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Endocrinology Vol. 140, No. 9 4065-4069
Copyright © 1999 by The Endocrine Society

ARTICLES

Stimulatory Actions of Insulin-Like Growth Factor-I and Transforming Growth Factor-{alpha} on Intestinal Neurotensin and Peptide YY1

Heung-Man Lee, Vidyavathi Udupi, Ella W. Englander, Srinivasan Rajaraman, Robert J. Coffey, Jr. and George H. Greeley, Jr.

Department of Surgery (H.-M.L., V.U., E.W.E.) and Department of Pathology (S.R.), The University of Texas Medical Branch, Galveston, Texas 77555; The Shriners Hospitals for Children (H.-M.L., E.W.E., G.H.G.), Galveston, Texas 77550; and Departments of Medicine and Cell Biology (R.J.C.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232

Address all correspondence and requests for reprints to: George H. Greeley, Jr., Ph.D., Department of Surgery, The University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555-0725. E-mail: ggreeley{at}utmb.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Proliferation of the gastrointestinal mucosa is stimulated by the growth factors, insulin-like growth factor-I (IGF-I) and transforming growth factor-{alpha} (TGF-{alpha}), or the closely related epidermal growth factor (EGF), as well as the gastrointestinal hormones, gastrin, neurotensin (NT), and peptide YY (PYY). The stimulatory actions of these growth factors or gastrointestinal hormones on the gastrointestinal mucosa may be direct or mediated in part by gastrointestinal peptides or the growth factors, respectively. The purpose of these studies therefore was to examine the effects of IGF-I and TGF-{alpha} on stomach gastrin and intestinal NT and PYY gene expression [i.e. messenger RNA (mRNA), peptide levels] and secretion. Mice were given recombinant human IGF-I (3, 6 mg/kg BW/day x 14 days). Transgenic mice with the rat TGF-{alpha} gene linked to a metallothionein promoter were used as a model of chronic TGF-{alpha} excess. IGF-I and TGF-{alpha} did not affect gastrin gene expression. Steady-state intestinal NT and PYY mRNA and peptide levels were elevated in a dose-related manner by IGF. TGF-{alpha} also increased intestinal expression of NT and PYY peptide, but not mRNA levels. Basal serum levels of PYY were elevated by IGF-I and TGF-{alpha}. IGF-I and TGF-{alpha} did not increase intestinal chromogranin A (CGA) gene expression, a marker of endocrine cells, or the density of PYY-containing cells in the colon, indicating that the elevations in intestinal gut peptide gene expression by IGF-I and TGF-{alpha} are not due simply to an increased number of enteroendocrine cells. IV infusion of EGF also stimulated release of PYY in the dog. Together, these findings indicate that IGF-I and TGF-{alpha} may cause secretion of gut hormones and exert a major upregulatory influence on the regulation of intestinal peptide hormone homeostasis.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
PROLIFERATION of the gastrointestinal mucosa is stimulated by the growth factors, insulin-like growth factor-I (IGF-I) and transforming growth factor-{alpha} (TGF-{alpha}), or the closely related epidermal growth factor (EGF), as well as the gastrointestinal peptide hormones, gastrin, neurotensin (NT), and peptide YY (PYY) (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12). It is possible that these growth factors or gastrointestinal hormones either act directly or that the gastrointestinal hormones mediate the effects of the growth factors, in part, or that the growth factors mediate the stimulatory effects of the gastrointestinal hormones.

We have reported that expression of gastrin, NT, and PYY in the gastrointestinal tract is elevated in GH transgenic mice (13). Gastrointestinal growth is also increased in GH transgenic mice (1, 13). Because GH activates IGF-I expression (14), the stimulatory effects of GH on gut growth and gastrointestinal hormone gene expression may be mediated in part by IGF-I. To examine this idea further, we tested whether IGF-I can influence gastrointestinal gene expression [i.e. messenger RNA (mRNA), peptide levels] and secretion of gastrin, NT, and PYY.

