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Mice Deficient in Liver Production of Insulin-Like Growth Factor I Display Sexual Dimorphism in Growth Hormone-Stimulated Postnatal Growth

Clinical Endocrinology Branch, NIDDK, National Institutes of Health, 10/8D12, 10 Center Drive, Bethesda, Maryland 20892-1758

Address all correspondence and requests for reprints to: Derek LeRoith, M.D., Ph.D., CEB/NIDDK, Building 10, Room 8D12, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892-1758. E-mail: Derek{at}helix.nih.gov

	Abstract

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Insulin-like growth factor I (IGF-I) is essential for normal intrauterine and postnatal growth and development. Using the Cre/loxP-induced conditional knockout system, we have established a liver-specific IGF-I-deficient (LID) mouse model. Circulating IGF-I levels were decreased by approximately75% without any apparent effect on their growth and development. To determine the role of extra-hepatic IGF-I in GH-induced postnatal growth, we tested the effects of GH on growth rates in these mice. Female, but not male, LID mice displayed significantly accelerated growth rates in response to daily injections of GH for 5 weeks. The GH-induced peripubertal growth in female LID mice was not affected by ovariectomy, nor did castration change the growth pattern in male LID mice. Thus, factors other than gonadal steroids mediate this sexual dimorphism. We postulate that the sexual dimorphic response to GH observed in LID mice may be related to genetically programmed differences in GH secretion patterns.

	Introduction

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GH AND insulin-like growth factor I (IGF-I) are essential for normal growth and development. These peptides induce growth by increasing cell size, cell number, and cellular differentiation. A deficiency in GH or the GH receptor causes severe postnatal growth retardation and proportionate dwarfism in humans and mice (1, 2). On the other hand, igf1 deficiency in humans and mice causes severe intrauterine and postnatal growth retardation and developmental defects in bone, muscle and reproductive systems and is perinatally lethal in the mouse (3, 4, 5, 6).

According to the ‘Somatomedin Hypothesis," proposed 3 decades ago, GH-mediated somatic growth is dependent on the endocrine form of IGF-I that is mainly produced and secreted by the liver (7). In agreement with this hypothesis, we demonstrated previously that igf1-null mice failed to respond to GH treatment and therefore IGF-I is essential for GH-stimulated postnatal growth (8). However, we have recently shown that liver IGF-I deficient (LID) mice, generated by a conditional Cre/loxP system, grow normally, suggesting that other mechanisms, besides the endocrine form of IGF-I, may be involved. Although 75% of circulating IGF-I is liver-derived, normal growth and development are possible even in the absence of liver IGF-I production (9, 10). Taken together, these data allowed us to hypothesize that GH mediates somatic growth via local IGF-I production, acting in a paracine/autocrine fashion. To further test this model, we treated LID mice with exogenous GH and studied postnatal growth (in response to long-term injections) and extra-hepatic IGF-I expression (following acute injections). In this study, we demonstrate that recombinant human GH (rhGH) stimulates local IGF-I production under conditions of liver IGF-I deficiency, particularly in adipose tissues. Interestingly, female LID mice respond to GH with respect to postnatal growth as determined by body weight and body length, whereas male mice are resistant to GH treatment. We also demonstrate that this sexually dimorphic response is not mediated by gonadal steroids.

	Materials and Methods

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Animal production
LID mice were generated using the Cre/loxP system as reported earlier (9, 11). For the purpose of this study, we used two groups of mice: control mice that contain exon 4 of the igf-1 gene flanked by two loxP sites (L/L) [referred to as L/L Cre- in our original paper (9) with virtually normal IGF-I expression, in both male and female mice] and LID mice [referred to as L/L Cre+]. Genotyping was performed by PCR and Southern blot analyses as reported previously (11). All animal experiments were approved by the Animal Care and Use Committee of the NIDDK, NIH (Bethesda, MD).

Growth response to GH
Mice were injected sc with rhGH (Genentech, Inc., South San Francisco, CA), 3 mg/kg twice daily, from postnatal age P15 to P49. Body weights were measured daily. At the end of the study (7 weeks of age), mice were anesthetized using 0.2% avertin, bled via the retro-orbital vein, body length (nose to anus) was measured, and organs of interest (brown fat, white fat, heart, skeletal muscle, liver, kidney, and spleen) were removed. Total RNA was extracted, using RNAzol B reagent (Tel-Test Inc., Friendswood, TX).

