Influence of metabolic substrates and obesity on growth hormone secretion

ELSEVIER

Influence of Metabolic Substrates and Obesity on Growth Hormone Secretion Carlos Dieguez and Felipe F. Casanueva

In addition to stimulating body growth, GH plays an important role in metabolism. In turn, various products of intermediary metabolism, such as glucose, free fatty acids, dietary proteins, and amino acids feed back on both the hypothalamus and the anterior pituitary to control the function of the somatotroph cell. Alterations in nutritional status, such as malnutrition and obesity, markedly influence GH secretion and/or GH actions at tissue level. Therefore, the interaction between metabolic substrates and GH secretion can be viewed as part of the overall regulation of feeding and fasting in order to maintain an adequate body weight and body composition. (Trends Endocrinol Metab 1995;6:55-59)

Unlike

other

pituitary

hormones,

GH

exerts its biologic actions not just on one target organ, but on almost every cell of the organism. surprising role

Therefore,

in the control

cesses.

In

turn,

and some

acids

Therefore,

influence

GH

the interaction

be-

substrates

can be viewed

overall regulation

and GH se-

as part

of the

of feeding and fasting

in order to maintain

an adequate

weight and body composition. of this

review

current

knowledge

by which

pro-

substrates

free fatty acids (FFA),

amino

tween metabolic cretion

of metabolic

metabolic

such as glucose, release.

it is not at all

that GH plays an important

is to

body

The aim

summarize

the

of the mechanisms

metabolic

substrates

such as

glucose and FFA influence

GH secretion.

Furthermore,

the effect

of

in order

to

obesity

we review

on GH

secretion

highlight its importance

in the control of

Carlos Dieguez and Felipe F. Casanueva are at the Departments of Medicine and Physiology, School of Medicine, University of Santiago, Santiago de Compostela 15700, Spain.

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GH secretion. As extensive reviews of the effect of diabetes, fasting, and malnutrition have been published recently (Maes et al. 1991, Giustina and Wehrenberg 1994), these topics are outside the scope of this review.

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Glucose and GH Secretion

It is well known that GH antagonizes insulin action on peripheral tissues. Thus, chronically elevated GH levels cause glucose intolerance, which may lead in some patients to frank diabetes mellitus (Dieguez et al. 1988, Giustina and Wehrenberg 1994). In turn, changes in plasma glucose levels have important effects on GH secretion. In fact, one of the first observations after the development of GH RIAs was the interaction of blood glucose levels and GH release. Acute hyperglycemia inhibits GH secretion, whereas hypoglycemia is one of the most powerful GH stimuli in normal subjects (Roth et al. 1963). These two opposite effects of glucose on GH secretion were, for many years, the basis for clinical testing in patients suspected of having a GH-secreting adenoma or of having defi-

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cient GH secretion. Important interspeties differences exist in the regulation of GH secretion by glucose. Thus, glucose plays an important regulatory role in primates, either monkey or human, whereas others, such as mouse, rat, or rabbit, are largely unresponsive to changes in plasma glucose levels (Dieguez et al. 1988). Therefore, in this review we summarize the present knowledge of the regulation of GH secretion by glucose based on data obtained in primates. Effect of Hypoglycemia

on GH Secretion

The stimulatory effect of hypoglycemia on GH secretion is exerted at the hypothalamic level. Studies carried out in monkeys have shown the existence of glucose-sensitive areas in the hypothalamus. Furthermore, intracellular glycopenia, elicited by administration of 2deoxyglucose, in neurons of the ventrolateral hypothalamus, is followed by a rise in plasma GH levels similar to that provoked by hypoglycemia (Himsworth et al. 1972). Studies carried out on normal human subjects have shown that the GH response to insulin-induced hypoglycemia is due to changes in blood glucose rather than hyperinsulinemia, because the effect can be abolished by concomitant administration of glucose (West and Sonksen 1977). Furthermore, this effect is exerted inside the bloodbrain barrier, because fructose, which does not cross this barrier, fails to counteract the effect of hypoglycemia (Vigas et al. 1990). Data gathered over the last few years indicate that hypoglycemia-induced GH secretion is not mediated via an increase in hypothalamic GHRH release, and the evidence is as follows. When GHRH and insulin were administered together, the peak GH and the total of GH secreted were higher than when they were administered separately (Page et al. 1987, Kelijman and Frohman 1988a). After prior GHRH administration, the subsequent GH responses to GHRH were abolished, whereas GH responses to hypoglycemia were enhanced (Vance et al. 1986, Shibasaki et al. 1985). Based on these findings, most authors hypothe-

