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10.1007/s00424-024-02996-z
Signaling and Cell Physiology
Effect of hypoxia on GLP-1 secretion – an in vitro study using enteroendocrine STC-1 -cells as a model
Sharma Ravikant 1
Raza Ghulam Shere 1
Sodum Nalini 1
Walkowiak Jaroslaw 2
Herzig Karl-Heinz karl-heinz.herzig@oulu.fi

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1 https://ror.org/03yj89h83 grid.10858.34 0000 0001 0941 4873 Research Unit of Biomedicine and Internal Medicine, Biocenter of Oulu, Medical Research Center, University of Oulu, Aapistie 5, 90220 Oulu, Finland
2 https://ror.org/02zbb2597 grid.22254.33 0000 0001 2205 0971 Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences, 60572 Poznań, Poland
29 7 2024
29 7 2024
2024
476 10 16131621
22 5 2024
16 7 2024
17 7 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Glucagon-like peptide (GLP)-1 is a hormone released by enteroendocrine L-cells after food ingestion. L-cells express various receptors for nutrient sensing including G protein-coupled receptors (GPRs). Intestinal epithelial cells near the lumen have a lower O2 tension than at the base of the crypts, which leads to hypoxia in L-cells. We hypothesized that hypoxia affects nutrient-stimulated GLP-1 secretion from the enteroendocrine cell line STC-1, the most commonly used model. In this study, we investigated the effect of hypoxia (1% O2) on alpha-linolenic acid (αLA) stimulated GLP-1 secretion and their receptor expressions. STC-1 cells were incubated for 12 h under hypoxia (1% O2) and treated with αLA to stimulate GLP-1 secretion. 12 h of hypoxia did not change basal GLP-1 secretion, but significantly reduced nutrient (αLA) stimulated GLP-1 secretion. In normoxia, αLA (12.5 μM) significantly stimulated (~ 5 times) GLP-1 secretion compared to control, but under hypoxia, GLP-1 secretion was reduced by 45% compared to normoxia. αLA upregulated GPR120, also termed free fatty acid receptor 4 (FFAR4), expressions under normoxia as well as hypoxia. Hypoxia downregulated GPR120 and GPR40 expression by 50% and 60%, respectively, compared to normoxia. These findings demonstrate that hypoxia does not affect the basal GLP-1 secretion but decreases nutrient-stimulated GLP-1 secretion. The decrease in nutrient-stimulated GLP-1 secretion was due to decreased GPR120 and GPR40 receptors expression. Changes in the gut environment and inflammation might contribute to the hypoxia of the epithelial and L-cells.

Graphical Abstract

Keywords

Hypoxia
GLP-1
Enteroendocrine cells
Fatty acid
GPR40 and GPR120
http://dx.doi.org/10.13039/501100011842 Opetushallitus OPH-1647-2022 OPH-1647-2022 Sharma Ravikant Herzig Karl-Heinz University of Oulu (including Oulu University Hospital)Open Access funding provided by University of Oulu (including Oulu University Hospital).

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pmcIntroduction

Glucagon-like peptide-1 (GLP-1) is an amino acid peptide hormone in different molecular forms (GLP-1 (1–37; 7–37; 7–36), released by enteroendocrine L-cells in response to nutrient load [13]. GLP-1 is an incretin that regulates blood glucose levels by insulin release from the pancreatic β-cells, food intake, and gut motility [27]. In human plasma, active forms are GLP-1 (7–36) amide and (7–37) amide, which are rapidly degraded by dipeptidyl peptidase 4 (DPP4) into GLP-1 (9–36) amide and (9–37) amide. Due to its quick inactivation, GLP-1 has a short half-life of less than 2 min and only 10–15% of the released GLP-1 enters the systemic circulation [2]. In humans, L-cells are localized in the proximal small intestine and progressively increase in density towards the distal part of the intestine and colon [27]. GLP-1 plasma concentrations are low (5–15 pmol/L) in the fasted state and increase 2- to 4 fold postprandially by nutrients such as carbohydrates, peptides, and lipids [7]. The apical surface of L-cells allows direct interaction with nutrients [8]. Sodum et al. recently reported that nutrient combinations such as amino acid and fatty acid potentiate GLP-1 secretion compared to individual nutrients in the L-cells [48]. L-cells express several receptors for nutrient sensing including G protein-coupled receptors (GPRs) [44]. Long chain fatty acids (LCFAs) including oleic acid, linolenic acid, alpha-linolenic acid (αLA), eicosadienoic acid, and arachidonic acid activate GPR120, GPR40, GPR119, inducing GLP-1 secretion [12]. Hirasawa et al. reported GPR120 but not GPR40, mediates FFA-induced Ca2+ response and GLP-1 secretion from STC-1 cells [26].

