Growth Hormone and Obesity

Growth Hormone and Obesity

The observation that growth hormone (GH) secretion is impaired in obesity, and is reversible upon weight loss, has prompted a great deal of research that has helped us understand how GH acts on adipocytes to regulate lipolysis and lipogenesis. Reciprocally, we are beginning to understand how adipocytes, as secretory organs, contribute to the regulation of GH secretion. The impaired secretion of GH in obesity, as well as the predominantly lipolytic effects of GH has prompted a number of studies where GH has been successfully used to induce significant weight loss in obese patients.

In this brief overview, I’d like to first look at the effects of GH on adipocyte function, then address the converse subject of adipocyte regulation of GH secretion, with particular emphasis on how obesity impairs GH secretion. Finally, we will look at how GH has been used therapeutically to treat obesity.

PHYSIOLOGICAL EFFECTS OF GH ON ADIPOCYTES

Two enzymes active in adipocytes which are of paramount importance in regulating lipogenesis (fat accumulation) and lipolysis (the breakdown of stored triglycerides into free fatty acids [FFA]) are lipoprotein lipase (LPL) and Hormone Sensitive Lipase (HSL); both are affected by GH. The accumulation of triglycerides in adipose tissue is controlled primarily by LPL. Triglycerides are transported to fat cells for storage in the form of very low-density lipoproteins (VLDL) and chylomicrons. LPL is synthesized by adipocytes and then secreted to the intracellular space, after which it attaches to the luminal portion of the vascular endothelium of the vessels supplying the adipocytes. There it hydrolyzes the triglyceride fraction of the VLDL and chylomicron particles, releasing FFA that are taken up by adipocytes. GH has been shown to have an inhibitory effect on adipose LPL (1,2), with a more pronounced reduction of LPL activity in intra-abdominal fat deposits than in subcutaneous fat (3). Exactly how GH inhibits LPL is unclear. GH treatment does not seem to affect LPL gene expression or mRNA levels, so it is assumed that the effect is post-translational, with GH somehow interfering with the activity of the enzyme (1). In any case, the net effect is that GH reduces the uptake of free fatty acids by fat cells, a clear antiadipogenic effect.

It should be noted that a number of other hormones affect LPL activity in significant ways. Insulin is the hormone with the greatest ability to stimulate LPL activity, contributing to the well-known lipogenic effect of this hormone. Conversely catecholamines (e.g. epinephrine) are strong downregulators of LPL, contributing to their ability to block fat accumulation. Testosterone and estrogen both inhibit LPL, contributing to their fat burning properties (4).

The second enzyme that dominates adipocyte metabolism is Hormone Sensitive Lipase (HSL). HSL is responsible for the hydrolysis of stored triglycerides to glycerol and free fatty acids. Thus hydrolyzed, the FFA can leave the adipocyte and travel in the blood to other tissues where they can be used as fuel, primarily in working muscle (As with fats entering adipocytes, the glycerol portion of the triglyceride must be removed in order for free fatty acids to leave the fat cell). GH amplifies the action of HSL in two ways. First, HSL is activated by catecholamines that act as agonists at beta 1, beta 2, and possibly beta 3 receptors in adipocytes. This is how sympathomimetic drugs like ephedrine and clenbuterol stimulate fat burning: they act as beta agonists to stimulate HSL. GH has been shown to be capable of inducing beta 2 receptors in adipocytes; more beta 2 receptors mean more HSL activity (5). As an aside, this is one way androgens promote lipolysis as well, via the upregulation of beta adrenoreceptors. Beta receptors employ the “second messenger” cyclic AMP (cAMP) to relay their signal within the cell that ultimately activates HSL. The signal is terminated by the enzyme phosphodiesterase. GH has been shown to have the ability to block phosphodiesterase, prolonging the activity of HSL (5). So we see GH promotes lipolysis via HSL by two routes: it upregulates the receptors that activate HSL, and it prolongs the signaling that keeps HSL functioning.

Besides affecting the metabolic functioning of adipocytes, GH controls adipocyte differentiation and proliferation. Differentiation refers to the process whereby immature preadipocytes activate the genes that direct them onto the path to becoming fully functioning mature adipocytes capable of carrying out the metabolic and secretory processes described above, as well as storing lipids. Proliferation refers to the increase in cell number via repeated cell division. The actions of GH are mixed here. We know that GH stimulates the hepatic production of Insulin-like Growth Factor 1 (IGF-1), which is responsible for many of the metabolic and perhaps anabolic actions of GH. It has been shown that IGF-1 is capable of stimulating the proliferation of preadipocytes, increasing the pool of potential adult fat cells (6). On the other hand, GH itself inhibits the differentiation of these precursor cells into adult adipocytes. Despite these contradictory effects of GH/IGF-1 on adipocyte proliferation and differentiation, the net effect of GH treatment in obese subjects in a number of studies is one of reduced adiposity.

