Endocrine Research Unit Mayo Clinic and Foundation Rochester, Minnesota 55905
Address all correspondence and requests for reprints to: Michael D. Jensen, M.D., Endocrine Research Unit, Joseph 5-194, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. E-mail: jensen.michael{at}mayo.edu.
In this issue of JCEM, van Hall et al. (1) report the results of studies in which recombinant human IL-6 (rhIL-6) was infused into normal healthy volunteers, and careful measures were made of lipid fuel metabolism. The rhIL-6 infusions resulted in increased levels of plasma free fatty acid (FFA) and glycerol concentrations and an increased rate of appearance (Ra) of FFA and glycerol as measured by isotope dilution techniques. One study group received a low dose of rhIL-6 (plasma concentrations increased to 140 pg/ml), and another group received a high dose of rhIL-6 (plasma concentrations increased to >300 pg/ml). The authors observed an increase in plasma FFA concentrations of approximately 60% and an increase in FFA Ra of approximately 25%, in response to the low-dose rhIL-6 infusion. Plasma cortisol concentrations increased by approximately 50%, and plasma epinephrine concentrations briefly increased with the high-dose rhIL-6. Resting energy expenditure (REE) increased by approximately 7% during the low-dose rhIL-6 infusion, whereas an average decrease of 4% occurred in oxygen consumption in volunteers who received the control saline infusion. The authors conclude that IL-6 is a novel lipolytic factor and that it is a potent modulator of lipolysis. Before adding IL-6 to the textbook hormonal regulators of lipolysis, however, we should consider the currently understood physiology of adipose tissue fuel export and its hormonal regulation.
Table 1 lists the hormonal regulators of lipolysis, the range of plasma concentrations that can be found in humans, and qualitative estimates of the potency and time of onset of these hormones with respect to their effects on lipolysis.
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Another potent circulating regulator of lipolysis is epinephrine (6). Plasma epinephrine concentrations can vary widely throughout the day and increase dramatically with exercise. Plasma epinephrine concentrations in the range of 30006000 pmol/liter can easily triple FFA Ra and concentrations (6) within 30 min. The half-maximal effect of epinephrine on lipolysis occurs with only a 3-fold increase in plasma epinephrine concentrations from basal (6), concentrations that are readily observed with stress and exercise (7). The lipolytic response to this half-maximal increase is on the order of a 100% increase in lipolysis-FFA concentrations. Thus, changes in plasma epinephrine concentrations that occur in everyday life can have a major, and virtually immediate, effect on lipolysis.
A less potent but nonetheless critically important hormone regulator of lipolysis is GH (8, 9, 10, 11). GH-deficient individuals can experience as much as a 40% reduction in plasma FFA concentrations and lipolysis (10), a defect that is corrected by replacement of GH (10). An iv pulse of GH (8, 9) that results in concentrations seen with exercise (12) can increase plasma FFA concentrations and lipolysis by 5070% within 23 h. Thus, GH, although not as potent a regulator of lipolysis as insulin and epinephrine, helps maintain basal lipolysis and likely is an important stimulator of lipolysis under conditions such as exercise and fasting.
Cortisol likely is an even less potent and more delayed regulator of lipolysis in humans. A difficulty in studying cortisol regulation of lipolysis in vivo has been the stimulation of insulin secretion from cortisol administration. The increased insulin easily offsets any cortisol-mediated increase in lipolysis in these experimental conditions. In experiments in which plasma insulin concentrations were prevented from changing, a 4-fold increase in plasma cortisol concentrations resulted in a 60% increase in plasma FFA concentrations and in lipolysis within 45 h (13). Whether the modest (50%) increases in plasma cortisol concentrations seen by van Hall et al. (1) resulted in the increase in lipolysis they observed is not known, but appears unlikely.
How then should we interpret the increases in lipolysis in response to rhIL-6 infusion reported by van Hall et al. (1)? Were there any confounding or missing variables? What is the relevance of the plasma concentrations they obtained? One missing component of this report is the response of plasma GH concentrations. Tsigos et al. (14) reported that rhIL-6 substantially increased GH in humans, although other investigators have not reported such an effect (15). Without knowing the GH responses in the subjects receiving rhIL-6 in the present study (1), it is not possible to exclude the possibility that increased GH mediated the delayed and modest increase in lipolysis. Certainly, the time course and magnitude of the change is consistent with a GH effect.
If GH concentrations did not increase in response to rhIL-6, is it reasonable to conclude that this cytokine is a potent lipolytic modulator? In my opinion, this is not likely. The plasma concentrations achieved by van Hall et al. (1) were greater than those found in men who have just completed a marathon (16). Exercise, the authors suggest, is one of the conditions wherein stimulation of IL-6 may play a role in regulation of lipolysis. During exercise, plasma insulin concentrations fall, whereas catecholamine and GH concentrations increase. With exercise, the hormone and lipolysis responses are rapid and consistent with the need for increased lipid fuel. It is reported that only a very gradual increase in arterial IL-6 concentrations occurs with prolonged, less intense exercise (17) (plasma IL-6 concentrations reached 6 pg/ml after 180240 min of one-legged exercise). It seems that the intensity and duration of exercise necessary to increase IL-6 concentrations to a level that could result in a moderate increases in lipolysis would put this cytokine well down in the hierarchy of lipolytic modulatorsthis may not be the same for the stress of severe illness, in which plasma IL-6 concentrations could play a role in increasing lipolysis over prolonged periods of time.
Finally, it is possible that the potency of the purported rhIL-6 effect on lipolysis was overestimated in the current study (1). The basal plasma FFA concentrations and FFA flux values in these volunteers were approximately 60% higher than average for overnight postabsorptive lean adults. We typically see this state if volunteers are somewhat energy- or carbohydrate-deprived the day before the study. The basal respiratory quotients reported by van Hall et al. (1) are consistent with this hypothesisthey were well under 0.80 for all groups. Under conditions of careful dietary control to assure true energy balance and a balance between dietary fat and carbohydrate, the average overnight postabsorptive respiratory quotients will be approximately 0.820.83 (18). This is important, because energy deprivation, such as occurs with fasting, increases the potency of lipolytic stimuli (4). Also, REE appears to be an important predictor of basal lipolysis (18), and thus, changes in REE, such as those seen with rhIL-6 infusion (1, 14), may need to be considered as another confounding variable in studies of cytokines.
In summary, the results of van Hall et al. (1) suggest that IL-6 is a hormonal regulator of lipolysis in humans. If IL-6 does independently stimulate lipolysis, high concentrations appear to be necessary, and the effect is seen after several hours. IL-6 concentrations of this magnitude are seen after prolonged, intense exercise and with severe illness. The reported effects are relatively modest compared with insulin and catecholamines. Before IL-6 is added to the list of proven lipolytic hormones, it will be necessary to determine whether it is GH concentrations that change in response to doses of IL-6 that stimulate lipolysis or to repeat these studies in GH-deficient humans. The effects of IL-6 on lipolysis during severe illness bears further investigation because insulin resistance, possibly worsened by increased FFA, is a common finding in critically ill patients.
Footnotes
This work was supported by Grants DK40484 and DK50456 from the U.S. Public Health Service and the Mayo Foundation.
Abbreviations: FFA, Free fatty acid; Ra, rate of appearance; REE, resting energy expenditure; rhIL-6, recombinant human IL-6.
Received April 18, 2003.
Accepted April 18, 2003.
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