Central infusions of leptin and GLP-1-(7-36) amide differentially stimulate c-FLI in the rat brain

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

doi:10.1152/ajpregu.1996.271.4.r1096

Cited by 102 publications

(112 citation statements)

References 8 publications

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“…18,19 In addition to its role in glycemic control, GLP-1 is a shortterm regulator of food intake, [20][21][22] an effect mediated via central GLP-1 receptors. 22,23 Agents with actions similar to GLP-1, particularly those resistant to degradation by DPPIV, may be potential therapeutic agents in the treatment of obesity. 24 Exenatide reduces food intake in rodents following either central [25][26][27] or peripheral 18,27-31 administration, and repeated or chronic exposure reduces body weight.…”

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

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: 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

127

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“…Since neonatal treatment with monosodium glutamate leading to destruction of the arcuate nucleus of the hypothalamus yields animals insensitive to i3vt GLP-1's anorexigenic action, GLP-1 receptors within, or neuronal pathways arising from this hypothalamic area appear to mediate GLP-1's inhibition of feeding. 33 We found that, besides elevating c-Fos-like immunoreactivity (c-FLI) in the PVN (31), i3vt GLP-1 also increased c-FLI in a number of other CNS regions, including the central nucleus of the amygdala, and areas in the brain stem such as the NTS, area postrema, and the parabrachial nucleus, 34 and this was later confirmed by others. 35,36 In general, these areas appear to overlap with those that are found to be c-fos-positive upon i3vt administration of CCK-8 in a dose that produces comparable reductions in short-term food intake to GLP-1.…”

Section: Glp-1 Reduces Short-term Food Intakementioning

confidence: 64%

“…To determine if GLP-1 is associated with aversive sideeffects, we first exposed rats to a 0.15% saccharine solution via an intraoral (io) cannula and then immediately gave them i3vt infusion of GLP-1 (10.0 µg); additional animals received i3vt infusion of leptin (3.5 µg) in a dose that produced similar short-term (4 h) anorexia as that produced by GLP-1. 34,53 Several days later, when re-exposed to the saccharine solution, control rats that received the saccharin and GLP-1 on separate days continued to ingest the saccharine solution. However, rats that had received the saccharin paired with GLP-1 on the same day actively rejected the tastant on the test day.…”

Section: Glp-1 Causes Conditioned Taste Aversionsmentioning

confidence: 99%

“…[34][35][36][37] We were struck by the similarity in the pattern of c-FLI produced by i3vt GLP-1 and ip injection of LiCl, particularly in brainstem regions that are thought to be involved with CTA learning, such as the NTS, area postrema (AP), and the lateral parabrachial nucleus (PBN). 60,61 Because GLP-1 is synthesized in brainstem neurons, we speculated that GLP-1…”

Section: Involvement Of Glp-1 Signaling In Licl-induced Neuronal Actimentioning

confidence: 99%

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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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“…This contrast with most other gut peptides that influence feeding behavior by modulating neuronal activity in hypothalamic and brainstem nuclei. CCK-8S increases Fos expression in the PVN, DMH and NTS [23,25,29,33,38] while systemic or icv application of the long-term satiety signal leptin induces neuronal activation in PVN and DMH neurons [12,44], and peptide YY increases Fos expression in NTS, AP [6], and ARC [4]. Glucagonlike peptide 1 modulates the number of Fos-ir positive neurons in ARC [44], PVN, NTS and AP [28,39], and peripheral amylin leads to increased neuronal activation in the NTS and AP [39].…”

Section: Discussionmentioning

confidence: 99%

Peripheral obestatin has no effect on feeding behavior and brain Fos expression in rodents

et al. 2008

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Obestatin is produced in the stomach from proghrelin by post-translational cleavage. The initial report claimed anorexigenic effects of obestatin in mice. Contrasting studies indicated no effect of obestatin on food intake (FI). We investigated influences of metabolic state (fed/fasted), environmental factors (dark/light phase) and brain Fos response to intraperitoneal (ip) obestatin in rats, and used the protocol from the original study assessing obestatin effects in mice. FI was determined in male rats injected ip before onset of dark or light phase, with obestatin (1 or 5 μmol/kg), CCK8S (3.5 nmol/kg) or 0.15 M NaCl, after fasting (16 h, n = 8/group) or ad libitum (n = 10-14/group) food intake. Fos expression in hypothalamic and brainstem nuclei was examined in freely fed rats 90 min after obestatin (5 μmol/kg), CCK8S (1.75 nmol/kg) or 0.15 M NaCl (n = 4/group). Additionally, fasted mice were injected ip with obestatin (1 μmol/kg) or urocortin 1 (2 nmol/kg) 15 min before food presentation. No effect on FI was observed after obestatin administration during the light and dark phase under both metabolic conditions while CCK8S reduced FI irrespectively of the conditions. The number of Fos positive neurons was not modified by obestatin while CCK8S increased Fos expression in selective brain nuclei. Obestatin did not influence the refeeding response to a fast in mice, while urocortin was effective. Therefore, peripheral obestatin has no effect on FI under various experimental conditions and did not induce Fos in relevant central neuronal circuitries modulating feeding in rodents.

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Central infusions of leptin and GLP-1-(7-36) amide differentially stimulate c-FLI in the rat brain

Cited by 102 publications

References 8 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

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

Peripheral obestatin has no effect on feeding behavior and brain Fos expression in rodents

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