Oxygen (O2) is a key factor affecting GLP-1 synthesis and release [55]. The epithelial cells near the lumen have a much lower O2 tension than at the base of the crypts with a steep oxygen gradient, which is critical for intestinal homeostasis [46]. The O2 tension in the villus falls significantly from 14–17 mmHg in the interdigestive phase to 4–7 mmHg postprandial [17]. Furthermore, O2 levels drop from 10–7.5% in the stomach to 1.5—0.5% at the colon-rectal junction [58]. These anatomical characteristics provide a sharp oxygen gradient across the tissue, making intestinal cells hypoxic even under physiological conditions, known as 'physiological hypoxia'. As a consequence, the colonic microbiome is primarily composed of anaerobic bacteria, predominantly Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, and Verrucomicrobia [41]. Anaerobes further contribute to the intestine's hypoxic environment by utilizing part of the O2 from the bloodstream [8].

Hypoxia induces the stabilization of the transcription factors hypoxia-inducible factor-1α (HIF-1α) and HIF-2α which is influenced by O2-regulated proteins such as prolyl-hydroxylases (PHDs) and factor-inhibiting HIF (FIH) [21]. The HIF-α subunit has three isoforms in vertebrate species: HIF-1α, HIF-2α, and HIF-3α. These proteins enter the nucleus and form complexes with the constitutively produced β subunit, regulating gene expression of several fundamental cellular processes such as metabolism and autophagy.

There are conflicting results on the effect of hypoxia on GLP-1 secretions: Moderate hypoxia (15.0% O2) for 7 h in healthy human subjects did not change plasma GLP-1 levels [39]. In addition, rats exposed to hypobaric hypoxia (simulated altitude of 7620 m) for 6-168 h decreased plasma CCK and GLP-1 [15]. In contrast, 64 cycles of intermittent hypoxia for 5 min (1% O2) and 10 min normoxia (21% O2) increased mRNA expression of PYY and GLP-1 in STC-1 cells [45].

We hypothesized that hypoxia might affect nutrient-stimulated GLP-1 levels from the mouse enteroendocrine cell line STC-1 [29]. Our study investigated the effect of hypoxia (1% O2) on nutrient-stimulated (αLA) GLP-1 secretion.

Materials and methods

Materials

Dulbecco’s modified eagle medium (DMEM, Cat. No. P04-03500 PAN Biotech, Aidenbach Germany), α-Linolenic Acid (Cat. No. L2376), DPP4 inhibitor (Cat. No. DPP4-010), and active GLP-1 ELISA kit (Cat. No. EGLP-35 K) were purchased from Merck (Darmstadt, Germany), Horse serum (Cat. No. 16050–122, ThermoFisher, Waltham, MA), fetal bovine serum (Cat. No. 10270106, ThermoFisher), L-glutamine Gibco (Cat. No. 25030–024, ThermoFisher), penicillin–streptomycin Gibco (Cat. No. 15140–122, ThermoFisher), protease inhibitor cocktail (Cat. No. 10516495, Sigma-Aldrich, St. Louis, MO), T-75 and 6 wells plates (Sarstedt AG & Co. KG, Nümbrecht, Germany), HIF-1α rabbit monoclonal antibody (Cat. No. D1S7W 36169, Cell Signaling Technology, Danvers, MA), GPR120 polyclonal antibody (Cat. No. PA5-50,973, ThermoFisher Scientific, Rockford, IL), GPR40 polyclonal antibody (Cat. No. PA5-67,931, ThermoFisher Scientific, Rockford, IL) GAPDH rabbit monoclonal antibody (Cat No. 2118 14C10, Cell Signaling Technology, Danvers, MA), Goat anti-rabbit IgG antibody (Cat. No. ab6721, abcam, Cambridge, United Kingdom), PVDF membrane (Cat No. 24937–79-9 Merck Millipore, Burlington, MA), Super Signal TM West Femto Substrate (Cat. No. 34095, Thermo Fisher Scientific, Rockford, IL). All reagents used were of analytical grades.

