Glucagon-Like Peptide-1 and Hypothalamic Regulation of Satiation: Cognitive and Neural Insights from Human and Animal Studies

Article information

Diabetes Metab J. 2025;49(3):333-347

Publication date (electronic) : 2025 May 1

doi : https://doi.org/10.4093/dmj.2025.0106

Joon Seok Park¹, Kyu Sik Kim², Hyung Jin Choi^,1,2,3,4,5,6

¹Department of Medicine, Seoul National University College of Medicine, Seoul, Korea

²Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea

³Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul, Korea

⁴Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, Korea

⁵Wide River Institute of Immunology, Seoul National University, Hongcheon, Korea

⁶Department of Brain and Cognitive Sciences, Seoul National University, Seoul, Korea

Corresponding author: Hyung Jin Choi https://orcid.org/0000-0003-0593-6978 Department of Medicine, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 03080, Korea E-mail: hjchoi@snu.ac.kr

Received 2025 February 9; Accepted 2025 April 16.

Abstract

KEY FIGURE

Highlights

INTRODUCTION

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have garnered significant attention in the global pharmaceutical market. Glucagon-like peptide-1 (GLP-1) is an incretin hormone derived from the transcription product of the proglucagon gene, primarily secreted by intestinal L-cells in response to nutrient intake [1]. It plays a critical role in glucose homeostasis, enhancing insulin secretion, suppressing glucagon release, and delaying gastric emptying.

In addition to its metabolic effects, GLP-1 acts centrally to maintain energy balance by activating glucagon-like peptide-1 receptors (GLP-1Rs) located in key regions of the brain. These include regions in the hypothalamus, brainstem, and mesolimbic reward pathways, which collectively regulate eating behavior such as food intake, satiation, and satiety. Additionally, the effects of GLP-1RAs on cognitive processes are currently being explored, broadening our understanding of their therapeutic mechanism in controlling metabolism.

This review will briefly cover the history of GLP-1 discovery and development of incretin-based drugs. Next, we will discuss human studies about the effects of GLP-1 on the central nervous system (CNS) and cognitive behavior, and animal studies that imply cognitive actions regulated by the hypothalamus. We will then go through the mechanism of GLP-1 acting on neural circuits within the CNS that regulate satiation and satiety, particularly focusing on regulation by the hypothalamus.

DISCOVERY OF GLP-1 AND DEVELOPMENT OF INCRETIN-BASED DRUGS

The discovery of secretin in 1902 was the hallmark for the initiation of gastrointestinal endocrinology [2]. In 1964, the development of insulin radioimmunoassay methods led to the discovery of the incretin effect, which demonstrated that oral glucose intake induces higher insulin secretion compared to intravenous (i.v.) glucose [3,4]. In 1973, Dupre et al. [5] proved that GIP, originally named ‘gastric inhibitory polypeptide,’ could explain this incretin effect by inducing glucose-stimulated insulin secretion, and renamed the peptide as ‘glucose-dependent insulinotropic polypeptide.’ Following the identification of GIP, the search for insulinotropic incretins persevered.

Meanwhile in 1982, Joel Habener’s group performed a cDNA study on anglerfish, a rich source of pancreatic islet hormone mRNAs. They revealed that the glucagon precursor gene encoded additional peptides beyond glucagon [6,7]. Subsequently, a study by Bell et al. [8] conducted cDNA analysis of preproglucagon in hamsters, which revealed that mammalian genes differ from those of anglerfish and identified two novel peptides, terming them glucagon-related peptides 1 and 2 (GLP-1, GLP-2).