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sized that GH responses to hypoglycemia are mediated through a decrease in hypothalamic somatostatin release. Direct evidence supporting this hypothesis, however, is lacking at present. Effect of Hyperglycemia

on GH Secretion

Glucose administration has a biphasic effect on GH secretion in humans. After oral glucose, plasma GH levels are initially suppressed for 2-3 h, followed by a marked rise in GH levels in the postabsorbtive phase, 3-5 h after glucose administration. Acute hyperglycemia blocks GH secretion elicited by arginine, exercise, and L-DOPA. It is also generally accepted that glucose exerts its action at the hypothalamic level, but the precise mechanism of action is unknown at present. Studies carried out in vitro have shown an inverse relationship between glucose concentration and somatostatin release from rat hypothalamus (Berelowitz et al. 1982). As basal or stimulated rat GH release is unaffected by hyperglycemia, however, the relevance of this finding to the human situation is unclear at present. In human subjects, the finding that hyperglycemia blocks GHRH-induced GH secretion release argued against the concept that glucose acts by inhibiting endogenous GHRH release (Sharp et al. 1987). On the other hand, the finding that pyridostigmine administration unblocks the inhibitory effect of hyperglycemia on GHRH-induced GH secretion in humans suggests, although it does not prove, that hyperglycemia acts by increasing somatostatin release (Peiialva et al. 1989). The acute inhibitory effect following glucose administration is followed by a marked rise in GH levels in the postabsorbtive phase. This late GH rise after glucose is not due to a fall to the hypoglycemic range in the postabsorbtive phase, as it can still be observed during a euglycemic glucose clamp (Sharp et al. 1987). Interestingly, oral glucose load markedly increase GH responses to GHRH when administered 2.5 h prior to GHRH, in contrast to the inhibitory effect found when administered 30-60 min prior to GHRH (Valcavi et al. 1990). Although direct evidence is again lacking at present, it has been suggested that the late GH rise following oral glucose load is due to a decrease in somato-

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statinergic tone. This hypothesis is supported by recent data showing that administration of somatostatin analogues just before GHRH inhibits GHRHinduced GH release, whereas there is a marked increase in responsiveness when GHRH is administered 5 h later (Dickerman et al. 1993). Thus, it is conceivable that hyperglycemia leads to a transient and marked increase in endogenous somatostatinergic tone and therefore to a decrease in GH secretion, followed by rebound GH secretion in response to hypothalamic somatostatin withdrawal.

??

Free Fatty Acids and GH Secretion

GH is involved in the control of lipid metabolism, stimulating lipolysis, leading to increased production of FFA and the production of ketones. Specifically, a feed-back relationship has been postulated between GH and FFA. Pharmacologic reductions in FFA cause an increase in basal GH release and GH responses to GHRH (Dieguez et al. 1988). To the contrary, plasma FFA elevations reduce or block in vivo GH secretion stimulated by a variety of physiologic or pharmacologic conditions (Imaki et al. 1986, Casanueva et al. 1987). This inhibitory effect of FFA is exerted in a dose-dependent fashion and has been reported in many species, including, rat, sheep, monkey, and human (Dieguez et al. 1988). Furthermore, the FFA effects on GH secretion are very specific. Thus, an increase in circulating levels of FFA in humans does not affect TSH, LH, or PRL responses to TRH (Casanueva et al. 1987, Estienne et al. 1989). Data gathered over the last few years have shown that FFA influence GH secretion by acting at both the hypothalamic and the pituitary level (Quabbe et al. 1990). There is a growing body of evidence that FFA are essential for normal development of the brain. Furthermore, there are cells in the hypothalamus that react to changes in FFA concentration by altering neuronal firing rate (Oomura 1976). The administration of either caprylic (C8) or oleic (C18:l) acid to fetal rat neurons in monolayer culture has been found to increase GHRH secretion while inhibiting somatostatin secretion and lowering somatostatin mRNA content (Sefiaris et al. 1992 and 1993). Data obtained in