STC-1 cell culture

The STC-1 cell line was cultured in T75 flasks in DMEM supplemented with 15% horse serum, 2.5% fetal bovine serum (FBS), 1% L-glutamine, and penicillin–streptomycin as previously described [40]. Cells were maintained in the above media at 37˚C, 5% CO2 until 85–90% confluency. Passage numbers 14–21 were used for the experiment. The mouse STC-1 cell line is the most commonly used GLP-1 secreting cell line and serves as a model cell line in the investigations of GLP-1 [26, 29, 40, 48]. In addition, other cell lines like mouse GLUTag cells secrete significantly less GLP-1 [29]. Human cell lines secreting GLP-1 are the colon cancer cell line Caco-2 and the NCI-H716 cell line from a 33-yr-old Caucasian male with poorly differentiated adenocarcinoma of the colon [42, 50]. Cell line models of L-cells differ from each other and from the natural L-cells [36]. However, there is abundant GLP-1 in the distal intestine in different species like mice, rats, pigs and humans responding to nutrient stimulation [30].

GLP-1 secretion in STC-1 cells under normoxia and hypoxia

STC-1 cells were seeded at 2.0 × 106 cells/well with 2 ml media in 6-well cell culture plates. Cells were counted by an automated cell counter (LUNA-II™, Logos Biosystems, Inc., Villeneuve-d´Ascq, France). On the day of experiments, cells were washed and incubated with DMEM for 12 h in normoxia (18% O2, 5% CO2) and hypoxia (1% O2, 5% CO2) using the hypoxic chamber, Sci-Tive-N/Ruskinn, Baker, Sanford, ME. After 12 h of incubation, the cells were washed twice with Krebs–Ringer Bicarbonate Buffer (KREBS; 118 mM NaCl, 4.7 mM KCl, 25 mM NaHCO3, 1.25 mM CaCl2, 1.2 mM MgSO4, and 1.2 mM KH2PO4) pH 7.4. Hypoxia was maintained throughout the experiment by keeping the cells in a hypoxia chamber and all the treatments including washing were performed inside the chamber. Following washing cells were acclimatized with KREBS buffer for 1 h. After 1 h of acclimatization, the buffer was aspirated, and cells were treated in triplicates with different treatments along with DPP4 inhibitor in KREBS buffer for 1 h at 37◦C: αLA (12.5 μM) as shown in Fig. 1 [48]. KREBS buffer with ethanol (0.1%) and DPP4 inhibitor (0.25%) was used as a control. After 1 h of treatment, the supernatant was collected, centrifuged at 13,000 g for 15 min at 4◦C and stored at -70◦C. Cells were washed with ice-cold PBS for protein analysis. Active GLP-1 was measured by an active GLP-1 ELISA kit as per manufacturer instructions [29] (n = number of individual experiments performed in triplicates).Fig. 1 Study design. STC-1 cells were incubated with DMEM under normoxia and hypoxia (1% O2, 5% CO2) for 12 h and treated with αLA (12.5 μM) for an additional 1 h. GLP-1 release were analyzed in the supernatant and cell lysates were used for protein expression of HIF-1α, GPR120 and GPR40 