GLP-1’s role as an insulinotropic incretin remained undetermined until GLP-1 (7-37), a truncated form of GLP-1, was identified by Mojsov et al. [9] as capable of stimulating insulin release in the rat pancreas, in contrast to GLP-1 (1-37), which did not alter insulin secretion. Holst et al. [10] further demonstrated that GLP-1 (7-37) extracted from pig intestine could stimulate insulin secretion in pig pancreas. In 1987, Kreymann et al. [11] performed studies in humans and confirmed GLP-1 (7-36) to be insulinotropic, suggesting its incretin nature. Indeed, i.v. infusion of GLP-1 (7-37) in subjects with and without diabetes elevated peak insulin levels by 10- and 3-fold respectively, and attenuated glucose levels [12]. These results suggested the possibility of GLP-1 as a treatment for diabetes, but limitations for therapeutic utility existed as endogenous GLP-1 had a short half-life in plasma of 1 to 2 minutes, degraded by the dipeptidyl-peptidase 4 (DPP-4) enzyme [13].

In 1992, Eng et al. [14] successfully isolated exendin-4 from the venom of the Gila monster (Heloderma suspectum), a lizard known for its infrequent but large meals weighing up to as much as one third of its body mass—suggesting the presence of adaptive metabolic mechanisms in the species [14,15]. Exendin-4, which shows 53% structural homology with GLP-1 (7-36), is as potent as endogenous GLP-1 in its insulinotropic effects via the mammalian GLP-1R. Strikingly, exendin-4 was stable against DPP-4 [16,17].

The isolation of exendin-4 led to the development of exenatide as the first U.S. Food and Drug Administration (FDA)-approved diabetes drug in 2005 by John Eng, with collaboration from Amylin Pharmaceutical (San Diego, CA, USA). Meanwhile, a group led by Knudsen at Novo Nordisk (Bagsværd, Denmark) employed the approach of fatty acid acylation to facilitate albumin binding and attenuate degradation [18]. The final product, liraglutide (Victoza, Novo Nordisk), proved its effects in type 2 diabetes mellitus (T2DM) and was approved by the FDA in 2010 [19]. Liraglutide (Saxenda, Novo Nordisk) was further developed with a higher dosage than Victoza for chronic weight management, and was approved by the FDA in 2014, proving its weight loss effects in numerous clinical studies performed worldwide [20,21].

The success of clinical trials with exenatide and liraglutide sparked growing interest in therapies based on GLP-1. Semaglutide, developed to achieve a longer half-life than liraglutide, enables once-weekly administration and induced clinically significant weight loss in randomized controlled clinical trials [22]. Recent randomized controlled trial studies have also proven that weekly semaglutide was superior compared to placebo in reducing cardiovascular risks for obese patients [23].

Meanwhile, dual and triple agonists targeting receptors beyond GLP-1R are continuously developed in preclinical models. In 2009 the first form of dual agonists was discovered by Day et al. [24], targeting GLP-1R and the glucagon receptor (GCGR). In 2013, Day et al. [25] also discovered dual agonists targeting both GLP-1 and GIP receptors (GIPR). In 2015, triple agonists simultaneously targeting the GLP-1R, GCGR, and GIPR were also developed, whose weight loss in mice exceeded those of the dual agonists [26]. Clinical trials for these coagonist incretin drugs are still continuously ongoing worldwide. Recently, the GIP/GLP-1R co-agonist tirzepatide has gone through several randomized controlled trials and was approved by the FDA for T2DM and obesity in 2022 and 2023, respectively. Once-weekly administered tirzepatide proved to be both noninferior and superior in reducing glycosylated hemoglobin levels in T2DM patients and demonstrated robust weight loss in obese patients [27,28]. The emergence of clinically effective dual and triple agonists holds promise for enhanced metabolic outcomes, although the precise mechanisms of drug actions remain to be fully elucidated.

GLP-1 AND IMPLICATIONS IN COGNITIVE SATIATION: HUMAN STUDIES

GLP-1 has long been identified and validated as a biomarker peptide for satiation and satiety under physiological conditions [29,30]. Satiation refers to the process occurring ‘during’ a meal event that prompts eating termination and is associated with meal size, while satiety refers to the process occurring ‘after’ a meal event, inhibiting further eating until the next meal [30,31]. Satiation gradually rises during a meal event as hunger diminishes, peaking at meal termination. After the meal event, satiety gradually drops over time and hunger returns, starting a new cycle [32].

