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Endocrinology Vol. 140, No. 9 4089-4094
Copyright © 1999 by The Endocrine Society

ARTICLES

Growth Hormone and Insulin-Like Growth Factors Have Different Effects on Sebaceous Cell Growth and Differentiation1

Dianne Deplewski and Robert L. Rosenfield

The University of Chicago, Pritzker School of Medicine, Departments of Medicine and Pediatrics, Chicago, Illinois 60637-1470

Address all correspondence and requests for reprints to: Dianne Deplewski, M.D., The University of Chicago, Pritzker School of Medicine, Departments of Medicine and Pediatrics, 5841 South Maryland Avenue (MC-5053), Chicago, Illinois 60637-1470. E-mail: ddeplews{at}peds.bsd.uchicago.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Several observations suggest that GH stimulates sebaceous gland growth and development. Therefore, we studied the effects of GH and insulin-like growth factors (IGFs), alone and with androgen, on sebaceous epithelial cell (sebocyte) growth and differentiation in vitro. The rat preputial cell culture model system was used to judge differentiation (induction of lipid-forming colonies, LFCs) and DNA synthesis. GH increased sebocyte differentiation. At a dose of 10-8 M in the presence of micromolar insulin, GH was 3.8 times more potent than IGF-I (38.1 ± 4.2%, SEM, vs. 10 ± 1.5% LFCs) and 6 times more potent than IGF-II (6 ± 0.5% LFCs). IGF-I 10-8 M alone stimulated a similar amount of differentiation as insulin 10-6 M, although it was less effective than insulin in augmenting the effect of GH on differentiation. GH had no effect on sebocyte uptake of 3H-thymidine at doses up to 10-6 M. On the other hand, IGF-I was the most potent stimulus of DNA synthesis (168% of control; P < 0.001 vs. all others). IGF-II 10-8 M stimulated 3H-thymidine incorporation similarly to insulin 10-6 M. In the presence of insulin, dihydrotestosterone (DHT) 10-6 M induced 31.4 ± 1.7% LFCs, and there was a tendency of DHT and GH to interact in promoting differentiation. When insulin was omitted from the system, differentiation was decreased overall, but GH ± DHT slightly improved differentiation. The IGFs had no effect on the response to DHT. DHT decreased DNA synthesis by 40%, an effect unaltered by GH or IGFs. These results suggest that GH and IGFs have different functions in sebaceous cell growth and differentiation: GH stimulated differentiation beyond that found with IGFs or insulin, yet had no effect on DNA synthesis, a parameter stimulated most potently by IGF-I. While GH augmented the effect of DHT on differentiation, the IGFs had no effect on the response of DHT. These data indicate that GH may in part act directly on sebocytes rather than indirectly through IGF production. These data are consistent with the concept that increases in GH and IGF production contribute in complementary ways to the increase in sebum production during puberty and in acromegaly.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE RAT PREPUTIAL GLAND is composed primarily of sebocytes, which are specialized epithelial cells that resemble human sebaceous cells in many ways (1, 2, 3). Both rat preputial glands and human sebaceous glands are androgen targets (4, 5, 6). Sebaceous gland development increases at puberty (7), and acne vulgaris is a disorder of the sebaceous gland that is dependent upon the pubertal rise in androgen levels (8). However, acne peaks in mid-adolescence and then normally wanes, whereas androgen levels remain high. This course corresponds less closely to plasma androgen levels than it does to GH and insulin-like growth factor (IGF)-I levels (9, 10, 11), suggesting an effect of GH and IGFs on sebaceous gland development. In addition, the GH excess of acromegaly is known to be associated with excess output of sebum, the fatty secretory product of sebocytes (12, 13).

Animal studies support the concept that GH is important for sebocyte growth and development. Ebling et al. demonstrated that preputial gland weight is markedly decreased in hypopituitary rats (6). Treatment of these rats with testosterone alone did not fully restore preputial growth unless GH was added. Ebling et al. also looked into sebum production from rat skin in normal and hypopituitary rats and found a similar dependency of the response to testosterone upon the addition of GH (14). Ozegovic et al. examined the effects of GH on female preputial glands and found that preputial gland growth could be stimulated by GH (15). These results are not necessarily indicative of a GH effect in view of the impurity of the pituitary GH available at the time.