Immunoblotting for protein analysis

Cells were scrapped from a 6-well plate using a cell scrapper and ice-cold RIPA lysis buffer (50 mM Tris, 150 mM NaCl, 0.1% Triton X-100, 0.5% sodium deoxycholate, 0.1% SDS), containing protease inhibitor cocktail (Sigma, St. Luis, MO). The suspension was passed using a 27G needle and centrifuged at 13,000 g for 20 min at 4˚C. Total protein concentrations were determined by the Bradford reagent (Bio-Rad Laboratories Inc., Hercules, CA). Equal amounts of protein (12.5 μg) were separated by 8% SDS-PAGE gel and transferred to a PVDF membrane. The membrane was blocked using 5% skim milk in Tris-buffered saline containing 0.1% Tween 20 (TBST) for 1 h and incubated with primary HIF-1α monoclonal antibody (1:1000), GPR120 polyclonal antibody (1:1000), GPR40 polyclonal antibody (1:1000) and loading control protein GAPDH (1:1000) overnight at 4˚C. After overnight incubation, the membrane was incubated with a secondary antibody (1:10,000 Goat anti-rabbit IgG horseradish peroxidase-conjugated anti-rabbit IgG) for 1 h at room temperature. Chemiluminescence for proteins was detected using SuperSignal™ West Femto Maximum Sensitivity Substrate according to the manufacturer´s instructions. Blots were visualized with an Odyssey Fc imaging system (LI-COR Biosciences, Ltd, Cambridge, UK).

Statistical analysis

One-way analysis of variance (ANOVA) was used to analyze statistical significance between the groups using GraphPad Prism, version 7 (GraphPad Software, Inc., La Jolla, CA). Dunnett’s multiple comparison test was used to analyze the difference between the treatment groups. The values are represented as mean ± standard errors of the mean (SEM) and differences were considered statistically significant when p < 0.05.

Results

In vitro GLP-1 secretions in STC-1 cells

12 h hypoxia did not significantly affect basal GLP-1 secretion, but nutrient (αLA) stimulated GLP-1 secretion was significantly reduced by 45% (Fig. 2). αLA significantly stimulated GLP-1 secretion under normoxia (~ 7 folds), but no significant change under hypoxia in STC-1 cells compared to buffer (control) (Fig. 2). In addition, αLA-stimulated GLP-1 secretion under hypoxia was significantly lower compared to normoxia αLA (Fig. 2). A total of 5 independent experiments were performed in triplicates.Fig. 2 Active GLP-1 secretion under normoxia and hypoxia in STC-1 cells. 12 h hypoxia did not significantly affect basal GLP-1 secretion compared to normoxia control. αLA significantly stimulated GLP-1 secretion under normoxia (~ 7 folds), but no significant change under hypoxia compared to buffer (control). In addition, αLA-stimulated GLP1 secretion under hypoxia was significantly lower compared to normoxia αLA. n = 5 (n = number of individual experiments in triplicates). The value represents the mean ± standard error of the mean (SEM) and differences were considered statistically significant when ***p < 0.001 and ****p < 0.0001

HIF-1α protein expression in STC-1 cells

All the blots clearly show the HIF-1α protein bands at ~ 120 kDa. 12 h hypoxia (1% O2) noticeably induced HIF-1α protein expressions in STC-1 cells (Fig. 3). Under normoxia, only faint HIF-1α protein bands were observed (Fig. 3). These blots clearly show that hypoxia was established in STC-1 cells as intense HIF-1α protein bands were visible.Fig. 3 Representative western blots of HIF-1α in STC-1 cells. In hypoxic conditions, all the blots showed intense HIF-1α protein bands at ~ 120 kDa and only faint bands under normoxia. A) 12 wells of 2 experiments in triplicates. B) 4 wells from one experiment in triplicates plus one additional well from another experiment under hypoxia. C) 7 wells from one experiment in triplicates and one additional well under normoxia