The satiety cascade, first proposed in the 1980s and modified throughout, indicates that satiation and satiety are governed by the interplay of metabolic, cognitive, and sensory factors, which are interconnected components [31,33,34]. Studies indicate that sensory and cognitive perceptions of food can indeed influence satiation by brain signaling, while the mechanism of this process is yet to be fully uncovered [35].

It is well known that peripheral injection of GLP-1R agonists interacts with the CNS [36,37]. Several human studies have proven that the actions of GLP-1R agonists in the brain are regulated by sensory and cognitive factors. We have previously investigated the acute effects of lixisenatide injection compared to saline in measurements of functional magnetic resonance imaging (fMRI) responses to visual food cues. In T2DM patients, lixisenatide reduced activation in brain areas including the hypothalamus, temporal lobar regions, lateral ventricle, and cortical areas in obese individuals in contrast to lean T2DM individuals, who showed increased activation in the areas [38].

fMRI studies on other GLP-1R agonists have also provided further evidence of their cognitive effects. In obese T2DM patients, exenatide reduced putamen activity to high-calorie food pictures, while enhancing putamen responses to low-calorie food pictures [39,40]. In a study conducted in obese male patients all exenatide responders, defined as those who consumed lower food calories by exenatide administration compared to placebo, exhibited significantly higher hypothalamic connectivity measured by food cue-paired fMRI compared with placebo injection [41]. Furthermore, liraglutide treatment for 10 days in obese T2DM patients attenuated insula and putamen fMRI responses to food pictures in fasted and post-meal conditions, compared with insulin glargine injection [42].

Interestingly, the effects of GLP-1R agonists have also been studied in non-obese patients without T2DM. In fasted healthy normal weight patients, GLP-1 (7-36) amide injection reduced fMRI activity induced by food images, in all brain areas studied (amygdala, insula, caudate, NAc, orbitofrontal cortex, and putamen), compared to saline injection [43].

Collectively, these results highlight the cognitive effects of GLP-1R agonists in response to food cues, implying that the effects of GLP-1R agonists on satiation and satiety extend to cognitive processes.

HYPOTHALAMIC FUNCTIONS IN COGNITIVE FEED-FORWARD REGULATION

The hypothalamus is a well-established area of the brain known to regulate feeding behavior and energy metabolism, where disruption can lead to obesity [44]. The actions of agouti-related peptide (AgRP) neurons and pro-opiomelanocortin (POMC) neurons in the arcuate nucleus (ARC), the most renowned cell types of the hypothalamus governing homeostatic actions and inducing hunger, were previously understood to be mainly regulated by internal nutritional status or hormones such as leptin or ghrelin [45]. However, fiber photometry studies validated that ARC^AgRP neural activity is inhibited within seconds after visual sensory cognition or the taste of food, in the preingestive stage [46-48]. Strikingly, the amount of reduction in ARC^AgRP neural activity was modulated by food calories, and the learning of nutritional value in a single trial promptly suppressed ARC^AgRP neural activity [49]. These results demonstrate the feed-forward nature of ARC^AgRP neurons through a learned anticipation process. The sudden drop in signals at the moment of sensory detection or food cognition may reflect the abrupt recognition of an anticipated resolution of energy deficit, rather than being driven by ingestive or hormonal signals which typically act over minutes to hours [50]. Our previous research further corroborated this viewpoint by proving that ARC^AgRP neural activity accounts for computational modeling of ‘need,’ defined as predicted deficiency, which is the sum of current deficiency and future predicted changes [51]. This definition of ‘need’ implies the preemptive update of deficiency prior to ingestion, which can indeed occur through sensory cognition and anticipation of the future and may be advantageous for survival [52].

