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. 2024 Jan 18;57(3):149–154. doi: 10.5483/BMBRep.2023-0117

Stomach clusterin as a gut-derived feeding regulator

Cherl NamKoong 1,#, Bohye Kim 2,3,#, Ji Hee Yu 4, Byung Soo Youn 5, Hanbin Kim 2, Evonne Kim 2, So Young Gil 1, Gil Myoung Kang 1, Chan Hee Lee 1, Young-Bum Kim 6, Kyeong-Han Park 7, Min-Seon Kim 1,4,*, Obin Kwon 2,3,*
PMCID: PMC10979347  PMID: 37817436

Abstract

The stomach has emerged as a crucial endocrine organ in the regulation of feeding since the discovery of ghrelin. Gut-derived hormones, such as ghrelin and cholecystokinin, can act through the vagus nerve. We previously reported the satiety effect of hypothalamic clusterin, but the impact of peripheral clusterin remains unknown. In this study, we administered clusterin intraperitoneally to mice and observed its ability to suppress fasting-driven food intake. Interestingly, we found its synergism with cholecystokinin and antagonism with ghrelin. These effects were accompanied by increased c-fos immunoreactivity in nucleus tractus solitarius, area postrema, and hypothalamic paraventricular nucleus. Notably, truncal vagotomy abolished this response. The stomach expressed clusterin at high levels among the organs, and gastric clusterin was detected in specific enteroendocrine cells and the submucosal plexus. Gastric clusterin expression decreased after fasting but recovered after 2 hours of refeeding. Furthermore, we confirmed that stomach-specific overexpression of clusterin reduced food intake after overnight fasting. These results suggest that gastric clusterin may function as a gut-derived peptide involved in the regulation of feeding through the gut-brain axis.

Keywords: Appetite regulation, Clusterin, Satiety response, Stomach, Vagus nerve

INTRODUCTION

Growing evidence from the effects of bariatric surgery and gut microbiota studies has suggested that the gut plays a crucial role in regulating energy homeostasis (1). Enteroendocrine cells, specialized epithelial cells found in the gastrointestinal (GI) tract, are responsible for sensing nutritional cues from the lumen and releasing biomolecules into the lamina propria or bloodstream as hormones (2). These gut-derived hormones coordinate digestive processes and convey satiety signals to the brain. Examples of such hormones include cholecystokinin (CCK), ghrelin, peptide YY3-36 (PYY3-36), and glucagon-like peptide-17-36 (GLP-17-36) (1, 3).

The vagus nerve serves as a major neuroanatomical connection between the GI tract and the brain (4). Its cell bodies reside in the nodose ganglia, and their axons project bidirectionally to both the brainstem and the gut (5). Peripheral terminals of the vagus nerve are distributed throughout the mucosal and muscular layers of the GI tract. Visceral sensory information from the gut is predominantly transmitted to the brain through the sensory fibers of the vagus nerve (6). Indeed, many studies have demonstrated that the vagal afferent terminals express receptors for various gut hormones, including CCK (7), ghrelin (8), PYY3-36 (9), GLP-17-36 (9, 10), and pancreatic polypeptide (11). Furthermore, these studies have shown that the effects of these hormones can be abolished by vagotomies.

Clusterin, also known as apolipoprotein J (Apo-J), is a secreted glycoprotein (12, 13). It was initially identified in ram rete testis fluid in 1983, where it was found to enhance cell aggregation in vitro, hence the name ‘clusterin’ (14). Clusterin is abundantly present in body fluids and exhibits ubiquitous expression in almost all mammalian tissues, including the brain, stomach, intestine, and liver (12, 15). Clusterin has been reported to influence carcinogenesis, lipid transportation, membrane recycling, and the complement system (14, 16). Recently, it has been revealed that circulating clusterin is produced and released by the liver, and it promotes insulin-induced glucose metabolism in muscle through the low-density lipoprotein receptor-related protein-2 (LRP2) (17).

We have previously reported clusterin as a novel anorexigenic neuropeptide (18, 19). Intracerebroventricular administration of clusterin significantly suppressed food intake and body weight gain (18). Moreover, clusterin was found to enhance the hypothalamic actions of leptin by facilitating the interaction between leptin and its receptor (19). However, the impact of peripheral-derived clusterin on energy metabolism has not been investigated thus far. In this study, we discovered that gastric clusterin can suppress fasting-induced hyperphagia. This effect was attenuated by vagotomy, suggesting the involvement of gastric clusterin in satiety regulation through the gut-brain axis.