The stimulatory action of TGF-{alpha}/EGF on gastrointestinal proliferation may also be mediated in part by NT, PYY, and gastrin. If this notion is correct, the initial step in TGF-{alpha}/EGF action may be a stimulation of gastrin, NT, or PYY secretion. Additionally, gastrointestinal mRNA and peptide levels of gastrin, NT and PYY may be up-regulated.

The purpose of these studies, therefore, was to investigate the effects of IGF-I and TGF-{alpha} on gene expression of gut hormones expressed primarily in three distinct regions of the gastrointestinal tract. In this report, we show that IGF-I treatment can increase intestinal NT and PYY mRNA and peptide levels. Overexpression of TGF-{alpha} also increases intestinal expression of NT and PYY peptides but not mRNA levels. Both IGF-I and TGF-{alpha} can increase basal serum levels of PYY. Gastrin gene expression is not affected by IGF-I or TGF-{alpha}.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Exp 1
Recombinant human IGF-I (rhIGF-I) (3, 6 mg/kg BW/day) was given by Alzet mini-osmotic pumps (Alza Corp., Palo Alto, CA) for 14 days. rhIGF-I was a gift of Genentech, Inc. (South San Francisco, CA) or Chiron Corp. (Emeryville, CA). Alzet mini-osmotic pumps were implanted sc in the nape of the neck. Mice (9–10 mice/group) were killed in the ad libitum fed condition. The antra, ilea, and colons were collected for analyses of gastrin, NT, and PYY mRNA and peptide levels. Ileal and colonic chromogranin A (CGA) mRNA levels were also measured.

Exp 2
Metallothionein (MT). TGF-{alpha} transgenic mice were obtained from Robert J. Coffey Jr. (Vanderbilt University, Nashville, TN). The transgene contains the entire open reading frame of the rat TGF-{alpha} precursor driven by the heavy metal-inducible MT promoter (15). Mice at approximately 3 months of age were given 25 mmol/liter ZnSO4 in drinking water ad libitum for 4 weeks before they were killed. TGF-{alpha} and wild-type (WT) mice (n = 6 mice/group) were killed in the ad libitum fed condition, and gastrointestinal tissues were collected for analyses of gastrin, NT, PYY, and CGA mRNA and peptide levels. The colons of WT and TGF-{alpha} transgenic mice were examined by immunohistochemistry for the density of PYY cells.

Exp 3
Conscious mongrel dogs (n = 5) fasted for 18–20 h, with free acces to water, were given recombinant human EGF (200 pmol/kg/h) IV for 1 h. Blood was collected before and at various intervals (15, 30, 60, 90 min) after start of EGF for determination of plasma PYY and pancreatic polypeptide (PP) levels. All animal studies were approved by the University Institutional Animal Care and Use Committee.

Measurement of gastrin, PYY, neurotensin, pancreatic polypeptide, and CGA
Serum and antral gastrin levels were measured using a specific double-antibody RIA procedure described in detail previously (16). The sensitivity and 50% inhibition (ID50) of bound 125I-labeled gastrin are 6 ± 1 and 30 ± 5 pg/tube, respectively. The gastrin antiserum does not recognize cholecystokinin (CCK).

A double-antibody RIA procedure was used to measure plasma, serum, and tissue levels of PYY (10, 17). The PYY antiserum was generated in rabbits against synthetic porcine PYY. This antiserum does not cross-react with neuropeptide Y or pancreatic polypeptide (ID50 is >10 ng/tube). The sensitivity and ID50 were 5 ± 1 and 25 ± 3 pg/tube, respectively. Intra and interassay coefficients of variance were <10%.

Intestinal NT and CGA levels were measured using RIA procedures described previously (18, 19). The CGA antiserum was produced in rabbits against synthetic rat CGA-(359 190 389) and recognizes human and rodent CGA. The plasma pancreatic polypeptide (PP) assay has been described earlier (20).

Immunoreactive PYY, NT, and CGA were extracted from the mouse intestine by homogenization of tissues in a 10-fold excess of 2 M acetic acid, followed by boiling for 20 min. Antral gastrin was extracted by homogenization of the antrum in a 10-fold excess of water, followed by boiling for 20 min. Supernatants were clarified by centrifugation, lyophilized, and resuspended in appropriate assay buffers. All extracts were assayed at several dilutions in a single assay. Efficiency for extraction of gastrointestinal peptides by these procedures is >75%.