GH response in castrated mice
To study the role of gonadal steroids in the GH response, LID mice were castrated at 3 weeks. Mice were anesthetized using ketamine hydrochloride (Ketaset, 25 mg/kg, Fort Dodge Laboratories, Fort Dodge, IA). For ovariectomy, a small midline dorsal skin incision was made at the lower 1/3 point of the back. Entrance to the peritoneal cavity was gained through lateral muscle incisions on both sides of the body. The ovaries, surrounded by a variable amount of fat, were removed from the cavity by grasping the periovarian fat. With pointed scissors, the junction between the Fallopian tube and the uterine horn, together with all accompanying blood vessels and fat, were severed with a single cut and the uterine horn returned to the peritoneal cavity (12). To castrate male LID mice, an incision was made at the lower tip of the scrotum under anesthesia. The scrotal sacs containing the testes were ligated and excised. The animals were allowed to recover for a week before treatment with rhGH (or vehicle), which was performed from P28 to P59. Completeness of the castration procedure was verified by RIA of serum estradiol and testosterone at the end of the study.

Effect of acute GH treatment on extra hepatic IGF-I expression
To test the effect of GH on extra-hepatic IGF-I production, 4-week-old LID mice were treated with rhGH. Mice were injected sc with 3 mg/kg of either rhGH or vehicle, twice at 0 and 8 h, and killed at 12 h. Total RNA was isolated from brown fat, white fat, heart, muscle, kidney, and spleen. IGF-I expression was determined using RNase protection assays as described earlier (13), and serum IGF-I concentration was determined by RIA.

RNase protection assay
The expression of IGF-I and GH receptor genes in various tissues was studied using the RNase protection assay (13). ³²P-labeled riboprobes were made from mouse IGF-I exon 4 (11), GH receptor exon 4 (BamHI/AvaI fragment) (2), and pActin (Ambion, Inc., Austin, TX). Protected bands were quantified using PhosphorImager 400E and normalized to ß-actin messenger RNA (mRNA) or 18S-rRNA levels.

Hormone assays and statistics
The serum concentration of total IGF-I, estradiol and testosterone (Diagnostics Systems Laboratories, Inc.), and GH (Amersham Pharmacia Biotech, Arlington Heights, IL) were determined by RIA. Statistical significance was determined by the two-tailed t test using the program SigmaStat 2.03 (Access Softek, Inc., San Rafael, CA). Growth curves were plotted using the program SigmaPlot 5.0 (SPSS, Inc., Chicago, IL).

	Results

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1) GH stimulates postnatal growth only in female LID mice
To test the hypothesis that GH mediates somatic growth via extra-hepatic, local IGF-I production, we studied the effects of exogenous GH on postnatal growth in LID mice. Two week old male and female control (L/L Cre-) and LID (L/L Cre+) mice were treated with twice daily injections of either rhGH or vehicle. Their growth rates as determined by body weight were followed for 5 weeks (P15 to P49).

No differences in body weight in control and LID mice were observed during postnatal growth (Fig. 1, A and B). However, treatment with rhGH significantly stimulated the growth of female LID mice. This difference became significant around P28, and continued to increase until it reached 19% (P < 0.001) at P49 study (Fig. 1A). The GH-induced changes in body weight are summarized in Table 1. The body weight gains in LID female mice, in response to GH treatment, are significantly greater than that in untreated controls. The increase in body length in GH-treated female mice (8.6 ± 0.1 vs. 8.4 ± 0.1) did not reach statistical significance. Male LID mice, on the other hand, were completely unresponsive to GH throughout the study, with respect to both body weight and body length (Fig. 1B, Table 1 and data not shown). Previously, we have demonstrated that this strategy of GH treatment accelerated growth in both male and female wild-type mice; wild-type males showed a weight gain of 16.7 ± 1.6 g in GH-treated vs. 10.9 ± 0.5 g in untreated mice (P < 0.025), whereas female wild-type mice responded to GH with a 12.1 ± 1.4 g increase compared with 7.9± 0.6 g in untreated mice (P < 0.037) (8).

View larger version (15K): [in this window] [in a new window]   Figure 1. The effects of rhGH on postnatal growth in LID mice. Two-week old mice were treated with twice daily injections of either rhGH or vehicle for 5 weeks. Their body weight was measured daily and body length determined at P49. The animals were homozygous igf1/loxP (control) and LID; female (A) and male (B). Numbers of animals in each group are shown in parentheses.

View this table: [in this window] [in a new window]   Table 1. Comparison of the body weight gain (mean ± SE) from P15 to P49 in various groups of animals shown in Fig. 1

View larger version (18K): [in this window] [in a new window]   Figure 2. The effects of rhGH on postnatal growth in castrated LID mice. Mice were genotyped and castrated at 3 weeks of age and treated with twice daily injections of rhGH (or vehicle) from P28 to P59 as in Fig. 1. A, Growth curves of ovarectomized (OVX) female mice treated with rhGH. B, Growth curves of castrated male mice treated with rhGH. Numbers of animals in each group are shown in parentheses. Statistical significance is described in the text.