RESULTS

Intraperitoneal injection of clusterin exhibits satiety effects

To determine whether peripherally administered clusterin affects food intake, overnight-fasted mice were intraperitoneally injected with clusterin peptides (18) at different doses (0.64, 1.6, and 4.0 mg/kg). We observed suppression of fasting-induced hyperphagia for up to 2 hours post-injection, with a significant reduction observed at the highest dose (4.0 mg/kg) of clusterin. However, this effect did not persist beyond that timeframe (Fig. 1A), and there were no discernible changes in body weight at 24 hours post-injection (data not shown), similar to the short-lasting action of CCK (20, 21). These findings suggest that a peripheral supply of clusterin can transiently promote satiation.

Fig. 1.

Fig. 1

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Peripheral administration of clusterin shows satiation properties, synergism with cholecystokinin and antagonism with ghrelin. (A) The intraperitoneal administration of clusterin (CLU) peptide in overnight-fasted mice significantly reduced food intake in a dose-dependent manner (0.64, 1.6, 4.0 mg/kg; n = 7-8). *P < 0.05, **P < 0.01 vs. saline-injected control. (B) The coadministration of CLU (4 mg/kg) and ghrelin (Ghr, 400 μg/kg) by intraperitoneal injection blunted ghrelin-induced hyperphagia in satiated mice (n = 5). *P < 0.05 vs. saline, †P < 0.05 vs. ghrelin alone. (C) The intraperitoneal coadministration of CLU at the sub-effective dose (1.6 mg/kg) and cholecystokinin (CCK, 2.5 μg/kg) synergistically reduced food intake in fasted mice (n = 6). *P < 0.05, **P < 0.01 vs. saline, †P < 0.05 vs. CCK alone. (D) The combination of CLU and CCK significantly decreased body weight gains after 24-hour post-injection (n = 6). *P < 0.05 vs. saline or CCK alone.

To further assess the interaction between clusterin and gut hormones known to regulate food intake, we co-administered clusterin intraperitoneally with ghrelin or CCK. Co-injection of clusterin (4.0 mg/kg) effectively attenuated ghrelin-induced hyperphagia in satiated mice (Fig. 1B). In contrast, the short-lasting satiety effect induced by CCK in overnight-fasted mice, which was insignificant at 4 hours post-CCK injection, was augmented and prolonged when suboptimal dose (1.6 mg/kg) of clusterin was co-administered (Fig. 1C). Importantly, co-administration of clusterin and CCK significantly suppressed body weight gains during the 24-hour post-injection period, whereas neither peptide alone had an impact on cumulative food intake or body weight during this period (Fig. 1C, D). Collectively, clusterin can enhance the satiation effect of CCK during feeding, resulting in a synergistic reduction in food intake, and it can also attenuate ghrelin-mediated hyperphagia in satiated condition.

Satiety effect of peripheral clusterin is mediated by the vagus nerve

It is evident that gut-derived CCK relays satiety signal to the nucleus tractus solitarius (NTS) in the brainstem through vagal afferent fibers, whose effect can be blocked by ghrelin (22). Neural circuits originating from the NTS project to the hypothalamic paraventricular nucleus (PVN), which plays a role in appetite regulation (23). Given that clusterin potentiated the satiety effect of CCK, we aimed to determine whether the satiety effect of peripheral clusterin depends on the vagus nerve. To address this question, we intraperitoneally injected CCK (1 μg/kg) or clusterin (3 mg/kg) into overnight-fasted mice that had undergone either sham surgery or vagotomy. As previously reported (24), peripheral injection of CCK (positive control) induced c-fos signals in the NTS, area postrema (AP), and PVN (Fig. 2A). The satiety effect of CCK was also completely abolished by vagotomy (Supplementary Fig. 1), confirming the success of the vagotomy procedure. Similarly, peripheral injection of clusterin increased c-fos expression in the NTS, AP, and PVN, and this effect was significantly diminished in vagotomized mice (Fig. 2A). Consistent with these findings, food intake in sham-operated mice was reduced by clusterin injection, but this effect was attenuated in vagotomized mice (Fig. 2B). These results indicate that peripheral clusterin can induce satiety through the vagus nerve.

Fig. 2.

