Peripheral Glucagon-like Peptide-1 (GLP-1) and Satiation

Punjabi, Mukesh; Arnold, Myrtha; Geary, Nori; Langhans, Wolfgang; Pacheco-López, Gustavo

doi:10.1016/j.physbeh.2011.02.038

Cited by 57 publications

(38 citation statements)

References 78 publications

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“…Accumulating evidence indicates that endogenous GLP-1 influences eating by acting in a paracrine fashion on vagal afferents terminating in the wall of the GI tract (2,11,15,23,24). The findings obtained with our model show that within the time frame of a normal meal, active GLP-1 increased in intestinal lymph and therefore at the site of GLP-1's supposedly paracrine action in the wall of the small intestine.…”

Section: Discussionmentioning

confidence: 56%

Meal-contingent intestinal lymph sampling from awake, unrestrained rats

Arnold

Dai

Tso

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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Standard procedures for intestinal lymph collection involve continuous, quantitative drainage of the lymph fluid in anesthetized or restrained animals that are often euthanized within 48 h. We here describe a novel technique for the nonocclusive cannulation of the major intestinal lymph duct in rats that allows for repetitive in vivo sampling of intestinal lymph from unrestrained, awake, and ad libitum-fed animals. The distinctive feature of this novel technique is that a 5- to 7-mm long piece of Vialon tubing (OD/ID: 0.8/0.7 mm) with a small hole in its wall is first implanted into the major intestinal lymph duct for stabilization. The tapered tip (OD: ≈0.1 mm) of the catheter is then inserted into the hole of the tubing and fixed in place with a polyamid suture and a drop of tissue glue. In our hands, catheters implanted this way remain patent for up to 6 wk after surgery. In an initial experiment we collected lymph from six adult rats before (0) and 15, 30, 45, 60, 75, 90, 120, and 180 min (120 μl, each) after the onset of isocaloric (12.5 kcal) low-fat (LF) or high-fat (HF) test meals and measured active glucagon-like peptide-1 (GLP-1). Intestinal lymphatic GLP-1 concentration increased (P < 0.05) from ≈4 pmol/l (0 min) to a peak of 33 ± 6 (means ± SE) or 22 ± 4 pmol/l at 15 (HF) or 30 min (LF) after meal onset and gradually returned to baseline levels by 180 min. With this new technique fewer animals are required to generate physiologically relevant data for various aspects of gastrointestinal physiology that involve the lymphatic system. Furthermore, the advantage of this system is that the animal can act as its own control when the effect of different experimental protocols is tested.

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Section: Discussionmentioning

confidence: 56%

Meal-contingent intestinal lymph sampling from awake, unrestrained rats

Arnold

Dai

Tso

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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“…From these studies, it appears that 2 h or less of elevated GLP-1r agonist is sufficient for long-lasting biological actions to reduce food intake. Although our data do not directly address the mechanism by which this occurs, current models of GLP-1-induced satiety include effects of circulating GLP-1r agonists to activate specific regions of the CNS (42)(43)(44) and for peptide released by L cells into the submucosa to stimulate afferent neural signals to the hindbrain (45,46). We presume that the ip treatments used in this study could activate either of these systems.…”

Section: Fig 5 A-c Effect Of Ip Ex-4 On Food Intake In Wt Mice (A)mentioning

confidence: 84%

Suppression of Food Intake by Glucagon-Like Peptide-1 Receptor Agonists: Relative Potencies and Role of Dipeptidyl Peptidase-4