GH has also been found to be important in various ways for fat cell differentiation, which bears certain similarities to sebaceous cell differentiation (16). Studies on clonal adipogenic cell lines have shown that GH stimulates fat cell differentiation (17, 18, 19), and IGF-I does not substitute for GH in promoting adipose conversion (20). However, studies on the effect of GH on both rat and human adipocytes in primary culture showed contrasting results (21, 22, 23, 24). These demonstrated a stimulatory effect of GH on the proliferation of adipocyte precursor cells, which appeared to be mediated by an increase in cellular IGF-I production, as the effect was abolished in the presence of antibodies against IGF-I. In contrast, adipocyte differentiation was decreased after treatment with GH, and addition of antibodies against IGF-I had no effect, which suggested a direct effect of GH.

Human GH is an important factor for organ growth and cell differentiation (25) and has both direct actions through binding to the GH receptor as well as indirect effects through IGF production (19, 26). The GH receptor has been found in the acini of both rat and human sebaceous glands by immunohistochemistry (27, 28, 29). This raises the possibility that GH may be a trophic factor acting directly on sebaceous epithelium. The IGFs make up a family of peptides that are partly GH dependent and mediate many of the mitogenic and anabolic actions of GH (19).

Insulin in high dose has also been found to be necessary for fat cell differentiation, where it likely serves as a key regulator of lipid biosynthetic enzymes (30, 31) and is one of many additives required for optimal growth of many epithelial cell types in culture (3, 32, 33). Insulin may act as an IGF-I surrogate as it has approximately 50% amino acid homology to the IGFs (34, 35, 36), and it binds to the IGF-I receptor at high concentrations (37).

Based on these considerations, we studied the role of GH, IGFs, and insulin on the growth and differentiation of sebocytes in vitro, as well as their possible interaction with androgen. The results show both distinct and interactive effects of these hormones.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Tissues and cells
Epithelial cell suspensions were prepared from the preputial glands of young adult male Sprague Dawley rats (Harlan, Indianapolis, IN), and cells were plated in culture dishes on a 3T3-J2 mitomycin-C treated feeder layer in DMEM with 10% FCS supplemented with choleratoxin (10-10 M), cortisol (10-6 M), and antibiotics (days 0–3) as previously reported (3). Treatments with recombinant human GH 10-10–10-6 M (Genentech, Inc.; San Francisco, CA), recombinant human IGF-I or IGF-II 10-9–10-8 M (Life Technologies, Inc., Gaithersburg, MD), insulin 10-12–10-6 M, or dihydrotestosterone (DHT) 10-6 M (Sigma Chemical Co.; St. Louis, MO) were performed in triplicate in a serum-free chemically defined cell culture medium (Cellgro Complete; Mediatech, VA) from days 3–9. At least four experiments were done for each treatment group.

Cell differentiation
Cells were fixed with calcium formalin and stained for lipid with Oil Red O in methanol as previously reported (38). Lipid accumulation in the epithelial cell colonies was quantified by light microscopy at 25–40x according to the number of stained cells per colony. Lipid forming colonies (LFCs) were defined as those colonies with greater than five cells positive for lipid droplets (39).

DNA synthesis
3H-thymidine incorporation into DNA was used as an index of cell proliferation. Cells were incubated with 3H-thymidine, 0.5 µCi/ml for 3 h in 95% air/5% CO2. The 3T3-J2 monolayer was removed with 4 C 0.02% EDTA. Sebocytes were washed successively with 4 C PBS/0.1% thymidine, and 0.2 N perchloric acid, and then stored in 1 N NaOH. After mixing with 60% perchloric acid, 3H-thymidine incorporation was counted by scintillation spectrometry.

Statistical analysis
Statistical significance was determined by one-way ANOVA followed by Scheffé’s posthoc test using Statview statistical software.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Insulin
Insulin enhanced preputial cell differentiation and proliferation (Figs. 1Go, 2Go, 3Go, and 4Go). The effect was dose-related (Fig. 1Go); a preliminary study (data not shown) demonstrated that insulin 10-7 M had an intermediate effect and a dose of 10-6 M was maximally effective. There was very little differentiation in the absence of insulin and a 4-fold greater effect at 10-6 M than 10-12 M (Fig. 1AGo, P < 0.05). Insulin was also important for DNA synthesis (Fig. 1BGo), with a concentration of 10-6 M being maximally effective (P < 0.001). Thus, 10-6 M insulin was used for all further experiments.