Northern analysis of gastrin, PYY, NT, and CGA
Total cellular RNA was prepared by homogenization of tissue specimens immediately after dissection in 4 M guanidine thiocyanate [including 25 mM sodium citrate (pH 7.0), 0.5% sodium N-lauroylsarcosine, and 0.1 M 2-mercaptoethanol] followed by centrifugation (18 h, 30,000 rpm) through a CsCl cushion (2 ml, 5.7 M) as described previously (10, 13). RNA concentrations in the samples were quantitated by absorbance at 260 nm. Gastrin (21), NT (22), PYY (23), and CGA (24) mRNA levels were examined using the appropriate cDNA/cRNA probes with either Northern or slot blotting analyses. All slot-blot analyses were accompanied by representative Northern blots for confirmation of mRNA transcript sizes and to scrutinize for nonspecific background hybridization. All blots were examined for homogeneity of RNA loading by monitoring 18S ribosomal mRNA expression (25).

Immunohistology of PYY in the intestine
Formalin-fixed paraffin-embedded tissue samples were used as described previously (13). The peroxidase-antiperoxidase (PAP) complex method for staining of paraffin sections was used. Briefly, the sections were deparaffinized, hydrated, and sequentially incubated with the primary rabbit antibody (antiporcine PYY serum) unlabeled or biotin-conjugated second antibodies directed against rabbit immunoglobulin, followed by the PAP complex, with frequent washes between incubations. The reaction product was visualized after incubation with diaminobenzidine and H2O2. For analysis of PYY containing cells, 1-cm segments of the colon (n = 3 WT and 3 TGF-{alpha} transgenic mice) were sectioned serially at 10 different levels for examination by light microscopy and immunohistology.

Statistical analysis
Results are means ± SE. Data were analyzed by either Student’s t test or a one-way classification ANOVA, followed by the Newman-Keuls test where pertinent. Differences with a P < 0.05 were considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Exp 1
IGF-I, at 3 or 6 mg/kg BW/day, did not affect antral gastrin gene expression (i.e. mRNA, peptide levels) (data not shown). In contrast, IGF-I treatment increased steady-state levels of intestinal neurotensin (NT) and PYY mRNA and peptide levels in a dose-related manner (Tables 1Go and 2Go; Figs. 1Go, 2Go, and 3Go). IGF-I, at 3 mg/kg BW/day, did not affect ileal NT mRNA levels, whereas at 6 mg/kg BW/day, ileal NT mRNA levels were increased 3-fold (~300% of control ileal NT mRNA levels) (Fig. 1Go). At 3 and 6 mg/kg BW/day, ileal NT peptide levels were increased 1.6- and 3-fold, respectively (~160 and 300% of control ileal NT peptide levels, respectively).


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  		Table 1. Stimulatory effects of IGF-I (3 mg/kg BW/day) on intestinal NT and PYY gene expression

 

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  		Table 2. Stimulatory effect of IGF-I (6 mg/kg BW/day) on intestinal NT and PYY expression

 


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  		Figure 1. Northern blotting analysis of ileal neurotensin (NT) mRNA levels in IGF-I (6 mg/kg BW/day) treated mice. mRNA was visualized by autoradiography. Representative lanes of three mice for each group are shown (n = 9–10 mice/group). Each lane contains 30 µg total RNA. In this and subsequent figures, the membranes were hybridized with either the rat NT or the rat PYY probe and the rat 18S ribosomal probe to monitor RNA loading.

 


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  		Figure 2. Northern blotting analysis of ileal PYY mRNA levels in IGF-I (3 mg/kg BW/day) treated mice.

 


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  		Figure 3. Slot blot analysis of ileal (top) and colonic (bottom) PYY mRNA levels in IGF-I (6 mg/kg BW/day) treated mice. Representative slots for three mice are shown (n = 9–10 mice/group). Each slot contains 2.5 µg total RNA.