GPR120 and GPR40 protein expression

All blots showed the bands for GPR120 at ~ 43 kDa (Fig. 4a) and for GPR40 at ~ 26 kDa (Fig. 4b). Our results demonstrated that hypoxia downregulated GPR120 and GPR40 expressions by 50% and 60% respectively, compared to normoxia (Fig. 4c). αLA upregulated GPR120 expression (10%), while GPR40 was downregulated (20%) under normoxia (Fig. 4d). αLA did not significantly change either of the receptors on the protein expression levels under hypoxia (Fig. 4d). Fig. 4 Protein expression for (a) GPR120 blots (b) GPR40 blots (c) Average Relative Density of GPR120 with GAPDH (d) Average Relative Density of GPR40 with GAPDH. Hypoxia downregulated GPR120 and GPR40 protein expressions in STC-1 cells. The value represents the mean ± standard error of the mean (SEM) and differences were considered statistically significant when p < 0.05 and n = 4

Discussion

Our study demonstrated that nutrient αLA significantly stimulated GLP-1 secretion from enteroendocrine STC-1 cells under normoxia but not under hypoxic conditions. However, no significant change in GLP-1 secretion was found under basal conditions between hypoxia and normoxia. αLA was used as a positive control to stimulate GLP-1 secretion in STC-1 cells as previously described [48]. Our results are consistent with previous findings under normoxia on GLP-1 secretion with fatty acids in STC-1 cells [29, 48]. Consistent with our findings on hypoxia, Kondrashina et al. showed that casein-stimulated GLP-1 secretion significantly decreased under hypoxia (7.5% O2) in STC-1 cells [34]. In addition, hypoxia (1% O2) decreased forskolin-stimulated GLP-1 secretion from enteroendocrine GLUTag cells [32]. The author suggested that the decrease in GLP-1 secretion could be due to reduced GLP-1 synthesis [32]. 6-168 h of hypoxia (simulated altitude of 7620 m) in rats decreased plasma CCK and GLP-1 [15]. In contrast, it has been shown that 64 cycles of intermittent hypoxia for 5 min (1% O2) and 10 min normoxia (21% O2) increased mRNA expression of PYY and GLP-1 in STC-1 cells [45]. Chronic hypoxia (14.4—14.7% O2) for four weeks, lowered body weight, and improved glucose, and lipid metabolism in HFD-induced obese mice [54]. In humans, normobaric hypoxia (fraction of inspired oxygen: FiO2:0.12 ~ 5000 m) for 10 h reduced appetite and hunger compared to normobaric normoxia (FiO2:0.21), but gut peptides were unfortunately not measured [4]. 17 h hypoxic exposure (12.5% inspired O2, simulating approximately ~ 4100 m) in humans increased plasma leptin and only a small increase in postprandial GLP-1 levels after 40 min [47]. In humans, reduced energy intake, plasma acylated ghrelin concentrations, and PYY concentrations were reported at a simulated altitude of 4000 m [56]. Matu et al. reported lower appetite and post-exercise acetylated ghrelin area under the curve at an altitude of 4300 m, but no change in GLP-1 secretions [37]. A reason might be that no DPP4 was added for the measurement of GLP-1.