et al. 2012

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Administration of the glucagon-like peptide-1 (GLP-1) receptor agonists GLP-1 and exendin-4 (Ex-4) directly into the central nervous system decreases food intake. But although Ex-4 potently suppresses food intake after peripheral administration, the effects of parenteral GLP-1 are variable and not as strong. A plausible explanation for these effects is the rapid inactivation of circulating GLP-1 by dipeptidyl peptidase-4 (DPP-4), an enzyme that does not alter Ex-4 activity. To test this hypothesis, we assessed the relative potency of Ex-4 and GLP-1 under conditions in which DPP-4 activity was reduced. Outbred rats, wild-type mice, and mice with a targeted deletion of DPP-4 (Dpp4 Ϫ/Ϫ ) were treated with GLP-1 alone or in combination with the DPP-4 inhibitor vildagliptin, Ex-4, or saline, and food intake was measured. GLP-1 alone, even at high doses, did not affect feeding in wild-type mice or rats but did reduce food intake when combined with vildagliptin or given to Dpp4 Ϫ/Ϫ mice. Despite plasma clearance similar to DPP-4-protected GLP-1, equimolar Ex-4 caused greater anorexia than vildagliptin plus GLP-1. To determine whether supraphysiological levels of endogenous GLP-1 would suppress food intake if protected from DPP-4, rats with Rouxen-Y gastric bypass and significantly elevated postprandial plasma GLP-1 received vildagliptin or saline. Despite 5-fold greater postprandial GLP-1 in these animals, vildagliptin did not affect food intake in Roux-en-Y gastric bypass rats. Thus, in both mice and rats, peripheral GLP-1 reduces food intake significantly less than Ex-4, even when protected from DPP-4. These findings suggest distinct potencies of GLP-1 receptor agonists on food intake that cannot be explained by plasma pharmacokinetics. (Endocrinology 153: 5735-5745, 2012) G lucagon-like peptide-1 (GLP-1) is secreted from L cells in the ileum and colon during meal ingestion and is essential for normal glucose tolerance (1, 2). The finding that GLP-1 potently lowers blood glucose in type 2 diabetic subjects has launched a broad effort to harness the GLP-1 signaling system for therapeutic use. Because circulating GLP-1 is rapidly inactivated in vivo by the serine protease dipeptidyl peptidase-4 (DPP-4) (3-5), alternative strategies for targeting the GLP-1 system have been developed, agonists that are resistant to DPP-4 (6) and DPP-4 inhibitors that prolong the circulating half-life of endogenous GLP-1 (7). These approaches have been effective, and several new compounds are now available to treat patients with type 2 diabetes (8, 9).In addition to a role in the regulation of blood glucose, GLP-1 also affects feeding behavior in rodents and humans (10 -12). The GLP-1r is expressed in brain areas involved in the control of food intake, including the hypothalamus and the caudal brainstem (13,14), and ad-

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“…Peripheral administration of exendin(9–39) increased food intake in only two studies to our knowledge (Asarian, et al, 2012; Williams, et al, 2009) and failed to do so in others (Dailey, Moghadam, & Moran, 2011; Punjabi, Arnold, Geary, Langhans, & Pacheco-Lopez; Ruttimann, Arnold, Geary, & Langhans, 2010). Although, the failure of the antagonist alone in the current study to increase food intake (Figure 2) does not support a GI site of action for endogenous GLP-1 on eating, higher doses of the antagonist infused at different times before, during and after a meal must be examined before this possibility is ruled out.…”

Section: Discussionmentioning

confidence: 64%

Exogenous glucagon-like peptide-1 acts in sites supplied by the cranial mesenteric artery to reduce meal size and prolong the intermeal interval in rats

et al. 2016

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Three experiments were done to better assess the gastrointestinal (GI) site(s) of action of GLP-1 on food intake in rats. First, near-spontaneous nocturnal chow meal size (MS), intermeal intervals (IMI) length and satiety ratios (SR = MS/IMI) were measured after infusion of saline, 0.025 or 0.5 nmol/kg GLP-1 into the celiac artery (CA, supplying the stomach and upper duodenum), cranial mesenteric artery (CMA, supplying small and all of the large intestine except the rectum), femoral artery (FA, control) or portal vein (PV, control). Second, infusion of 0.5 nmol/kg GLP-1 was tested after pretreatment with the GLP-1 receptor (GLP-1R) antagonist exendin-4(3–39) via the same routes. Third, the regional distribution of GLP-1R in the rat GI tract was determined using rtPCR. CA, CMA and FA GLP-1 reduced first MS relative to saline, with the CMA route more effective than the others. Only CMA GLP-1 prolonged the IMI. None of the infusions affected second MS or later eating. CA and CMA GLP-1 increased the SR, with the CMA route more effective than the CA route. CMA exendin-4 (3–39) infusion reduced the effect of CMA GLP-1. Finally GLP-1R expression was found throughout the GI tract. The results suggest that exogenous GLP-1 acts in multiple GI sites to reduce feeding under our conditions and that GLP-1R in the area supplied by the CMA, i.e., the small and part of the large intestine, plays the leading role.

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Peripheral Glucagon-like Peptide-1 (GLP-1) and Satiation

Cited by 57 publications

References 78 publications

Meal-contingent intestinal lymph sampling from awake, unrestrained rats

Meal-contingent intestinal lymph sampling from awake, unrestrained rats

Suppression of Food Intake by Glucagon-Like Peptide-1 Receptor Agonists: Relative Potencies and Role of Dipeptidyl Peptidase-4

Exogenous glucagon-like peptide-1 acts in sites supplied by the cranial mesenteric artery to reduce meal size and prolong the intermeal interval in rats

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