In addition, the leptin-receptor-expressing (LepR) neural activity in the dorsomedial hypothalamus (DMH), which sends GABAergic inhibitory inputs to ARC^AgRP neurons, is also known to be rapidly increased by sensory detection, the taste of food, or food cues [48,53,54]. DMH^LepR neurons receive afferents from the lateral hypothalamus (LH)^Vglut2 neurons, which are known to be necessary for the rapid responses to food cues [54]. Overall, these animal studies demonstrate the cognitive feed-forward hunger regulation mechanism that occurs in the hypothalamic region.

The hypothalamus can also be hypothesized to regulate satiation or satiety in a feed-forward manner. Indeed, in physiological conditions, plasma GLP-1 has been suggested to increase not only after meals, but also in the pre-ingestive, cephalic phase, with its peak observed about an hour prior to meal initiation in rats [55]. The following part of the review will discuss the hypothalamic actions regarding GLP-1, including its effects on satiation in cognitive stages.

HYPOTHALAMIC CONTROL OF GLP-1 ACTIONS ON SATIATION AND SATIETY: ANIMAL STUDIES

Various studies have focused on the hypothalamus as a target of different types of GLP-1R agonists. A study using fluorescently labeled lipidated analogues of exendin-4 showed that they are distributed in the hypothalamus [56]. Fluorescently labeled liraglutide reaches hypothalamic regions such as the ARC, paraventricular nucleus (PVH), and supraoptic nucleus (SON) after peripheral administration, with GLP-1R undergoing internalization after binding to liraglutide [57]. GLP-1RA binding to GLP-1R is indeed mediated by internalization of GLP-1R and GLP-1RA, consistent with the fact that GLP-1R is classified as a class B G protein-coupled receptor (GPCR) [57,58]. Whole brain microscopy following the injection of fluorescently labeled semaglutide revealed that semaglutide is present in parts of the hypothalamus, including the DMH, ARC, PVH, medial mamillary nucleus, and SON [59].

The specific mechanism of how GLP-1RAs can cross the blood-brain barrier and reach the hypothalamus has been a matter of debate. Hypothalamic tanycytes are glial cells located along the walls and floor of the third ventricle, which are known to play neuroendocrine roles such as detecting and transporting nutrients and hormones like insulin and GLP-1, as well as regulating neuronal activity [60-62]. The role of hypothalamic tanycytes has been studied in different types of GLP-1RAs. These cells are actively involved in the transport of exendin-4 to the brain cerebrospinal fluid [63]. In addition, GLP-1R expressions are found in tanycytes, and it is known that tanycytic GLP-1R is required for liraglutide’s anti-obesity actions via its transport to hypothalamic cells [64]. Semaglutide can also bind to and activate tanycyte GLP-1Rs [59]. Further elucidation is needed about the function of tanycytes and tanycytic GLP-1R-dependent transport of GLP-1RAs.

The distribution of GLP-1R and the role of GLP-1R expressing neurons along with the effects of GLP-1RA in different areas of the hypothalamus have been thoroughly studied in various studies (Table 1, Fig. 1) [65-67].

Table 1.

Animal studies of GLP-1R, GLP-1R neurons, GLP-1RA effects on hypothalamus

Fig. 1.

Overview of hypothalamic glucagon-like peptide-1 receptor (GLP-1R) neurons. PVH, paraventricular hypothalamic nucleus; Oxt, oxytocin-expressing; Crh, corticotropin-releasing hormone-expressing; MC4R, melanocortin 4 receptor-expressing; DMH, dorsomedial hypothalamus; LepR, leptin-receptor-expressing; LH, lateral hypothalamus; dDMH, dorsal DMH; vDMH, ventral DMH; GLP-1, glucagon-like peptide-1; ARC, arcuate nucleus; AgRP, agouti-related peptide; POMC, pro-opiomelanocortin; TRH, thyrotropin-releasing hormone-expressing; VMH, ventromedial hypothalamus; i.p., intraperitoneal.