 
IGF-I, at 3 and 6 mg/kg BW·day, increased ileal PYY mRNA levels in the ileum approximately 1.6- and 4.3-fold, respectively (~160 and 430% of control ileal PYY peptide levels, respectively) (Figs. 2Go and 3Go). Colonic PYY mRNA levels were unchanged by IGF-I treatment at 3 mg/kg BW/day, whereas at 6 mg/kg BW/day, colonic PYY mRNA levels were increased approximately 2-fold (~213% of control colonic PYY mRNA levels) (Fig. 3Go). Intestinal CGA mRNA levels were unchanged by IGF-I treatment (data not shown).

Exp 2
Gastrin mRNA and peptide levels were unaffected in TGF-{alpha} transgenic mice (data not shown). Ileal neurotensin and PYY peptide levels were elevated significantly in TGF-{alpha} transgenic mice when compared with WT-control mice (Table 3Go). Ileal neurotensin (data not shown) and PYY mRNA levels (Fig. 4Go) were not changed in TGF-{alpha} transgenic mice. Serum levels of PYY increased significantly in TGF-{alpha} mice (control mice: 183 ± 15 vs. TGF-{alpha} transgenic: 454 ± 20 pg/ml). Ileal CGA mRNA levels were decreased significantly, whereas ileal CGA protein levels were unchanged in TGF-{alpha} transgenic mice when compared with WT-control mice (Table 3Go). The density of intestinal PYY cells in TGF-{alpha} transgenic and control-wild-type (n = 3/group) mice did not differ significantly (WT: 31 ± 5 vs. TGF-{alpha} transgenic: 30 ± 5 PYY cells/100 glands; P > 0.05).


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  		Table 3. Effects of TGF-{alpha} overexpression on intestinal neurotensin peptide, PYY peptide, and Chromogranin A (CGA) mRNA levels

 


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  		Figure 4. Northern blotting analysis of colonic PYY mRNA levels in TGF-{alpha} transgenic mice. Representative lanes of three mice for each group are shown (n = 6 mice/group).

 
Exp 3
IV administration of EGF in conscious dogs resulted in a significant elevation (P < 0.05) of plasma PYY levels (Fig. 5Go). Plasma PP levels were not affected (data not shown).



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  		Figure 5. Stimulatory effect of exogenous EGF on peptide YY (PYY) release in fasted conscious dogs (n = 5).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present findings demonstrate that the growth factors, IGF-I and TGF-{alpha}/EGF exert potent stimulatory actions on intestinal peptide hormone gene expression and secretion. More specifically, IGF-I may regulate NT and PYY by transcriptional and translational mechanisms since IGF-I can increase expression of intestinal NT and PYY mRNA and peptide levels whereas TGF-{alpha} appears to influence NT and PYY by translational mechanisms. It is also possible that increases in steady-state mRNA levels may simply reflect increased mRNA stability and that increases in tissue levels of gastrointestinal peptides with IGF-I or TGF-{alpha} treatment reflect decreased secretion or decreased tissue degradation. However, because secretion of PYY is elevated in IGF-I-treated and in TGF-{alpha} transgenic mice and there is no evidence to date showing that these growth factors influence peptide proteolysis, increased translation seems more likely. In the present experiments, overexpression of TGF-{alpha} stimulates elevations of intestinal NT and PYY peptide levels only. We also have preliminary in vitro data to indicate that IGF-I can activate the PYY promoter because IGF-I treatment of mouse fibroblast 3T3 cells transiently transfected with the PYY promoter (-770 bp, 5' upstream region) fused to a luciferase reporter showed activation of the promoter. Interestingly, gene expression of a stomach peptide hormone, gastrin, is unaffected by IGF-I and TGF-{alpha}. This finding argues for a specificity of action of TGF-{alpha} and IGF-I on intestinal peptide expression. Previously, we reported that constitutive overexpression of GH increased gastrointestinal expression of gastrin, NT, and PYY (13). Because IGF-I treatment did not increase gastrin gene expression, the stimulatory action of GH on the gastrin gene appears direct and not mediated by IGF-I, whereas the stimulatory effects of GH on intestinal NT and PYY gene expression may be mediated in part by IGF-I.