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  		Figure 1. Differentiation (A), and proliferation (B) of preputial sebocytes in primary culture after treatment with insulin (Ins) ± GH 10-8 M in serum-free medium from days 3–9 (n = 4). Means ± SEMs are shown. A, The effects of these treatments on lipid-forming colonies. ORO, Oil Red O. There was a dose-response effect of insulin in the absence and presence of GH, with 10-6 M being most potent. GH added to 10-6 M insulin caused significantly more differentiation than all other treatment groups (P < 0.001). B, The effect of these treatments on 3H-thymidine incorporation in comparison to the control group treated with 10-6 M insulin. There was very little DNA synthesis with the lower doses of insulin, compared with insulin at 10-6 M (P < 0.001). GH had no significant effect on DNA synthesis when added to insulin.

 


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  		Figure 2. Differentiation of preputial sebocytes in primary culture after treatment with GH ± DHT 10-6 M (n = 5). Means ± SEMs of lipid-forming colonies are shown. A, Responses in the presence of insulin 10-6 M. GH had a dose-response effect commencing at 10-10 M (P < 0.001 vs. control and higher doses of GH). DHT induced a significant amount of differentiation over control (P < 0.001). DHT augmented the effect of GH 10-10 M (P < 0.01), and the higher doses of GH (10-8 and 10-6 M) augmented the effect of DHT (P < 0.001). B, Responses in the absence of insulin. Insulin 10-6 M is shown for a comparison to the above graph. Inset depicts results of the treatments without insulin on a magnified scale. Although differentiation was less without insulin, in this set of experiments GH 10-8 M induced significantly more differentiation than control (P < 0.001), as did the combinations of DHT with the higher doses of GH (P < 0.001).

 


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  		Figure 3. 3H-thymidine incorporation in preputial sebocytes in primary culture after treatment with GH ± DHT 10-6 M (n = 5). Means ± SEMs are shown in comparison to the control group treated with 10-6 M insulin. A, Responses in the presence of insulin 10-6 M. GH had no significant effect on DNA synthesis at any doses tested. DHT caused a significant decrease in DNA synthesis (P < 0.001), an effect unaltered by the addition of GH. B, Responses in the absence of insulin. Insulin 10-6 M is shown for a comparison to the above graph. Inset depicts results of the treatments without insulin on a magnified scale. There was very little DNA synthesis overall in the absence of insulin (<10% of control with insulin; P < 0.001). DHT further suppressed proliferation in these studies (P < 0.001 vs. no DHT), an effect again unaltered by GH.

 


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  		Figure 4. Differentiation of preputial sebocytes in primary culture after treatment with GH, IGF-I, or IGF-II (n = 4). Means ± SEMs of lipid-forming colonies are shown. A, Effects in the presence of insulin 10-6 M. At 10-8 M, GH was 3.8 times more potent than IGF-I, and 6 times more potent than IGF-II (P < 0.001). IGFs (10-9–10-8 M) were no better than insulin 10-6 M alone (control group) in stimulating differentiation. B, Effects without insulin. Note the change in scale. Insulin at a concentration of 10-6 M is shown for a comparison to the above graph. Although GH was not as effective in the absence of insulin, there was still a response to GH 10-8 M. IGF-I and IGF-II induced similar amounts of differentiation with and without insulin (See 4A).

 
GH
GH increased cell differentiation in a dose-related fashion: GH 10-10, 10-8, 10-6 M caused 26 ± 1.8%, 38 ± 4.2%, and 39 ± 3.8% LFCs, respectively, in the presence of insulin (Fig. 2AGo). This GH effect was markedly attenuated in the absence of insulin: in two separate sets of experiments, GH 10-8 M induced an average of only 4.7 ± 1.1% LFCs vs. 1.8 ± 0.7% in control (P < 0.05 by paired t test) (Figs. 2BGo and 4BGo). Insulin at a concentration of 10-6 M was necessary to see the maximum GH response (Figs. 1AGo and 2Go). GH overall induced the greatest percent of highly differentiated colonies (those containing over 50 lipid-positive cells per colony) than any other treatment. For example, at a concentration of 10-8 M in the presence of insulin, GH induced 6.8 ± 1.9%, IGF-I induced 0.29 ± 0.1%, IGF-II induced 0%, and control 0.25 ± 0.1% highly differentiated colonies (Fig. 4AGo).

GH had no effect on DNA synthesis at any dose tested. It could not replace the effect of insulin on this parameter (Fig. 3Go, A and B).

IGF-I
IGF-I doses from 10-9–10-8 M stimulated the same amount of differentiation as insulin 10-6 M, and there was no additive effect when insulin and IGF-I were used together (Figs. 4Go and 5Go). IGF-I was less than one-third as potent as GH (both at 10-8 M) in the presence of insulin (10 ± 1.5% LFCs for IGF-I vs. 38.1 ± 4.2% LFCs for GH; P < 0.001) (Fig. 4Go). IGF-I was only able to partially take the place of insulin 10-6 M in enhancing the effect of GH 10-8 M (Fig. 5Go). IGF-I 10-9 M plus GH induced 24.2 ± 1.2% LFCs vs. 31.6 ± 1.3% with insulin plus GH (P < 0.001). A higher dose of IGF-I (10-8 M) was no more effective in this regard, and, indeed, yielded significantly less differentiation (P < 0.001).