Fig. 2

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Clusterin delivers satiety signals to the brain through the vagus nerve. (A) Sham-operated (Sham op) mice with intraperitoneal injection of clusterin (CLU, 3 mg/kg) or cholecystokinin (CCK, 1 μg/kg) showed enhanced expression of c-fos in the nucleus tractus solitarius (NTS) and area postrema (AP) in the medulla, and the paraventricular nucleus (PVN) in hypothalamus. In vagotomized mice (Vx), c-fos expression in the NTS and PVN by CLU was inhibited. CC, central canal; 3V, third ventricle. Scale bar, 20 μm. (B) Food intake reduced by CLU (3 mg/kg, intraperitoneal injection) in fasted mice was almost abrogated by vagotomy (n = 5). *P < 0.05. NS, not significant.

Gastric neuroendocrine cells express clusterin

Clusterin is ubiquitously detected throughout the body, including the brain, body fluids, and stomach (12, 15). Considering that clusterin can act antagonistically against gastric ghrelin and the vagus nerve transmits clusterin-induced satiety signals, we next focused on endogenous clusterin expression in the stomach. To examine the basal expression of gastric clusterin, immunohistochemistry was conducted on mouse gastric tissues. Consistent with previous reports (15, 25), strong immunoreactivity of clusterin was detected in the gland cells of oxyntic and pyloric mucosa in wild-type mice, using the anti-clusterin antibody validated in clusterin knockout mice (Fig. 3A). Additionally, clusterin was detected in some mucosal enteroendocrine cells, as indicated by co-localization of clusterin with chromogranin-A (CgA) (Fig. 3B), suggesting that clusterin might function as a stomach-derived hormone.

Fig. 3.

Fig. 3

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Clusterin expresses in C57BL/6 mouse stomach. (A) Validation of anti-clusterin antibody was performed using the gastric mucosa tissues of wild-type (CLU+/+) and clusterin knockout (CLU−/−) mice. (B) Double immunostaining of clusterin and chromogranin-A (CgA, a marker of enteroendocrine cells) in the gastric mucosa. White arrows indicate double positive cells. (C) Double immunostaining of clusterin (CLU) and leptin (Lep) in the gastric mucosa and submucosa. White arrows indicate some gastric epithelial cells expressing CLU only. Right column, a higher magnification of a submucosal cell. (D) Double immunostaining of CLU and ghrelin (Ghr) in the stomach. CLU was colocalized with Ghr in the submucosal cells, not in the mucosal cells. (E) Double immunostaining of CLU and protein gene product 9.5 (PGP9.5, a marker of plexus neurons) in the submucosa. (F) Double immunostaining of Ghr and vesicular acetylcholine transporter (VAChT) in the gastric submucosa. M, mucosa; SM, submucosal. Scale bar, 20 μm.

Some gastric cells produce the critical appetite-regulating hormone leptin (26). Interestingly, most of the leptin-expressing gastric epithelial cells in the stomach coexpressed clusterin. In contrast, some clusterin-expressing cells did not express leptin (Fig. 3C). Both leptin and clusterin were also coexpressed in the submucosal cells, particularly in the submucosal plexus labeled by its marker, protein gene product 9.5 (PGP9.5) (Fig. 3E). Furthermore, both ghrelin and clusterin were detected in the same submucosal cells (Fig. 3D), which showed immunoreactivity to the parasympathetic/cholinergic neuron marker vesicular acetylcholine transporter (VAChT) (Fig. 3F). Taken together, these results suggest that gastric clusterin might be closely related to the neuroendocrine systems in the stomach.

Gastric clusterin functions as a satiety factor

It can be hypothesized that if gastric clusterin regulates appetite, its expression may be influenced by meal status. To validate this hypothesis, gastric mucosa and submucosa were collected from the mice in three different groups: ad libitum fed (Ad lib. group), fasted for 18 hours (Fasted group), and refed for 2 hours after an 16-hour fast (Refed group). The transcript levels of gastric clusterin revealed that overnight food deprivation significantly decreased gastric clusterin expression, which was restored to the level observed in the Ad lib. group after refeeding (Fig. 4A). These trends were consistent with the levels of gastric clusterin protein as determined by Western blot analysis (Fig. 4B, C). These findings indicate that gastric clusterin expression is regulated by food intake and suggests its potential role as a satiety factor.

Fig. 4.