3) Gender variations in GH receptor expression
In an attempt to understand the gender variation that enabled female LID mice to respond to GH treatment, we compared the level of GH receptor mRNA in untreated LID mice (male and female). As shown in Fig. 3, female LID mice (7 weeks old) have slightly lower levels of GH receptor mRNA in the liver, and almost twice the amount of GH receptor mRNA in white fat compared with the male littermates. In younger mice (4 weeks old), no gender-related GH receptor expression was detected (data not shown).

View larger version (21K): [in this window] [in a new window]   Figure 3. GH receptor mRNA levels in various tissues from male and female LID mice. GH receptor mRNA levels were determined by RNase protection assay in 7-week-old mice (untreated with GH). The relative abundance of GH receptor mRNA is expressed relative to the ß-actin mRNA level. The numbers of animal are shown in parentheses (*P < 0.05, by t test).

4) Effect of GH on extra-hepatic IGF-I gene expression in LID mice
The effect of GH on extra-hepatic IGF-I gene expression 12-h after acute injections was studied in male and female LID mice. As shown in Fig. 4, acute administration of rhGH resulted in a significant increase in IGF-I expression in white and brown adipose tissues (1.5- to 1.9-fold). It is interesting to note that, when grouped by gender, female mice displayed a significantly greater response to GH than did their male littermates in adipose tissues (Table 3). IGF-I mRNA expression in LID male mice was increased 1.8-fold in brown fat but unchanged in white fat and other tissues, whereas in LID female mice we detected increases of 2.5-fold and 1.8-fold in IGF-I mRNA in brown and white adipose tissues, respectively (Table 3). Changes in other tissues, including the cardiac and skeletal muscles, kidney, spleen, and the very low levels of expression in the liver (0.5% of normal) were not significant. As reported previously (9), liver-specific IGF-I gene deletion caused a 75% reduction in serum IGF-I concentration. Although acute treatment of GH stimulated adipose tissue expression of the IGF-I gene, it did not cause a corresponding increase in IGF-I in the circulation measured 12 h after injection (Fig. 4). In addition, the 5-week GH treatment (Fig. 1) caused no significant change in either serum IGF-I concentration or IGF-I gene expression in the tissues examined (brown and white fat, heart, muscle, liver, kidney, and spleen) (data not shown). Therefore, whereas GH can stimulate extra-hepatic production of IGF-I, the liver seems to be the major GH-responsive tissue which secretes IGF-I into the circulation.

View larger version (15K): [in this window] [in a new window]   Figure 4. Effect of acute rhGH administration on (A) extra-hepatic expression of IGF-I gene and (B) serum IGF-I concentration in LID mice. Four-week-old mice were treated with rhGH (3 mg/kg, sc) at 0 and 8 h and killed at 12 h. IGF-I mRNA levels were determined by RNase protection assay and expressed as relative abundance compared with vehicle (control) LID mice. (**, P < 0.01 vs. control). In panel B, serum IGF-I concentrations in LID mice and LID mice treated with rhGH were compared with control mice that have intact liver IGF-I production (n = 9 to 11). (***, P < 0.001 vs. control.)

	Discussion

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There are a variety of possible underlying causes of the gender-specific GH secretory patterns. These may include hypothalamic endocrine imprinting, GH-releasing hormone (GHRH) and somatostatin secretion, pituitary differentiation, GH synthesis, GH clearance, somatotroph responsiveness, hypothalamic GH feedback, and levels of GH receptor expression. In addition, the antagonistic effects of estrogens toward GH action may be involved in these gender-specific differences. These possible etiological factors have been recently reviewed (24, 25, 26, 27). Extensive experimental evidence indicates that the episodic pattern of GH release from the pituitary gland is generated by the reciprocal interaction of two hypothalamic hormones, the stimulatory GHRH, found in the arcuate nucleus, and its inhibitory counterpart, somatostatin, principally derived from periventricular neurons (28). In male mice, somatostatin, which is released from the hypothalamus with a resultant periodicity of 3.3 h, affects both the somatotroph cells in the pituitary and the GHRH neurons in the hypothalamus. The secretion of GHRH is postulated to occur in an approximately 1-h rhythm and is modulated by the level of somatostatin in the hypothalamus. Furthermore, GH controls its own release through feedback stimulation on somatostatin neurons. In support of this model, sexually dimorphic expression of somatostatin receptor subtypes 1 and 2 (sst1 and sst2) has been found in the arcuate nucleus and in the anterior pituitary (29).

