Glucagon-like peptide 1 (GLP-1) and eating

doi:10.1016/j.physbeh.2004.04.019

Physiology & Behavior

Volume 82, Issue 1, August 2004, Pages 17-19

https://doi.org/10.1016/j.physbeh.2004.04.019 Get rights and content

Abstract

New information regarding gastrointestinal mechanisms that participate in the control of food intake has extended our understanding of appetite control. Although each new signaling pathway discovered in the gut is a potential target for drug development in the treatment of obesity, the growing number of such signaling molecules indicates that a highly complex process controls food intake. The present summary focuses on the role of glucagon-like peptide 1 (GLP-1) in this regulatory process. The different biological effects of GLP-1 (glucose-lowering properties, inhibition of appetite and food intake) provide a powerful impetus for development of GLP-1-based new drugs.

Introduction

Food intake is a complicated regulated system. Afferent signals from the gastrointestinal tract provide information to the central nervous system, which is the center for the control of satiety [1], [2], [3]. Many factors are involved in this central control system of appetite regulation [4], [5]. To rationalize the different putative factors found to play a role in this control, several approaches have been used to better understand the mechanisms regulating appetite and food intake. The normal state is based on a nutrient balance or a homeostatic model; in this model the different nutrient stores are tightly controlled. Obesity and anorexia nervosa can then be viewed as homeostatic failures of the nutrient balance resulting from a failure of nutrient signals to be properly integrated into an effective feedback system [3], [4], [5], [6].

The food-intake system has several components:

1.
A controller located in the brain.
2.
A control system consisting of nutrient intake, nutrient digestion, absorption, storage and metabolism of food.
3.
A feedback system that keeps the controller up to date about the state of the control system.
4.
Efferent control elements that modulate food intake and/or energy expenditure.

In the present review we will focus on afferent feedback signals, particularly glucagon-like peptide 1 (GLP-1) as a satiety signal.

Section snippets

Gastrointestinal signals

The brain receives information from food components in the gastrointestinal tract for regulating nutrient balance from three distinct sources [4], [5]. The first source is gastrointestinal distension, the second source is the release of gastrointestinal hormones (these hormones can act as satiety signals) and the third source is through the effects of luminal or absorbed nutrients. The role of gastrointestinal distension is probably not of prime importance for regulating nutrient balance, but

GLP-1, its receptor and analogs

GLP-1 is synthesized in intestinal endocrine cells in two major molecular forms, as GLP-1(7–36)amide and as GLP-1(7–37) [8]. The majority of circulating biologically active GLP-1 is found as GLP-1(7–36)amide, with lesser amounts of the GLP-1(7–37) also detectable [8]. Both peptides appear equipotent in all biological actions studied to date. When the gastrointestinal hormone GLP-1 was discovered to be a key brain neurotransmitter, it was not anticipated that this molecule would prove to be

GLP-1 receptor antagonists and GLP-1 analogs

The availability of potent and selective GLP-1 receptor antagonists has made it possible to characterize the role of endogenous GLP-1 in regulating physiological functions. Infusion of exendin(9–39) to healthy subjects documented that endogenous GLP-1 regulates plasma glucose levels [19]; furthermore, its effects on plasma glucagon levels and on gastric emptying appear to be physiological [20]. The effect of exendin(9–39) on food intake and appetite has not been investigated yet.

Exendin-4 is a

GLP-1 analogs as antiobesity agents

Medline searches of the literature published over the last 5 years do not retrieve hits for many studies on the antiobesity-related responses to GLP-1 analogs. The natural ligand GLP-1 is fully active on the GLP-1 receptor, but is lacking in metabolic stability and oral bioavailability. As chemical designs become more sophisticated, it would seem to be possible to produce GLP-1 analogs with greater metabolic stability and oral bioavailability. These compounds would inhibit food intake with

Concluding remarks

Clearly, a definitive judgment concerning the clinical effectiveness of GLP-1 analogs as antiobesity drugs will require properly controlled double-blind trials. A number of pharmaceutical companies have agents ready for studies in humans. Because GLP-1 is a central key player in regulating digestive processes described in the introduction to this brief review, a great deal of caution is needed, particularly with agents that will have to be taken over long periods of time. Even so, at present it

Acknowledgements

This study was supported by grant no. 3200-065588.01/1 from the Swiss National Science Foundation.