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  		Figure 5. Effect of insulin 10-6 M (Ins) and IGF-I on the ability of GH 10-8 M to augment sebocyte differentiation (n = 4). Means ± SEMs of lipid-forming colonies are shown. Insulin at 10-6 M stimulated a similar amount of differentiation as both doses of IGF-I alone. Although IGF-I plus GH stimulated more differentiation than either compound alone (P < 0.05), it stimulated significantly less differentiation than the combination of insulin and GH (P < 0.05). The combination of IGF-I, insulin, and GH was also less effective than GH and insulin.

 
IGF-I was the most potent compound in terms of stimulating DNA synthesis (Fig. 6Go). IGF-I alone at 10-8 M induced the highest degree of DNA synthesis and stimulated 168 ± 25% as much DNA synthesis as insulin alone (P < 0.01; Fig. 6Go). However, the addition of insulin to this dose of IGF-I blunted the IGF-I effect to only 126 ± 18.5% of control (P < 0.05; Fig. 6AGo).



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  		Figure 6. 3H-thymidine incorporation in preputial sebocytes in primary culture after treatment with GH, IGF-I, or IGF-II (n = 4). Means ± SEMs are shown in comparison to the control group treated with 10-6 M insulin. A, Studies in the presence of insulin 10-6 M. GH had no effect on DNA synthesis. IGF-I increased DNA synthesis. IGF-II induced significantly less DNA synthesis than IGF-I at comparable doses (P < 0.05). B, The same treatments without insulin. IGF-I 10-8 M induced the greatest amount of DNA synthesis and significantly more DNA synthesis than the control (10-6 M insulin) (P < 0.001). IGF-II induced an intermediate degree of DNA synthesis at comparable doses (P < 0.05).

 
IGF-II
IGF-II in doses of 10-9, 5 x 10-9, and 10-8 M did not have a significant effect on differentiation with or without insulin (Fig. 4Go). At these doses, IGF-II had no effect on DNA synthesis in the presence of insulin. However, in the absence of insulin, IGF-II stimulated DNA synthesis in a dose-response manner; IGF-II 10-8 M was less potent than IGF-I and yielded an effect comparable to insulin 10-6 M (Fig. 6Go).

DHT
In the presence of insulin, DHT alone stimulated 31.4 ± 1.7% LFCs (P < 0.001 vs. control) (Fig. 2AGo). The addition of GH 10-10 M to DHT caused more LFCs than GH alone (26.1 ± 1.8% LFCs with GH alone, 36.9 ± 4.3% LFCs with GH plus DHT (P < 0.01), and GH >= 10-8 M plus DHT increased LFCs to 46 ± 4.2% (P < 0.001 vs. DHT alone). In the absence of insulin, differentiation was decreased overall, but the combination of DHT plus the higher doses of GH partially restored differentiation (P < 0.001) (Fig. 2BGo). In a separate set of experiments IGF-I could substitute for insulin in enhancing the DHT effect (17.9 ± 3.1% LFCs with DHT plus insulin, 22.5 ± 1.6% with DHT plus IGF-I 10-9 M, 11.2 ± 3.5% with insulin alone, 11.6 ± 2.5% with IGF-I alone, and 5.2 ± 1.3% with DHT alone). The addition of IGF-I to DHT in the presence of insulin caused no further increase in differentiation (n = 4; data not shown).

DHT, however, decreased DNA synthesis by about 40% (P < 0.001 vs. control), and this effect was unaltered by GH or IGF-I (10-9–10-8 M) (Fig. 3Go; IGF data not shown). When IGF-II at these doses was added to DHT, there was even less DNA synthesis (34.4 ± 2.1% of control with DHT plus IGF-II at 5 x 10-9 M vs. 60 ± 7.3% of control with DHT alone, P < 0.05) (n = 4; data not shown).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
These data indicate that GH and IGFs have distinct effects on sebaceous cell growth and differentiation. GH was approximately 3 times more potent than IGF-I and 6 times more potent than IGF-II in stimulating differentiation in the presence of insulin. GH also augmented the effect of DHT on differentiation in the presence of insulin beyond what IGF-I accomplished. In contrast, GH had no effect whatsoever on DNA synthesis, whereas IGF-I was the most potent stimulus for DNA synthesis. Because GH treatment in the presence of insulin or IGF-I caused more differentiation than treatment with insulin or IGFs alone and had no effect on DNA synthesis, it appears that GH may act directly on sebocytes, rather than through IGF production. The finding of GH receptors in sebaceous glands of the rat and human (27, 28, 29) supports the concept of a direct action of GH.