FREE FATTY ACIDS AND GH SECRETION

GH and FFA function together in a regulatory feedback fashion. We have seen above how GH stimulates lipolysis, resulting in elevated levels of FFA. FFA in turn act back in a negative feedback manner to inhibit GH secretion. Circulating free fatty acids, elevated in obesity, are thought to be partly responsible for the suppression of GH seen in this condition (Plasma levels of FFA are elevated in obesity primarily because a greater than normal amount of FFA is released from the expanded adipose tissue mass even though the rate of lipolysis from individual fat cells appears to be normal).

It is generally accepted that circulating FFA rapidly partition into the plasma membranes of pituitary cells which secrete GH. This is believed to alter the function of proteins embedded in the plasma membrane, perturbing intracellular signaling and inhibiting GH release (9). Animal studies have shown that FFA are also capable of acting directly on the hypothalamus to increase the release of somatostatin, with a resulting inhibitory effect on GH release. It is controversial whether this hypothalamic effect exists in humans (10). No known stimulus for GH release seems to be able to escape the suppressive effects of elevated FFA. As just one example of relevance to athletes, exercise is a well-known stimulus for GH release. Seemingly paradoxically, exercise also elevates FFA acid levels, as lipolysis increases in order to supply FFA to muscle to serve as a fuel source. However, when nicotinic acid, a potent inhibitor of FFA release from adipocytes is administered during exercise, the low FFA levels resulting from nicotinic acid feeding were associated with a 3- to 6-fold increase in concentrations of human growth hormone throughout exercise. Exercise performance was also negatively impacted by the lack of availability of FFA as a fuel substrate (11). This could have practical implications for anyone using nicotinic acid to elevate HDL cholesterol levels, as many anabolic steroid using athletes are known to do (Anabolic steroids in general, and oral 17 alpha alkylated steroids in particular, are known to significantly lower HDL, or “good” cholesterol).

Somewhat surprisingly, in light of the evidence discussed above that FFA inhibit GH release, GH secretion is increased during fasting both in obese and normal subjects after administration of GHRH, despite an increase in fasting related FFA levels. This has been cited as contradictory to the theory that FFA impair GH secretion in obesity (12). However, as mentioned above, ghrelin may be more important than GHRH in stimulating GH release during fasting. While FFA do reduce the ability of ghrelin to stimulate GH release, ghrelin is partially refractory to this inhibitory effect of FFA. So it is possible that the results described in (12) were confounded by the effects of ghrelin on GH during fasting.

In any case, GH is generally low in obesity, and as a consequence there is a loss of the usual lipolytic effect of GH seen in normal individuals. This has prompted the experimental use of GH to attempt to reverse obesity in a number of studies.

INCREASED GH CLEARANCE RATE IN OBESITY

Studies have shown besides decreased production of GH in obesity, GH clearance rates are increased as well. While not necessarily being an effect directly attributable to the action of adipocytes on GH, it does contribute to lower overall GH plasma levels (13). Not well understood, this phenomenon has been attributed to either increased glomerular filtration of GH, changes in liver metabolism, or accelerated processing by excessive body fat stores.

EFFECT OF ADIPOSE TISSUE ON IGF-1

Despite the fact that GH levels are typically depressed in obesity, total serum IGF-1 levels are normal or high, and free IGF-1 levels are consistently elevated (5). This may seem surprising since—as discussed above—IGF-1 is normally produced in the liver under the stimulus of GH. One might expect the opposite to be observed: low GH in obesity leading to low circulating IGF-1. However, the observation that IGF-1 mRNA levels in fat cells are nearly as high as those found in the liver has led to the suggestion that adipocytes could contribute significantly to circulating levels of IGF-1 (5). If this is the case, then the normal negative feedback of IGF-1 on GH secretion could contribute in part to the depressed levels of GH seen in obesity. Adipocytes seem to secrete IGF-1 in response to GH, and in obesity, individual fat cells may secrete less IGF-1 than in normal subjects. The net overall effect of the increased number of fat cells in obese subjects would offset this, leading to the observed elevation in IGF-1. The depressed GH due to elevated IGF-1 in obesity provides another rationale for the use of GH to treat obesity.

INHIBITION OF GH SECRETION AND SIGNALING BY INSULIN

Insulin resistance and hyperinsulinemia are often associated with obesity. Research has shown that both normal physiological levels of insulin (14) as well as obesity-associated hyperinsulinemia blunt the GH response to GHRH and may contribute to the GH deficiency seen in obesity (15). Although the exact mechanism by which insulin regulates GH secretion is not known, a number of possibilities exist. Specific insulin binding sites have been found in both rat and human anterior pituitary adenoma cells. Inhibition of GH synthesis and release, and suppression of GH mRNA content, has also been observed when pituitary cells are exposed to insulin. So insulin could have a direct inhibitory effect on the pituitary. Insulin receptors are also present in the hypothalamus, so it is possible insulin is acting there. It has also been suggested that insulin could inhibit GH release by lowering plasma amino acid levels, since amino acids stimulate GH release. It has also been observed that insulin lowers circulating levels of the potent GH secretagogue ghrelin (16).