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vivo in rats passively

immunized

with

antisomatostatin serum suggest that the inhibitory effects of FFA on GH secretion could be mediated, at least in part, by an increase in somatostatin secretion (Imaki et al. 1986). Similar conclusions were drawn from in vivo studies carried out in humans (Peiialva et al. 1990). These findings, however, are somewhat in contrast with data obtained in vitro (just described here). The reasons for these discrepancies are unclear at present. It is possible that they are due to the loss of the normal anatomic organization associated with the culture of dispersed neurons or to the use of fetal tissue. Strong support for a direct effect at the pituitary level is derived from both in vivo and in vitro studies carried out in rats. Elevation in plasma FFA levels following lipid-heparin infusion was found to exert a similar inhibitory effect on GHRH-induced GH release in sham-operated rats, rats with medial hypothalamic ablation, and hypophysectomized rats bearing two hypophyses under the renal capsules (Figure 1) (Alvarez et al. 1991). In keeping with this observation, administration of caprylic acid and oleic acid was found to inhibit basal GH release and GH responses to GHRH by monolayer cultures of rat anterior pituitary cells (Casanueva et al. 1987). In summary, with all the available data taken together, it is clear that FFA can influence GH secretion, mainly by acting at the pituitary level.

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GH Secretion in Obesity

In obesity, GH secretion has been found to be clearly impaired. Studies conducted in young obese subjects have shown decreased integrated 24-h GH secretion. Because GH secretion is normalized after weight loss, there is no doubt that altered GH secretion develops as a consequence of obesity. Similar studies carried out in genetically obese Zucker rats have also demonstrated a marked decrease in GH secretion. Nevertheless, in light of the marked differences between rodents and primates, in terms of the regulatory mechanisms involved in GH secretion, it is possible that the underlying mechanisms responsible for this alteration in the two species are different.

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ried out recently have focused on some of the remaining alternatives, such as increased somatostatinergic tone or an

C

alteration

-30

-15

0

15

30

-30

-15

0

15

30

-30

-15

0

15

30

Time, min Figure 1. Mean f SEM GH levels after administration of GHRH (1 mg/kg) alone (O), GHRH plus 1 mL of a commercial soy bean emulsion (Intralipid) (0), and antisomatostatin antiserum plus GHRH and 1 ml of Intralipid (A) in sham-operated rats (a); in rats with medial hypothalamus ablation (b); and in hypophysectomized rats bearing two hypophyses under the renal capsule (c). *p < 0.05. From Alvarez et al. (1991).

GH Secretion in Obese Rats Because

cannot be infed rats, most of the studies have been carried out in the genetically obese Zucker rats. As in humans, spontaneous GH secretion is markedly reduced in obese rats in comparison with lean siblings. This decrease is probably due to alterations at both the hypothalamic and pituitary levels. Increased, unchanged, or decreased hypothalamic somatostatin levels have been reported in Zucker rats, and GHRH content and GHRH mRNA levels are reduced in obese rats in comparison to their lean siblings (York 1987, Sheppard et al. 1980, Tannenbaum et al. 1990, Ahmab et al. 1993). At the pituitary level, obese Zucker rats showed, in vivo and in vitro, decreased GHRH-induced GH release despite the lack of differences in affinity and number of GHRH-binding sites (Abribat et al. 1991). This indicates that blunted GH secretion is probably related to a decrease in GH synthesis, as demonstrated by reduced GH mRNA levels in the pituitaries of obese rats (Ahmab et duced

massive

obesity

in normally

al. 1992). Decreased GH secretion in obesity is unlikely to be due to an increase in somatostatinergic tone or increased somatotroph sensitivity to somatostatin, as passive immunization to somatostatin failed to increase GH response to GHRH, besides which pituitary somatostatin binding sites are unchanged in obese rats in comparison to their lean siblings (Tannenbaum et al.

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01995.

1990). On the other hand, it was recently found that decreased GH responses to GHRH and GHRP-6 in obese rats result from high concentrations of plasma IGF-I that feed back negatively on stimulated GH secretion (Bercu et al. 1992). Taken together, these data suggest that in genetically obese Zucker rats, impaired GH secretion is due, at least in part, to decreased hypothalamic GHRH synthesis and secretion and increased IGF-I levels, thereby leading to reduced GH synthesis as well as reduced basal and stimulated GH secretion.