Fig. 4

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Gastric clusterin per se exerts satiety signal. (A) Relative transcript levels for clusterin from the mucosa and submucosa tissues in mice. In the ‘Fasted’ group, the mice were fasted for 18 hours. In the ‘Refed’ group, fasted mice for 16 hours were refed for 2 hours. (B) Representative western blot for secreted form of clusterin (sCLU, arrow) detection from the mucosa and submucosa tissues in mice. β-actin was used for the loading control. (C) Quantification of band intensity in (B). All data (A-C) were pooled from the three independent experiments (Ad lib., n = 14; Fasted, n = 16; Refed, n = 15), and one-way ANOVA with Tukey’s multiple comparisons were used. (D) Representative western blot showed that CLU was overexpressed in the gastric mucosa and submucosa of Ad-CLU-injected C57BL/6 mice. (E) At 3 days post-injection, fasting was initiated and maintained for 16 hours, after which food was supplied. Cumulative food intake was calculated at each indicated time (Ad-GFP, n = 4; Ad-CLU, n = 9). Two-way repeated ANOVA with Sidak’s multiple comparisons. *P < 0.05, **P < 0.01, ***P < 0.001.

We next investigated whether increased clusterin expression in the stomach can affect food intake or satiety formation. For this, we microinjected adenovirus expressing rat clusterin (Ad-CLU) or control (Ad-GFP) (18) into the gastric walls. Before the in vivo experiment, we validated whether Ad-CLU effectively increases clusterin expression using NIH/3T3 cells. Western blot analysis of the infected cell lysates demonstrated successful induction of clusterin expression by Ad-CLU (Supplementary Fig. 2A). After injection of Ad-CLU, we monitored food intake and body weight for three days in ad libitum fed condition and then conducted a fasting-refeeding study. At the end of the study, we conducted a postmortem analysis of the stomach to confirm successful clusterin overexpression in the Ad-CLU group (Fig. 4D). There were no differences between the groups in daily food intake and body weight gain (Supplementary Fig. 2B). However, in the fasting-refeeding study, 1-hour food intake was significantly lower in the Ad-CLU group than in the Ad-GFP group (Fig. 4E), and the tendency of reduction in food intake at 2 hours and 4 hours after commencement of refeeding was also observed in Ad-CLU-injected mice. Thus, the gain-of-function experiment of gastric clusterin supports the potential role of stomach clusterin as a satiety-inducing gut hormone.

DISCUSSION

This study provides evidence for the involvement of gastric clusterin in the generation of gut-derived satiation signals. The results demonstrate that peripheral administration of clusterin effectively suppresses feeding in the short term by interacting with appetite-regulating gut hormones. The involvement of the vagus nerve, a crucial pathway in the gut-brain axis, is proposed as a mediator of the satiety effect induced by peripheral-derived clusterin. Notably, while clusterin is expressed ubiquitously, the stomach exhibits an abundant expression of clusterin, which is also detected in the enteroendocrine system and enteric nervous system of the stomach. The expression of gastric clusterin is regulated by food intake, and enhanced expression of gastric clusterin shows a short-term satiety effect in refeeding conditions. To our knowledge, this is the first study proposing a potential role of gut-derived clusterin in the physiological regulation of food intake.

The satiety effect observed with peripheral clusterin administration was short-lasting, similar to the effect of CCK injection. CCK is released by enteroendocrine cells upon food ingestion and promotes reductions in meal size by eliciting satiation signals (27). Notably, the satiety effect of CCK could be enhanced and prolonged (reduced food intake and body weight gain for 24 hours) when clusterin was co-administered, even at a suboptimal dose (1.6 mg/kg) selected for this synergism study. Similar to a previous report demonstrating that stomach leptin augments CCK-induced satiety (28), our results suggest a potential role of peripheral clusterin as a co-factor of CCK in the regulation of satiety. This short-term satiety effect of clusterin alone may no longer be intact in a satiated context (Fig. 1B), which is a relevant property for maintaining homeostasis.

Considering that CCK and ghrelin are representative gut-derived hormones that regulate food intake through the vagal afferent nerve (8, 27), it was hypothesized that the vagus nerve may mediate the effects of peripheral clusterin. During a meal, gut-derived satiety signals are transmitted to the NTS in the caudal brainstem, a critical brain area for gustatory, satiety, and visceral sensations, via vagal afferents (29). These signals eventually reach the hypothalamic PVN (30). This effect was recapitulated by peripheral clusterin administration, which was significantly attenuated by truncal vagotomy, indicating the dependence of the satiety effects of peripheral clusterin on the vagus nerve.