Dorsomedial hypothalamus

GLP-1R are known to be expressed in the neurons of the DMH of mice and humans, and previous studies have emphasized its role in regulating metabolic responses by exendin-4 [68,69]. Direct injection of exendin-4 to the DMH reduced blood glucose levels, while liraglutide injection into the DMH did not alter 24-hour food intake or body weight [70,71]. Brain slice studies have shown that exendin-4 can increase the firing rates of DMH neurons, enhancing the neurons’ sensitivity to a high-fat diet (HFD) compared to a control diet [72]. Long-term ablation of DMH GLP-1R resulted in hyperphagia and obesity, and blunted exendin-4-induced anorexigenic metabolic effects [68,73].

The DMH GLP-1R expressing cells are known to be predominantly GABAergic, while a smaller percentage of the population do express vesicular glutamate transporter 2 (VGLUT2) mRNA [68]. Activated by GLP-1, DMH GLP-1R neurons are known to be crucial for glucose regulation, mediated by a cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) dependent pathway. These glucose-sensitive actions operate through downstream connections to the dorsal motor nucleus of the vagus (DMV) to the pancreas [70,73].

To further investigate the function of DMH GLP-1R neurons, our group conducted a translational study to elucidate their behavioral role. Optogenetic activation of the neurons triggered immediate meal termination and reduced bout duration and frequency, while neural inhibition prolonged bout duration and increased food intake, showing that the neurons are necessary and sufficient for satiation. Furthermore, calcium signal recording of DMH GLP-1R neurons highlighted that learned anticipation of food induces a significant increase in neural activity even before contact with food. In addition, exendin-4 injection enhanced calcium signals in DMH GLP-1R neurons in the pre-ingestive stage, and exendin-4-induced pre-ingestive satiation was mitigated by optogenetic inhibition of DMH GLP-1R neurons. These findings confirm that DMH GLP-1R neurons mediate pre-ingestive, cognitive satiation elicited by GLP-1R agonists, a phenomenon that we also observed in a human study [69]. The role of DMH GLP-1R neurons can be likened to stepping on a vehicle’s brake in response to a traffic signal—a learned anticipatory mechanism that prepares for meal termination independently of gut-derived feedback. This demonstrates a cognitive regulation of satiation, in which a feed-forward mechanism increases satiation before the initiation of a meal, eventually leading to meal termination (Fig. 2).

Fig. 2.

Feed-forward cognitive control of satiation. The role of dorsomedial hypothalamus (DMH) glucagon-like peptide-1 receptor (GLP-1R) neurons regulating cognitive satiation can be likened to stepping on a vehicle’s brake in response to traffic signals— a preemptive action taken before reaching the actual stop goal, reflecting a feed-forward control mechanism. These neurons project inhibitory signals to arcuate nucleus (ARC) agouti-related peptide (AgRP) neurons, ultimately contributing to meal termination. Notably, glucagon-like peptide-1 receptor agonists (GLP-1RAs) can potentiate the activity of DMH GLP-1R neurons.

GLP-1R-LepR co-expressing neurons, localized primarily in the DMH in rodent and non-human primate models, mediate the suppression of food intake by liraglutide [74-76]. A recent study combining single-nucleus sequencing and spatial transcriptomics pinpointed the human hypothalamic GLP-1R-LepR co-expressing cluster, which strongly correlated with the mouse hypothalamic cluster that exhibits the second highest expression of GLP-1R in the hypothalamus [76]. Notably, GLP-1R-LepR co-expressing cells proved to be crucial targets of newly synthesized GLP-1/leptin dual agonists, which create a negative energy balance and assist the action of leptin [75].