The interactions of insulin and IGF-I are complex in this system. Insulin is well known to promote the growth of epithelial cells in culture, and we here report that a pharmacologic dose of insulin (10-6 M) is necessary for optimal baseline growth and differentiation of sebocytes in serum-free media. Insulin is probably acting as an IGF-I surrogate in these regards since IGF-I in physiologic dosage (10-9 M) is at least as effective as insulin in promoting the baseline level of lipid droplet accumulation and is more effective than insulin in stimulating proliferation. The insulin and IGF-I receptor bear a close resemblance (40), and either compound can bind to either receptor, although with different affinities. The affinity of the IGF-I receptor for insulin is 100- to 1000-fold less than for IGF-I, whereas the affinity of the insulin receptor for IGF-I is 100-fold less than for insulin (37). Insulin likely serves as a mixed IGF-I agonist/antagonist, as insulin inhibits the effects of higher doses of IGF-I on proliferation through unknown mechanisms.

Although both insulin and IGF-I amplified the GH effect on sebocyte differentiation, insulin 10-6 M was significantly more effective than IGF-I 10-8 M. The maximal effect of GH required this pharmacologic dose of insulin. Similar doses of insulin are also necessary for maximal lipid synthesis in adipocyte cultures (24, 41, 42). The difference between the ability of insulin and IGF-I to augment the GH effect on differentiation is unclear but may be due to distinct capacities of these compounds to regulate GH receptor expression. Indeed, GH receptor expression has been found to be correlated with cell differentiation in various model systems, including differentiated cells lines such as 3T3-F442A adipocytes (19) and a model of hepatic carcinogenesis (43). Insulin may up-regulate sebocyte GH receptor expression, as it seems to do in the livers of diabetic rats (44), and IGF-I may down-regulate sebocyte GH receptor expression, as it does in rat osteoblasts (45, 46). Another possibility is that sebocytes produce sufficient IGF binding proteins to limit the effectiveness of IGF-I but not insulin. Alternatively, insulin may be more effective than IGF-I by acting on postreceptor processes as a key regulator of lipid biosynthetic enzymes (30, 31).

The IGFs have been found to exert a mitogenic effect in many cells (37). Thus, it was not surprising to find that IGF-I was a very potent stimulator of sebocyte proliferation. IGF-I has been localized to the peripheral cells of the sebaceous gland in normal rat skin by immunohistochemistry (47). This location of IGF-I corresponds with the position of the basal, highly mitotic cells of the gland that give rise to the more differentiated cells in the center of the glands.

IGF-II partially blocked the effects of insulin on both differentiation and DNA synthesis, suggesting that it is competing with insulin for binding to the insulin and IGF-I receptors. The actions of IGF-II are thought to be mediated through the IGF-I receptor, rather than the IGF-II receptor (37). The IGF-I receptor has a 2- to 15-fold lower affinity for IGF-II compared with IGF-I (48, 49). IGF-II can also bind to the insulin receptor, although at a much lower affinity than insulin or IGF-I.

In summary, GH appeared to directly stimulate differentiation, but not DNA synthesis. On the other hand, IGF-I was the most potent factor in promoting DNA synthesis. Insulin in high dosage was an important factor in sebocyte growth and differentiation, and dose-response considerations suggested that its effect of potentiating the GH induction of differentiation exceeded that expected from its action as an IGF-I surrogate. In the presence of insulin, GH seemed to augment the DHT effect on differentiation more than IGF-I. The exact mechanism by which GH affects sebocyte differentiation is not completely understood, and much remains to be clarified in the chain of events following GH stimulation.


   Acknowledgments
 
We are indebted to Nancy Ciletti for her excellent assistance and support.


   Footnotes
 
1 This research was supported in part by USPHS Grants HD-06308 (to R.L.R.) and grants from the Children’s Research Foundation and Eli Lilly & Co. (to D.D.). Preliminary reports were presented at the 79th Annual Meeting of The Endocrine Society, Minneapolis, Minnesota, 1997; and the 80th Annual Meeting of the Endocrine Society, New Orleans, Louisiana, 1998. Back

Received October 26, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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