Given that CCK originates from the duodenum and ghrelin from the stomach, both located in the upper GI tract, and the fact that the vagus nerve is innervated in this segment, we hypothesized that this region could also be the source of endogenous peripheral clusterin involved in the observed phenomenon. Clusterin, as an extracellular chaperone, is predominantly expressed at fluid-tissue interfaces in various organs, protecting cell membranes from injury, such as gastric juice-induced damage in the stomach (13). Previous studies have mainly focused on the high expression of clusterin in the gland cells of the gastric mucosa (15). However, in our study, we further detected immunoreactivity of clusterin in gastric enteroendocrine cells and the enteric nervous system, particularly in co-localization with gut-derived hormones, providing a potential clue to the underlying mechanism of this molecule.

It is well established that the secretion of these gut-derived hormones is stimulated by food intake or fasting. Considering that the level of gastric clusterin decreases after fasting and increases after refeeding, it is plausible to consider clusterin as another relevant endogenous factor involved in the regulation of food intake. This changes in clusterin levels are unlikely to be derived from plasma clusterin, as its levels increase after starvation and decrease after 1 hour of refeeding (18). Furthermore, the gastric tissues used in this study were harvested after transcardiac saline perfusion to remove blood-borne clusterin. It should be noted that clusterin produced by the liver can be transported to multiple metabolic organs, including the stomach and intestine (17). This raises questions about the extent of influence that liver-derived clusterin may have on food intake through the vagal afferent nerve. Future research is needed to determine the full impact of these factors. Lastly, the induced expression of gastric clusterin could recapitulate the short-term satiety effect observed with intraperitoneal clusterin injection, further strengthening the potential role of gastric clusterin as a putative satiety factor.

The mechanism through which the fasting and refeeding cycle regulates the expression of gastric clusterin requires further study. This regulation can be either cell-autonomous or dependent on upstream signals. Putative upstream regulatory mechanism involving gut-derived hormones with metabolic roles include efferent neuronal networks in the brain-stomach axis, including (but not limited to) the vagus nerve, as well as humoral (hormonal) responses related to energy status of the body. An example is ghrelin, whose secretion can be regulated by various mechanisms. Ghrelin acylation, crucial for its physiological function, can be influenced by the supply of dietary lipids from food in the stomach via an enzyme called ghrelin O-acyl-transferase (31). Furthermore, both cholinergic and adrenergic neurotransmission have shown evidence of involvement in the release of ghrelin (31). Similarly, if identified, the regulatory mechanism of gastric clusterin expression could be a potent target for enhancing satiety.

Currently, the exact mechanism by which gastric clusterin acts locally to reduce food intake remains unknown. Based on our results and previous knowledge, several hypotheses can be proposed. One possibility is that clusterin may extend the short half-life of CCK or facilitate the interaction of CCK with its receptors on the vagal afferent nerve, considering the role of clusterin as a chaperone (13). Another possibility is the direct action of clusterin through its putative receptors on the vagal afferent nerve. Various receptors have been suggested as potential clusterin receptors, including LRP2, transforming growth factor beta receptor 1 or 2 (TGFBR1 or 2), LRP8/apolipoprotein E receptor 2 (ApoER2), very low-density lipoprotein receptor (VLDLR), and plexin A4 (32-35). According to a single-cell atlas of jugular and nodose ganglia containing vagal sensory neurons by Ernfors group (GSE124312) (36), the most prevalent transcript (% of positive cells) was Plxna4 (70.03%), followed by Lrp8 (47.51%), Vldlr (36.27%), Tgfbr1 (26.03%), and Tgfbr2 (4.71%). Interestingly, the lowest expression was observed for Lrp2 (0.38%), although clusterin acts on LRP2 in the hypothalamus (18, 19). Moreover, interactions between clusterin and plexin A4 have recently attracted attention as a therapeutic target for Alzheimer’s disease (35). Further studies are needed to determine whether the same interaction on vagus nerve can serve as a mechanism for clusterin as a satiety factor.

In conclusion, our findings provide evidence that gastric clusterin may function as a gut-derived peptide involved in the regulation of feeding through the gut-brain axis.  

MATERIALS AND METHODS

Materials and methods are described in the Supplementary Information.

Funding Statement

ACKNOWLEDGEMENTS This work was supported by the National Research Foundation of Korea funded by the Korean government (2020R1A2C3004843, 2022M3E5E8017213 to M-S.K., 2020R1C1C1008033 to O.K.).

Footnotes

bmb-57-3-149-supple.pdf (359.3KB, pdf)

CONFLICTS OF INTEREST

The authors have no conflicting interests.

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