As previously mentioned, DMH LepR neurons are known to be activated by sensory cue information and the taste of food [48,53,54]. Activation of DMH LepR neurons has been shown to be sufficient to inhibit food intake [53]. However, the authors concluded that DMH LepR neurons are not essential for satiation or satiety, as the study found no significant increase in food intake or body weight following inhibition or disruption of these neurons [54]. More recently, another study demonstrated that DMH LepR neurons respond to oro-sensory cues, acting as negative feedback signals to promote meal termination. Chemogenetic inhibition of DMH LepR neurons led to increased food intake by increasing the number of licking bouts without altering bout length, in contrast to the increased bout duration in DMH GLP-1R neurons, implying that DMH LepR neurons play a role in satiety [48]. Some of this discrepancy may result from differences in observed behavior (licking vs. eating), or from the complexities of semantic distinctions between terms such as satiation or satiety. Additionally, some discrepancies may be explained by our findings, which show that mRNA co-localization of LepR and GLP-1R varies depending on the anatomical location within the DMH, with a higher overlap percentage in the caudal part of the DMH than the rostral part [69]. Some studies have also found a higher density of GLP-1R-positive cells in the dorsal DMH (dDMH) than the ventral DMH (vDMH), and a higher density of GLP- 1-positive neuronal fibers in the vDMH than the dDMH [72]. Moreover, the LepR neurons specifically within the dDMH were recently studied for their role in activating brown adipose tissue (BAT) thermogenesis, while not altering food intake [77]. Further research is needed to clarify regional differences within the DMH in the expression of GLP-1R and LepR, their upstream and downstream circuits, and how they can contribute to satiation or satiety in different feeding phases. Furthermore, the role of DMH GLP-1R neurons or LepR neurons in sensory-specific satiety, a phenomenon in which repeated exposure to a particular taste reduces food intake, is an area for further study.

ONGOING FUTURE STUDIES OF GLP-1R AGONISTS

Ongoing studies imply that the usage of GLP-1R agonists can be expanded to other areas, beyond their conventional roles in controlling food intake or energy balance. GLP-1RAs are being studied for their significant associations with reduced risks of various cardiovascular diseases, neuropsychiatric or substance use disorders, infectious illnesses and respiratory conditions, indicating their potential for broader therapeutic applications [111]. Notably, GLP-1R agonists have recently been suggested to have a role in mitigating reward-seeking. A vast number of preclinical and clinical studies have provided evidence for the potential role of GLP-1R agonists in modulating reward-seeking of food, alcohol, cocaine, and amphetamine, offering the possibility of a novel therapeutic alternative for treating addiction [112]. Randomized controlled clinical trials investigating the use of semaglutide in patients with alcohol use disorders (AUD) and comorbid obesity are currently underway, based on the potential of GLP-1R agonists for AUD treatment [113]. More studies are needed to clarify the underlying mechanism of drug and GLP-1 actions on reward circuits.

Recently, novel drugs combining GLP-1R agonism with other options, beyond the forementioned dual or triple agonist drugs, are being developed to maximize efficacy and minimize adverse effects in obesity and diabetes treatment. For instance, combinations of GLP-1R agonists with amylin analogues or peptide YY (PYY) analogues are currently undergoing clinical trials [114]. In addition, in preclinical stages, a combination of GLP-1R agonism with N-methyl-D-aspartate (NMDA) receptor antagonism (GLP-1-MK-801) has been developed [115]. Furthermore, small molecule oral agonists such as danuglipron are also under development, highlighting the potential for improved patient compliance through non-injectable delivery forms [116].

Several challenges remain to be addressed. The presence of non-responders to GLP-1R therapy continues to complicate treatment outcomes, underscoring the need for a deeper understanding of individual variability in response [117,118]. Additionally, the issues of weight regain and altered metabolic outcomes following drug discontinuation emphasize the importance of long-term studies investigating the impacts of the hormonal and CNS on weight regain to optimize safety and efficacy [119,120].

In conclusion, the DMH is a key target of GLP-1RAs, mediating pre-ingestive satiation, which is a cognitive process. GLP-1R neurons in the DMH and other hypothalamic nuclei regulate multiple aspects of eating behavior, presenting potential therapeutic targets for GLP-1R-based therapies and other drug candidates.

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