Effect of Obesity in the Regulation GH Secretion in Humans

of

Studies undertaken in obese patients have shown a blunted GH release after stimulation with hypoglycemia, LDOPA, arginine, glucagon, exercise, clonidine, or GHRH (Williams et al. 1984). Recent studies using deconvolution analysis have shown that obese subjects harbor a double defect in GH dynamics involving both GH secretion and clearance (Veldhuis et al. 1991). Nevertheless, the severity of the secretory deficit ap-

secretory defect plays a much more important role. Although serum FFA and serum IGF-I levels may negatively influence GH release induced by GHRH, it has not been possible to account for the decrease in GH secretion in obese subjects via these mechanisms. Studies car-

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capacity of the

Figure 2. Mean + SEM GH levels in a group of six obese subjects after the administration of either GHRH (100 ug, i.v.) (0) or GHRH + GHRP-6 (100 ug, i.v.) (A). The GH response to GHRH + GHRP-6 in normal subjects is represented by the shaded area. From Cordido et al. (1993).

peared proportionate to the degree of obesity. The daily production rate of GH in obese subjects was altered much more than the clearance, indicating that the

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in the secretory

somatotrophs. Although the blunted GH response can be reversed after weight reduction by surgery, the first demonstration of a partial reversibility came after shortterm calorie restriction (Kelijman and Frohman 1988b). The fact that pyridostigmine, which reduces somatostatinergic tone, notably potentiates GHRH stimulation in obese subjects suggested, although it does not prove, that an enhanced somatostatinergic tone was at the root of the altered somatotroph function in this state (Cordido et al. 1989 and 1990, Ghigo et al. 1989, Castro et al. 1990). Even after administration of pyridostigmine, however, the response in obese subjects was always lower than that in nonobese counterparts after similar stimuli, suggesting that other alterations may also be at work. The possibility that impaired GH secretion in obesity could be due to an alteration in somatotroph secretory capacity was studied by assessing the GH responses to the combined administration of GHRP-6 and GHRH. GHRP-6 is a synthetic hexapeptide that elicits a dose-dependent and specific GH release. Combined administration of these peptides releases GH synergistically in vivo, and the individual peptides act directly on the pituitary via different pituitary receptors and biochemical pathways to release GH (Bowers et al. 1991, Goth et al. 1992). In

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40-

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GHRH

.

GHRH*GHRP-6

1; 3b 4;

$0

40

120

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normal subjects, the combined administration of both peptides is probably the most powerful stimulus of GH release (Bowers et al. 1990, Peiialva et al. 1993). In obese subjects, the GH response to the combined administration of both peptides was also substantially greater than after each was administered individually (Figure 2) (Cordido et al. 1993). The level of this discharge, with a mean peak of 40 ug/L (vs 60 l.tgK in controls), indicated that the secretory capacity of the somatotroph cell was not severely compromised in obesity.

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Acknowledgments

This work was supported by grants from the Fondo de Investigaciones Sanitarias (FIS), and the Ram6n Areces Foundation. The authors thank David Smith for critical reading of the manuscript. References Abribat T, Finkelstein JA, Gaudreau P: 199 1. Alteration of somatostatin but not growth hormone-releasing factor pituitary binding sites in obese Zucker rats. Regul Pept 36263-270. Ahmab I, Steggles AW, Finkelstein JA: 1992. In situ hybridization study of obesity associated alteration in GH mRNA levels. Int J Obes Relat Metab Disord 16:435441. Ahmab I, Finkelstein JA, Downs TR, Frohman LA: 1993. Obesity-associated decrease in growth hormone-releasing hormone gene expression: a mechanism for reduced growth hormone mRNA levels in genetically obese Zucker rats. Neuroendocrinology 58:332-337. Alvarez C, Mallo F, Burguera B, Cacicedo L, Dieguez C, Casanueva FF: 1991. Evidence for a direct pituitary inhibition by free fatty acids of in vivo growth hormone responses to growth hormone releasing hormone in the rat. Neuroendocrinology 53:185-189. Bercu BB, Yang S, Masuda R, Hu CS, Walker RF: 1992. Effects of coadministered GHRH and GHRP-6 on maladaptive aspects of obesity in Zucker rat. Endocrinology 131:2800-2804. Berelowitz M, Dudlak D, Frohman LA: 1982. Release of somatostatin-like immunoreactivity from incubated rat hypothalamus and cerebral cortex: effects of glucose and glucoregulatory hormones. J Clin Invest 69: 12931301. Bowers CY, Reynolds GA, Durham D, Ban-era CM, Pezzoli SS, Thomer MO: 1990. Growth hormone (GH)-releasing peptide stimulates GH release in normal men and act synergis-

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