It is well documented in several species that IGF-I, EGF, and TGF-{alpha} are potent mitogens for the gastrointestinal tract (1, 2, 3, 4, 5, 6, 7, 8, 9). Both acute and prolonged, systemic administration of IGF-I to adult and developing rats increases growth of the gastrointestinal tract. Enteric administered IGF-I is also effective. For example, overexpression of des (1, 2, 3) human IGF-I in mammary glands of dams increases gastrointestinal growth in nursing rat pups (26) and oral administration of IGF-I to calves and piglets stimulates gut epithelial proliferation (2, 27). Although increased gastrointestinal mucosal growth is evident in GH transgenic mice, this increase may be due to increased liver-derived IGF-I. Other studies have shown that GH does not stimulate mucosal growth (28). EGF and IGF-I receptors are found throughout the GI tract (29, 30, 31, 32). The findings that IGF-I and TGF-{alpha} can increase intestinal expression of NT and PYY suggest that intestinal peptide hormones mediate, in part, the stimulatory actions of IGF-I and EGF/TGF-{alpha} on gut epithelial proliferation. Physiologically, enteral nutrition is known to play an important role in the maintenance of mucosal proliferation (33, 34), intestinal IGF-I gene expression (35, 36), and in regulation of gastrointestinal hormone gene expression (37, 38, 39). Hence, nutrient-induced stimulation of intestinal IGF-I expression may serve to maintain intestinal peptide expression and ultimately intestinal mucosal integrity.

In the present study, we found that circulating levels of PYY are elevated in TGF-{alpha} transgenic mice and that acute administration of EGF in dogs stimulated PYY secretion. Although our findings in dogs confirm an earlier study that showed that EGF can stimulate PYY release in rats (40), it is important to show that the stimulatory effects of EGF/TGF-{alpha} on PYY secretion are not limited to a single species. It is noteworthy too that both EGF and PYY are potent enterogastrones (41, 42, 43, 44, 45); the stimulatory action of EGF on PYY secretion suggests that the inhibitory action of EGF on gastric acid secretion is exerted partly by PYY. Whether ingestion of nutrients causes acute release of TGF-{alpha} or EGF into the intestinal lumen or systemic circulation, which then stimulates PYY release from the distal intestine, is not known. The notion that TGF-{alpha} or EGF can stimulate release of PYY is not overly speculative because our laboratory has shown earlier that secretion of PYY from the distal intestine is regulated by endocrine factors or neural pathways originating in the upper gut (46). The present findings suggest that EGF participates in stimulation of PYY release by the proximal gut.

In TGF-{alpha} transgenic mice, the increased intestinal levels of PYY peptide are not merely due to an increased number of intestinal PYY cells because examination of colonic sections immunostained for PYY containing cells showed no differences in the density of intestinal PYY cells. Furthermore, we can probably assume that IGF-I treatment did not increase intestinal PYY cell density based upon earlier findings showing that GH excess did not increase intestinal PYY cell numbers in spite of elevated IGF-I expression (1, 13). Furthermore, IGF-I (like GH) and TGF-{alpha} did not increase intestinal CGA expression, a marker for enteroendocrine cells (19, 47), indicating that enteroendocrine cell number [i.e. ileal neurotensin ("N" cells), ileal/colonic PYY ("L" cells)] is not increased by either of these growth factors.


   Footnotes
 
1 This work was supported by grants from the National Institutes of Health (RO1-DK-15241) and the National Science Foundation (IBN 9219978). Back

Received January 11, 1999.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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G. Wang, A. B. Leiter, E. W. Englander, and G. H. Greeley Jr.
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R. Varghese, A. D. Gagliardi, P. E. Bialek, S.-P. Yee, G. F. Wagner, and G. E. Dimattia
Overexpression of Human Stanniocalcin Affects Growth and Reproduction in Transgenic Mice
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