Several peptides including GLP-1 are secreted from the intestinal tract, which has a distinct oxygen gradient. A vertical oxygen gradient has been found in the more distal colonic parts of the gastrointestinal (GI) tract. The epithelial cells lining of intestinal mucosa reside in a relatively low pO2 environment [10]. The pO2 of the colonic muscle wall is 42–71 mmHg (7–10%), vascularized submucosa 42 mmHg (6%), crypt-lumen interface 5–10 mmHg, ascending colon 11 mmHg (2%) and sigmoid colon 3 mmHg (0.4%) [25]. During low-oxygen conditions, cells adapt to hypoxic stress by increasing the HIFs expression, which regulates metabolic processes and energy metabolism [43]. Hence in our study, we incubated STC-1 cells for 12 h (1% O2, 5% CO2) to induce and stabilize HIF-1α. HIF-1α protein expressions clearly state that hypoxia was maintained throughout the experiment (Fig. 3). We observed faint HIF-1α protein bands under normoxia, which has also been reported in other studies [18, 19, 49]. Acute infection and inflammation cause significant changes in tissue metabolism, resulting in severe tissue hypoxia [22]. A study on murine dendritic cells subjected to hypoxia (2% oxygen for 24 h) demonstrated an elevation in transcript levels of Toll-like receptors TLR2 and TLR6 [35]. In addition, hypoxic environment affects the intestinal microbiome. Following a high-fat diet (HFD) through meat consumption, both humans and animals showed a higher abundance of Firmicutes and a decrease in Bacteroidetes. Changes in the gut microbiota populations activate the Toll-like receptor (TLR) signaling pathway, resulting in increased intestinal permeability to endotoxins [12]. In mice colon, Bacteroidetes were reported about 3 times higher in abundance during hypoxia (simulated altitude of 5500 m for 24 h) [53]. In mice, the ratio of total aerobic to anaerobic bacteria changed from 1:2.79 to 1:7.34 under exposure to a high-altitude environment for 30 days and the total number of anaerobes increased about 105 times higher [1]. The Bacteroidetes abundance increased from days 1 to 14 in mice during environmental hypoxia with HIF-1ß deficiency in their bone marrow cells [23]. These disturbances in gut microbiota might cause a reduction in GLP-1 secretion. Colonocytes use butyrate produced by the bacteria as an energy substrate and maintain the anaerobic environment in the lumen [11]. In Caco-2 cells, butyrate increased O2 consumption and stabilized HIF-1α, leading to lower barrier permeability [31]. In human NCI-H716 cells, butyrate stimulated dose-dependently and biphasic GLP-1 secretion [57]. Yet, butyrate promotes epithelial barrier function by depleting oxygen levels near the epithelium and stabilizing HIF [3], stimulating mucin production [24]. The microbiome generates biofilms, which further contributes to the decreased oxygen gradient in the colon [5, 51]. Oxygen concentrations are high at the liquid surface and low in the deeper parts of the biofilm. In addition, the oxygen diffusion rate (about 60% of the rate observed in water) is lower in biofilms [33] which also contributes to the hypoxic environment in the colon.

Intestinal HIF affects GLP-1 secretion via the lipid sensor G-protein–coupled receptor enriched in L-cells. The enteroendocrine cells sense fatty acids (FAs) via GPR120 and GPR40 [52]. Thus, we investigated GPR120 and GPR40 protein expressions. We found that hypoxia (increased HIF-1α) decreased αLA stimulated GPR120 and GPR40 protein expression (Fig. 3). The decreased GLP-1 secretions could be due to receptor internalization. In addition, it has been shown that HIF-2α increased GPR40 in L-cells and potentiates fatty acid-induced GLP-1 secretion via extracellular signal-regulated kinase (ERK) [38]. In our study, under hypoxia, GPR120 and GPR40 were downregulated, which led to decreased GLP-1 secretion. Previously it has been shown that dual GPR120 and GPR40 agonist (DFL23916) delays receptor internalization and induce GLP-1 secretion in vitro and in vivo [6]. Internalization of receptors under hypoxia has been described in the brain before. Hypoxia-induced desensitization and internalization of adenosine A1 receptors in the rat hippocampus and internalization of Kappa (κ) opioid receptors [9].

Conclusions

Hypoxia did not affect the basal GLP-1 secretion but decreased nutrient-stimulated GLP-1 secretion in enteroendocrine cells. In addition, hypoxia decreased the expression of long-chain fatty acid receptors GPR120 and GPR40. The decrease in nutrient-stimulated GLP-1 secretion could be due to downregulations of GPR120 and GPR40 receptors. Changes in the gut environment and inflammation might contribute to the hypoxia of the epithelial and L-cells.

Authors contribution

RKS: Investigation, writing the first draft, GSR: Investigation, methodology, writing- review & editing, NS: Methodology, editing & review. JW: Conceptualization, funding acquisition, editing. KHH: Conceptualization, funding acquisition, writing- review & editing, supervision, project administration.

Funding

Open Access funding provided by University of Oulu (including Oulu University Hospital). This study received financial assistance from the Finnish National Agency for Education (EDUFI) (OPH-1647–2022).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Consent for publication

The authors have no competing interests for publication.

Competing interests

The authors declare no competing interests.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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