It is reasonable to assume that mice have similar dimorphism in GH secretory patterns. Moreover, the baseline concentration of GH was elevated 6-fold in the LID mice compared with control mice (9). Therefore, we propose that the body growth of male LID mice was already maximally stimulated by the high intrinsic GH secretion in those animals. Thus, we propose that female LID mice grew at a suboptimal rate, and their growth could be further stimulated by repeated injections of exogenous GH. The fact that castration caused no change in their response to GH indicates that the gender differences may have been imprinted early in the development of these animals, as reported by others (27, 30). It further suggests that sexual dimorphic responses to GH are not caused by the different gonadal steroid environments or the concurrent peri-pubertal changes in these female mice.

It has been demonstrated that males and females differed in their response to GH with respect to body growth. Men with GH deficiency were more sensitive to GH therapy than women, at least regarding the increase in IGF-I secretion and improvement in body composition. Moreover, to achieve the same level of growth, women need higher doses of GH (31, 32). We do not favor the possibility that a differential sensitivity to GH plays a significant role in this sexual dimorphism, based on the observation that GH treatments did not up-regulate expression of its cognate receptor. However, it is interesting to note that GH receptor levels in white fat were significantly higher in female than in male LID mice. Furthermore, the response to acute injections of GH was associated with a greater increase in IGF-I mRNA in fat tissues from female LID mice (Fig. 3 and Table 3). Finally, one has to be cautious about the GHR mRNA results because the probe used detects both GHR and GHBP mRNAs and, while mRNA levels usually correlate with receptor levels on the membrane and the receptor activity, this is not always the case.

Differential gonadal environment influences body growth by altering the level of GH receptor expression and therefore GH responsiveness (31). It was shown by some investigators that GH receptor expression in the liver is highly sexually dimorphic in the rat, with higher levels of GH receptor mRNA found in females than in males, and that estrogen treatment in males increases GH receptor expression (33, 34, 35, 36). There are contradicting reports on the differential effects of hypophysectomy on liver GH receptor expression in males and females, and on the effect of GH treatments on liver GH receptor expression (37, 38, 39, 40). Recently, in cultured hepatocytes prepared from virgin female mice, it was shown that GH could only stimulate expression of its own receptor in the presence of estradiol (41). Therefore, one would predict that female mice respond better to GH treatment because they have more GH receptors present in target tissues than do males and that this difference should be reversed by ovariectomy. In fact, in the LID mice, GH receptor expression was slightly reduced in the liver but higher in fat of female mice, compared with males. GH stimulated body growth in both intact mice and those having undergone ovariectomy, and there was no change in GH receptor expression in several tissues examined in female LID mice. Thus, we ruled out the possibility that GH induced up-regulation of its own receptors in these female mice.

In previous reports, we have demonstrated that liver-derived endocrine IGF-I is not required for normal growth and development (9, 10). The current study further suggests that endocrine IGF-I is not involved in GH-stimulated body growth. This hypothesis is based on the finding that exogenous GH, via acute or chronic treatments, failed to influence circulating IGF-I levels and that female mice exhibited growth stimulation in the absence of liver-derived IGF-I. Therefore, the involvement of IGF-I may be via a paracrine/autocrine mechanism, although the exact targets have not yet been identified.

In summary, using the Cre/loxP-induced LID mouse model, we demonstrate that GH can stimulate body growth in the absence of liver-derived IGF-I. This effect is seen only in female and not in male animals and does not require intact ovaries. The effect is not due to up-regulation of GH receptor expression. Moreover, we have shown that, acutely, GH stimulates local production of IGF-I, and the liver seems to be the only producer of endocrine IGF-I that responds to GH stimulation. Our results provide further support to the notion that exogenous GH accelerates somatic growth through stimulation of local production of IGF-I, as well as by other mechanisms, which remain to be identified.

	Acknowledgments

 
The authors thank Dr. Michael Allar (Pennsylvania State University at Hershey, PA) for instructions on the ovariectomy procedure, Dr. J. O. Jansson (Göteborg University, Sweden) for helpful communications, Dr. John J. Kopchick (Ohio University, Athens, OH) for providing the GH receptor probe and Dr. Peter Rotwein (Oregon Health Sciences University, Portland, OR) for the mouse IGF-I probe.

	Footnotes

 
¹ Current address: Fraser Labs, M3–15, Royal Victoria Hospital and McGill University, 687 Pine Avenue West, Montréal, Québec QC H3A 1A1, Canada.

Received June 21, 2000.

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