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Cited by (39)

Opportunities and challenges of incretin-based hypoglycemic agents treating type 2 diabetes mellitus from the perspective of physiological disposition
2023, Acta Pharmaceutica Sinica B
Citation Excerpt :
Although the physiological disposition of these drugs is satisfactory in most conditions, there is a strong need to improve it. GLP-1 RAs are unsuitable for people suffering from gastric diseases because GLP-1 has strong effects on the gastrointestinal tract and gastric distension, which can modulate GLP-1 through c-FOS201,202. DPP-4 inhibitors are not suitable for people suffering from liver diseases.
The treatment of patients with diabetes mellitus, which is characterized by defective insulin secretion and/or the inability of tissues to respond to insulin, has been studied for decades. Many studies have focused on the use of incretin-based hypoglycemic agents in treating type 2 diabetes mellitus (T2DM). These drugs are classified as GLP-1 receptor agonists, which mimic the function of GLP-1, and DPP-4 inhibitors, which avoid GLP-1 degradation. Many incretin-based hypoglycemic agents have been approved and are widely used, and their physiological disposition and structural characteristics are crucial in the discovery of more effective drugs and provide guidance for clinical treatment of T2DM. Here, we summarize the functional mechanisms and other information of the drugs that are currently approved or under research for T2DM treatment. In addition, their physiological disposition, including metabolism, excretion, and potential drug–drug interactions, is thoroughly reviewed. We also discuss similarities and differences in metabolism and excretion between GLP-1 receptor agonists and DPP-4 inhibitors. This review may facilitate clinical decision making based on patients' physical conditions and the avoidance of drug–drug interactions. Moreover, the identification and development of novel drugs with appropriate physiological dispositions might be inspired.
Antidiabetic effect of an engineered bacterium Lactobacillus plantarum-pMG36e -GLP-1 in monkey model
2021, Synthetic and Systems Biotechnology
Glucagon-like peptide-1 (GLP-1) reduces postprandial hyperglycaemia, but its short half-life inhibits clinical application. The aim of the current study was to evaluate the treatment efforts of an engineered strain, Lactobacillus plantarum-pMG36e-GLP-1 (L. plantarum-pMG36e-GLP-1), that continuously expresses GLP-1 in spontaneous type 2 diabetes mellitus (T2DM) monkeys. After 7 weeks of oral supplementation with L. plantarum-pMG36e-GLP-1, the fasting blood glucose (FPG) of monkeys was significantly (p < 0.05) reduced to a normal level and only a small amount of weight was lost. The results of metagenomic sequencing showed that L. plantarum-pMG36e-GLP-1 caused a substantial (p < 0.05) reduction in the intestinal pathogen Prevotella and marked enhancement of butyrate-producing Alistipes genera. According to the functional analysis using Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathways, 19 metabolism-related pathways were significantly enriched in T2DM monkeys after treatment with L. plantarum-pMG36e-GLP-1. LC-MS faecal metabolomics analysis found 41 significant differential metabolites (11 higher and 30 lower) in monkeys after treatment pathways linked to the metabolism of cofactors and vitamins were the most relevant. The present study suggests that L. plantarum-pMG36e-GLP-1 had an impact on the gut microbial composition and faecal metabolomic profile in spontaneous T2DM monkeys and may be a novel candidate for diabetes treatment.
Obesity: Current and potential pharmacotherapeutics and targets
2017, Pharmacology and Therapeutics
Citation Excerpt :
GLP-1 mediates appetite control via insulin release, glucagon inhibition as well as absorption and metabolism of macronutrients (Naslund et al., 1999; Flint et al., 2001). GLP-1 receptors are members of the GPCR family and are expressed widely in pancreatic islets, kidney, lung, heart, and numerous regions of the peripheral and central nervous systems (Bullock et al., 1996; Gutzwiller et al., 2004; Drucker, 2006). Within the islets, GLP-1 receptors are localized predominantly to β-cells (Drucker, 2006).
