Central infusion of GLP-1, but not leptin, produces conditioned taste aversions in rats

Thiele, Todd E.; Dijk, Gertjan van; Campfield, L. Arthur; Smith, Franklin R.; Burn, Paul; Woods, Stephen C.; Bernstein, Ilene L.; Seeley, Randy J.

doi:10.1152/ajpregu.1997.272.2.r726

Cited by 134 publications

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“…route of administration is also associated with CTA. 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: Discussionmentioning

confidence: 99%

“…Central GLP-1 receptor activation in brain has been associated with preclinical measures of malaise such as conditioned taste aversion (CTA) 21,[32][33][34] and kaolin consumption. 34 Ingestion of kaolin (non-nutritive clay) in rodents is commonly used to determine the emetic properties of drugs and can be induced by a number of known emetic agents like the chemotherapeutic cisplatin.…”

Section: Introductionmentioning

confidence: 99%

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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

129

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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: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

129

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“…Both LiCl and GLP-1 produce similar physiological consequences, many of which are proxies of nausea/ malaise. These effects include a reduction in food intake (McCann et al, 1989;Tang-Christensen et al, 1996) and gastric emptying (McCann et al, 1989;Wettergren et al, 1993), generation of CTA (Nachman and Ashe, 1973;Thiele et al, 1997) and pica (Mitchell et al, 1976;Kanoski et al, 2012). GLP-1 antagonists have successfully been used to block the aversive-like behaviors (eg reduction in food intake, pica, CTA) induced by LiCl (Rinaman, 1999b;Seeley et al, 2000), indicating that these manifestations of LiCl are, at least in part, mediated through GLP-1R signaling.…”

Section: Discussionmentioning

confidence: 99%

The Aversive Agent Lithium Chloride Suppresses Phasic Dopamine Release Through Central GLP-1 Receptors

Fortin

Chartoff

Roitman

2015

Neuropsychopharmacol

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Unconditioned rewarding stimuli evoke phasic increases in dopamine concentration in the nucleus accumbens (NAc) while discrete aversive stimuli elicit pauses in dopamine neuron firing and reductions in NAc dopamine concentration. The unconditioned effects of more prolonged aversive states on dopamine release dynamics are not well understood and are investigated here using the malaise-inducing agent lithium chloride (LiCl). We used fast-scan cyclic voltammetry to measure phasic increases in NAc dopamine resulting from electrical stimulation of dopamine cell bodies in the ventral tegmental area (VTA). Systemic LiCl injection reduced electrically evoked dopamine release in the NAc of both anesthetized and awake rats. As some behavioral effects of LiCl appear to be mediated through glucagon-like peptide-1 receptor (GLP-1R) activation, we hypothesized that the suppression of phasic dopamine by LiCl is GLP-1R dependent. Indeed, peripheral pretreatment with the GLP-1R antagonist exendin-9 (Ex-9) potently attenuated the LiCl-induced suppression of dopamine. Pretreatment with Ex-9 did not, however, affect the suppression of phasic dopamine release by the kappa-opioid receptor agonist, salvinorin A, supporting a selective effect of GLP-1R stimulation in LiCl-induced dopamine suppression. By delivering Ex-9 to either the lateral or fourth ventricle, we highlight a population of central GLP-1 receptors rostral to the hindbrain that are involved in the LiClmediated suppression of NAc dopamine release. Neuropsychopharmacology (2016) 41, 906-915;

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“…Interestingly, i3vt infusion of leptin, in a dose that caused long-term reductions in food intake as well as body weight, did not condition a CTA. 54 We later showed that the lowest dose of i3vt GLP-1 (3 µg) to reduce food intake was also the lowest dose to produce a CTA (ref. 55; but see ref.…”

Section: Glp-1 Causes Conditioned Taste Aversionsmentioning

confidence: 99%

“…visceral illness). 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.…”

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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Central infusion of GLP-1, but not leptin, produces conditioned taste aversions in rats

Cited by 134 publications

References 0 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 Aversive Agent Lithium Chloride Suppresses Phasic Dopamine Release Through Central GLP-1 Receptors

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

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