³

et al. 2006

Int J Obes

127

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“…As ligands are accessible to both forebrain and hindbrain GLP-1Rs with forebrain ventricular GLP-1R agonist delivery, it is difficult to ascribe this to the CNS sites mediating this effect, but ventral forebrain parenchymal application of GLP-1R ligands does elicit behavioral responses, and this result does support a direct role for forebrain GLP-1R and forebrain neural processing in for the observed effects. 44,45 Neither our study 33 nor the central agonist delivery studies of others 28,44,45 address the sites of central mediation of responses resulting from endogenous activation of central GLP-1Rs. Although the source of the proglucagon-expressing neurons is located in the NTS of the caudal brainstem, these neurons project to both hindbrain and forebrain nuclear targets.…”

Section: Glp-1mentioning

confidence: 88%

The nucleus tractus solitarius: a portal for visceral afferent signal processing, energy status assessment and integration of their combined effects on food intake

2009

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For humans and animal models alike there is general agreement that the central nervous system processing of gastrointestinal (GI) signals arising from ingested food provides the principal determinant of the size of meals and their frequency. Despite this, relatively few studies are aimed at delineating the brain circuits, neurochemical pathways and intracellular signals that mediate GI-stimulation-induced intake inhibition. Two additional motivations to pursue these circuits and signals have recently arisen. First, the success of gastric-bypass surgery in obesity treatment is highlighting roles for GI signals such as glucagon-like peptide-1 (GLP-1) in intake and energy balance control. Second, accumulating data suggest that the intakereducing effects of leptin may be mediated through an amplification of the intake-inhibitory effects of GI signals. Experiments reviewed show that: (1) the intake-suppressive effects of a peripherally administered GLP-1 receptor agonist is mediated by caudal brainstem neurons and that forebrain-hypothalamic neural processing is not necessary for this effect; (2) a population of medial nucleus tractus solitarius (NTS) neurons that are responsive to gastric distention is also driven by leptin; (3) caudal brainstem-targeted leptin amplifies the food-intake-inhibitory effects of gastric distention and intestinal nutrient stimulation; (4) adenosine monophosphate-activated protein kinase (AMPK) activity in NTS-enriched brain lysates is elevated by food deprivation and reduced by refeeding and (5) the intake-suppressive effect of hindbrain-directed leptin is reversed by elevating hindbrain AMPK activity. Overall, data support the view that the NTS and circuits within the hindbrain mediate the intake inhibition of GI signals, and that the effects of leptin on food intake result from the amplification of GI signal processing.

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“…First, while i3vt GLP-1 produces taste aversions at all doses that reduce food intake, 54,55 central infusion of GLP-1 directly into the paraventricular nucleus of the hypothalamus (PVN) has been shown to reduce shortterm food intake at doses that do not support a CTA. 65 Thus, GLP-1 receptors in the PVN appear to be involved with regulating food intake, in the absence of producing aversive side-effects. Secondly, while LiCl can produce very robust CTAs over a wide range of doses, this drug does not easily produce anorexia except at high doses (e.g.…”

Section: Dissociation Between Effects Of Central Glp-1 On Satiety Andmentioning

confidence: 99%

Glucagon-like peptide-1 (7–36) amide: a central regulator of satiety and interoceptive stress

Dijk

Thiele

1999

Neuropeptides

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INTRODUCTIONIngestion of food is a necessary and pleasant occupation that allows humans and other species to maintain caloric homeostasis and a certain level of body weight. Ironically, in doing so, one's 'milieu interieur' is put at risk because meal-induced fuel excursions can have deleterious effects on metabolic (e.g. glycosylation causing loss of enzymatic efficacy) and cardiovascular (e.g. triglyceride accumulation, increased blood pressure, etc.) processes. 1,2 To reduce these perturbations to a minimum, evolution has provided many species (including humans and rodents) with a fine-tuned system enabling ingested nutrients to be anticipated, efficiently digested, and stored. 3 One of these mechanisms includes passage of nutrients through the digestive tract, triggering the release of a number of peptides from endocrine cells located in the wall of various parts of the gastrointestinal tract. These peptides serve important functions in facilitating the process of nutrient digestion/storage. Among these, the truncated (i.e. 7-36) amidated form of glucagon-like peptide-1 (GLP-1) has attracted considerable attention over the last several years. Firstly, because of its remarkable peripheral insulinotropic effects that could be useful for clinical purposes. Secondly, because more recent data suggest an important role of this peptide in the central nervous system (CNS) control of ingestive behavior. Although the present paper mainly focusses on the latter issue, a short review of peripheral GLP mechanisms is necessary for a better understanding of the processes that relate GLP-1 to food intake. GLP-1 FROM THE GASTROINTESTINAL TRACTGLP-1 is processed from proglucagon in mucosal L cells of the distal portion of the ileum and in the A cells of the pancreas. Ingested food, particularly when rich in carbohydrates, causes the level of circulating GLP-1 (mainly of ileal origin) to increase, and in turn, GLP-1 potently stimulates the secretion of insulin from pancreatic B cells via receptor-mediated processes (for reviews, see refs 4 and 5). In contrast, it reduces the secretion of glucagon, at least under ad libitum feeding conditions. 6 While GLP-1 may have some direct stimulatory effects on glucose clearance in peripheral tissue 7,8 (presumably via activation of specific GLP-1 receptors in liver, muscle, kidney Summary Glucagon-like peptide-1 (7-36) amide (GLP-1) is processed from proglucagon in the distal ileum as well as in the CNS. In the periphery, GLP-1 acts as an incretin factor and profoundly inhibits upper gastrointestinal motility ('ileal brake'), the latter presumably involving the CNS. Within the CNS, GLP-1 has a satiating effect, since administration of GLP-1 into the third cerebral ventricle reduces short-term food intake (and meal size), while administration of GLP-1 antagonists have the opposite effect. In addition, activation of GLP-1 receptors in certain brain regions elicits strong taste aversions. Similarities between toxin-and GLP-1-induced neuronal activity in the CNS (brain stem) suggest a role f...

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PVN infusion of GLP-1-(7—36) amide suppresses feeding but does not induce aversion or alter locomotion in rats

Cited by 127 publications

References 28 publications

Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures

Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures

The nucleus tractus solitarius: a portal for visceral afferent signal processing, energy status assessment and integration of their combined effects on food intake

Glucagon-like peptide-1 (7–36) amide: a central regulator of satiety and interoceptive stress

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