Obesity is a global epidemic that contributes to a number of health complications including cardiovascular disease, type 2 diabetes, cancer and neuropsychiatric disorders. Pharmacotherapeutic strategies to treat obesity are urgently needed. Research over the past two decades has increased substantially our knowledge of central and peripheral mechanisms underlying homeostatic energy balance. Homeostatic mechanisms involve multiple components including neuronal circuits, some originating in hypothalamus and brain stem, as well as peripherally-derived satiety, hunger and adiposity signals that modulate neural activity and regulate eating behavior. Dysregulation of one or more of these homeostatic components results in obesity. Coincident with obesity, reward mechanisms that regulate hedonic aspects of food intake override the homeostatic regulation of eating. In addition to functional interactions between homeostatic and reward systems in the regulation of food intake, homeostatic signals have the ability to alter vulnerability to drug abuse. Regarding the treatment of obesity, pharmacological monotherapies primarily focus on a single protein target. FDA-approved monotherapy options include phentermine (Adipex-P®), orlistat (Xenical®), lorcaserin (Belviq®) and liraglutide (Saxenda®). However, monotherapies have limited efficacy, in part due to the recruitment of alternate and counter-regulatory pathways. Consequently, a multi-target approach may provide greater benefit. Recently, two combination products have been approved by the FDA to treat obesity, including phentermine/topiramate (Qsymia®) and naltrexone/bupropion (Contrave®). The current review provides an overview of homeostatic and reward mechanisms that regulate energy balance, potential therapeutic targets for obesity and current treatment options, including some candidate therapeutics in clinical development. Finally, challenges in anti-obesity drug development are discussed.
CNS regulation of appetite
2012, Neuropharmacology
Citation Excerpt :
As GLP-1 injection into the NAc core reduces food intake it has been proposed that this projection links satiation signalling in the hindbrain with forebrain signalling of food reward (Dossat et al., 2011). GLP-1R are also found in the peripheral organs including but not exclusive to the heart, lung, kidney, pancreas and the GI tract (Gutzwiller et al., 2004); however, it would appear that not all of these receptors are associated with appetite (Kim et al., 2009). Although initial evidence suggested that GLP-1 can cross the blood brain barrier to act directly on receptors located in high cortical centres (Kastin et al., 2002), vagotomy studies later indicated that the satiating effect of this hormone is significantly attenuated by the loss of the vagal communication pathway (Abbott et al., 2005).
This article reviews the regulation of appetite from a biopsychological perspective. It considers psychological experiences and peripheral nutritional systems (both episodic and tonic) and addresses their relationship with the CNS networks that process and integrate their input. Whilst such regulatory aspects of obesity focus on homeostatic control mechanisms, in the modern environment hedonic aspects of appetite are also critical. Enhanced knowledge of the complexity of appetite regulation and the mechanisms that sustain obesity indicate the challenge presented by management of the obesity epidemic. Nonetheless, effective control of appetite expression remains a critical therapeutic target for weight management. Currently, strategies which utilise a combination of agents to target both homeostatic and hedonic control mechanisms represent the most promising approaches.
This article is part of a Special Issue entitled ‘Central Control of Food Intake’.
Reduced levels of active GLP-1 in patients with cystic fibrosis with and without diabetes mellitus
2012, Journal of Cystic Fibrosis
Citation Excerpt :
However, oral hypoglycemic agents, normally effective for the treatment of type 2 diabetes (T2D) have no proven effect in the treatment of CFRD [6] although some data suggest a possible role for sulfonylurea [12]. Glucagon-like protein 1 (GLP-1) is a potent incretin hormone released by intestinal L-cells in the distal ileum in response to food intake [13]. It is released as a bioactive peptide (7-36)amide or (7-37) with a half-life of just a few minutes due to rapid deactivation by dipeptidyl peptidase-IV (DPP-IV), a functional amino peptidase in the CD26 complex [14].
Glucagon like peptide 1 (GLP-1) is an incretin hormone released as a bioactive peptide from intestinal L-cells in response to eating. It acts on target cells and exerts several functions as stimulating insulin and inhibiting glucagon. It is quickly deactivated by the serine protease dipeptidyl peptidase IV (DPP-IV) as an important regulatory mechanism. GLP-1 analogues are used as antidiabetic drugs in patients with type 2 diabetes.