In vitro, insulin has also been shown in nonhepatic tissue to block the translocation of the GH receptor from the cytosol to the cell surface, with the effect of inhibiting binding of GH to its receptor. This may be another way hyperinsulinemia associated with obesity disrupts GH signaling (17)

GROWTH HORMONE THERAPY TO TREAT OBESITY

We have discussed a number of reasons why GH might potentially be of therapeutic use in the treatment of obesity due to its lipolytic action. Nevertheless, the results of trials have been inconsistent. This inconsistency, coupled with side effects of treatment which include insulin resistance, edema, arthralgia, and carpel tunnel syndrome to name a few, has prompted some critics to take a strong stand against the use of GH to treat obesity:

OBJECTIVE: To summarize the reports in the literature regarding the effect of growth hormone (GH) treatment of obesity. RESEARCH METHODS AND PROCEDURES: Clinical trials of GH treatment of obese adults were reviewed and summarized. Specifically, information regarding the effects of GH on body fat and body fat distribution, glucose tolerance/insulin resistance, and adverse consequences of treatment were recorded. RESULTS: GH administered together with hypocaloric diets did not enhance fat loss or preserve lean tissue mass. No studies provided strong evidence for an independent beneficial effect of GH on visceral adiposity. In all but one study, glucose tolerance during GH treatment suffered relative to placebo. CONCLUSION: The bulk of studies indicate little or no beneficial effects of GH treatment of obesity despite the low serum GH concentrations associated with obesity (18).

Despite the harsh tone of these investigators, a number of studies have shown a positive effect of GH on fat loss, with the abovementioned side effects being reversible upon termination of treatment. Additionally, countless anecdotal reports by bodybuilders and athletes contribute to the evidence that GH can be efficacious for fat loss.

In stark contrast to the assessment of the GH trials in (18) are reports by Lucidi et al (19) and Nam et al (20) that cite a number of studies where “GH is effective in reducing fat mass, especially visceral fat” (20). Nam et al discuss why some studies may have shown negative results. In their paper, the authors reported significantly enhanced fat loss (1.6 fold) compared to placebo, with a greater loss in visceral fat and an increase in lean body mass (20). Kim et al used low dosages of GH (0.18 U/kg Ideal Body Weight/week) and a hypocaloric diet, and believed this accounted for at least part of the success of their trial. They point out that one of the well known and dose dependent side effects of GH administration is insulin resistance and hyperinsulinemia. Insulin is well known to be an adipogenic hormone, and the hyperinsulinemia that often accompanies GH treatment could offset the lipolytic effect of the administered GH. To quote from the authors,

In addition, as the product of GH-induced lipolysis, FFA has been considered to be the principle factor in peripheral insulin resistance. These findings suggest that GH-induced hyperinsulinemia may antagonize the lipolytic effect of GH. In our study, GH treatment did not induce a further increase in insulin levels. [This] suggest[s] that although GH might induce insulin insensitivity and hyperinsulinemia, low-dose GH therapy with diet restriction in obesity could overwhelm the antilipolytic action of insulin.

The frequency of side effects depends on the dose of GH. We observed only minor side effects which spontaneously subsided, indicating that the dose of GH in this study was lower in comparison with other studies (20).

So it may very well be that many of the studies that failed to demonstrate weight loss after GH administration employed excessively high doses, which either aggravated pre-existing hyperinsulinemia or subsequently induced hyperinsulinemia, which offset any lipolytic effects of GH.

We have discussed a number of ways by which GH promotes lipolysis, the main effect being to stimulate Hormone Sensitive Lipase in adipocytes. But lipolysis, the term used to describe the mobilization of fatty acids so that they can potentially be used as fuel, is not the same thing as the actual oxidation of those fatty acids for energy in muscle tissue. Perhaps the failure of some trials to show fat loss during GH treatment is a result of a failure to oxidize the lipids that GH makes available as a potential fuel source. This seems not to be the case however, as research has shown that GH actually increases lipid oxidation at the expense of glucose oxidation by activating the so called glucose-fatty acid cycle where the preferential use of fat as a fuel substrate inhibits the use of glucose as fuel (21) (This process actually provides a mechanistic explanation of how GH administration induces insulin resistance: when more fatty acids are used as fuel, cells take up less glucose for use as a fuel substrate, leading to glucose intolerance). In addition to promoting the preferential use of fat as a fuel substrate by increasing its availability through enhanced lipolysis, GH also appears to directly stimulate the oxidation of lipids, perhaps by upregulating key mitochondrial enzymes involved in lipid oxidation (22).

Moreover, another well-known effect of growth hormone is to slow skeletal muscle breakdown during fasting (23). Teleologically speaking, the body secretes GH during periods of caloric restriction in an attempt to preserve skeletal muscle at the expense of increased fat oxidation for fuel. So during periods of caloric restriction, GH is responsible for less reliance on glucose and protein for energy, with fat being preferentially oxidized.