We served patients with cystic fibrosis (CF, n = 29), cystic fibrosis related diabetes (CFRD, n = 19) and healthy controls (n = 18) a standardized breakfast (23 g protein, 25 g fat and 76 g carbohydrates) after an overnight fasting. Blood samples were collected before meal as well as 15, 30, 45 and 60 min after the meal in tubes prefilled with a DPP-IV inhibitor. The aim of the study was to compare levels of GLP-1 in patients with CF, CFRD and in healthy controls.
We found that active GLP-1 was significantly decreased in patients with CF and CFRD compared to in healthy controls (p < 0.01). However, levels in patients with CFRD tended to be lower but were not significantly lower than in patients with CF without diabetes (p = 0.06). Total GLP-1 did not differ between the groups, which points to that the inactive form of GLP-1 is more pronounced in CF patients. The endogenous insulin production (measured by C-peptide) was significantly lower in patients with CFRD as expected. However, levels in non-diabetic CF patients did not differ from the controls.
We suggest that the decreased levels of GLP-1 could affect the progression toward CFRD and that more studies need to be performed in order to evaluate a possible treatment with GLP-1 analogues in CF-patients.
Peripheral glucagon-like peptide-1 (GLP-1) and satiation
2011, Physiology and Behavior
Citation Excerpt :
Further potential physiological effects of GLP-1 include an influence on learning and memory [11], neuroprotection [12,13], and the inhibition of eating and drinking [14,15]. Administration of GLP-1 or of potent, long-acting natural or synthetic GLP-1 analogs, such as exendin-4 (Ex-4) or liraglutide, inhibits eating in many species, including humans [16–22]. Ex-4 is a naturally occurring peptide resistant to rapid enzymatic degradation by dipeptidyl peptidase 4 (DPP-4) [23].
Peripheral GLP-1 is produced by post-translational processing of pro-glucagon in enteroendocrine L-cells and is released in response to luminal nutrient (primarily carbohydrate and fat) stimulation. GLP-1 is well known for its potent insulinotropic and gluco-regulatory effects. GLP-1 receptors (GLP-1R) are expressed in the periphery and in several brain areas that are implicated in the control of eating. Both central and peripheral administration of GLP-1 have been shown to reduce food intake. Unresolved, however, is whether these effects reflect functions of endogenous GLP-1. Data collected in our laboratory indicate that in chow-fed rats: 1) Remotely controlled, intra-meal intravenous (IV) or intraperitoneal (IP) GLP-1 infusions selectively reduce meal size; 2) hindbrain GLP-1R activation is involved in the eating-inhibitory effect of IV infused GLP-1, whereas intact abdominal vagal afferents are necessary for the eating-inhibitory effect of IP, but not IV, infused GLP-1; 3) GLP-1 degradation in the liver prevents a systemic increase in endogenous GLP-1 during normal chow meals in rats; and 4) peripheral or hindbrain GLP-1R antagonism by exendin-9 does not affect spontaneous eating. Also, although our data indicate that peripheral GLP-1 can act in two different sites to inhibit eating, they argue against a role of systemic increases in endogenous GLP-1 in satiation in chow-fed rats. Therefore, further studies should examine whether a local paracrine action of GLP-1 in the intestine or and endocrine action in the hepatic-portal area is physiologically relevant for satiation.

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Glucagon-like peptide 1 (GLP-1) and eating

Abstract

Introduction

Section snippets

Gastrointestinal signals

GLP-1, its receptor and analogs

GLP-1 receptor antagonists and GLP-1 analogs

GLP-1 analogs as antiobesity agents

Concluding remarks

Acknowledgements

Neuropeptides

Metabolism

J. Biol. Chem.

Signals that regulate food intake and energy homeostasis

Science

Food intake and the regulation of body weight

Annu. Rev. Psychol.

Afferent signals regulating food intake

Proc. Nutr. Soc.

Central nervous system control of food intake

Nature

A role for glucagon-like peptide-1 in the central regulation of feeding [see comments]

Nature

Glucagon-like peptide-1, a gastrointestinal hormone with a pharmaceutical potential

Curr. Med. Chem.

Minireview: the glucagon-like peptides

Endocrinology

Preserved incretin effect in type 1 diabetic patients with end-stage nephropathy treated by combined heterotopic pancreas and kidney transplantation

Acta Diabetol.