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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 12 4139-4143
Copyright © 1997 by The Endocrine Society

Original Studies

Isoproterenol and Somatostatin Decrease Plasma Leptin in Humans: A Novel Mechanism Regulating Leptin Secretion1

William T. Donahoo, Dalan R. Jensen, Trudy J. Yost and Robert H. Eckel

Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Health Sciences Center, Denver, Colorado, 80262

Address all correspondence and requests for reprints to: Robert H. Eckel, Box B-151, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Denver, Colorado 80262. E-mail: robert.eckel{at}uchsc.edu


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
In cultured adipocytes, leptin is increased by insulin and decreased by cAMP. In animal models, insulin and agents that increase intracellular cAMP have been shown to similarly affect plasma leptin in vivo. This study was undertaken to test the hypothesis that in humans increased cAMP induced by isoproterenol would decrease leptin. Five groups of normal weight subjects were studied: 1) subjects infused with isoproterenol at a rate of 24 ng/kg/min (ISO24); 2) subjects infused with isoproterenol at a rate of 8 ng/kg/min (ISO8); 3) subjects infused with somatostatin/insulin/GH followed by coinfusion with 8 ng/kg/min isoproterenol (ISO8 + SRIH); 4) subjects infused with somatostatin/insulin/GH alone (SRIH); and 5) control subjects infused with saline (NS). ISO24 infusion resulted in a 27% decrease in plasma leptin over 120 min. ISO24 also increased plasma insulin over the infusion. ISO8 resulted in a 16% decrease in leptin. Saline did not change leptin. SRIH alone decreased leptin 19% over the first 120 min, however no additional fall was seen over the next 120 min the SRIH group. Nonetheless, the addition of 8 ng/kg/min ISO during the second 120 min (ISO8 + SRIH) caused a 15% further decline in plasma leptin. Therefore both isoproterenol and somatostatin reduce plasma leptin in humans. The effect of isoproterenol is likely mediated by ß-adrenergic receptors, whereas the effect of somatostatin suggests a novel mechanism for the regulation of leptin.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
LEPTIN, a marker of total body lipid, acts through a feedback mechanism to regulate feeding and energy expenditure (1, 2, 3, 4). As such, during times when lipid stores in adipocytes are decreasing (e.g. with fasting-induced lipolysis), plasma leptin levels would be expected to be suppressed, stimulating food intake (5, 6). Conversely, during times when lipid levels in adipocytes are increasing (following overnutrition), plasma leptin levels would be expected to rise, curbing additional food intake (7).

The mechanisms that regulate leptin secretion are incompletely understood. Several studies have shown a stimulatory effect of insulin on leptin secretion (8, 9, 10). However, in in vivo studies in humans, a direct response of leptin to short-term insulin (<6 h) infusion has not been demonstrated (11, 12, 13). In cell culture and in animals, increases in intracellular cAMP have been found to reduce leptin (14, 15, 16, 17). It is unknown whether agents that increase intracellular cAMP in vivo in humans will also decrease leptin. Isoproterenol is a nonspecific ß-adrenoreceptor agonist that will increase intracellular cAMP. In adipose tissue this results in increased lipolysis, however in the whole organism, hyperinsulinemia also occurs (18). The isoproterenol studies were therefore designed to determine whether or not leptin secretion does indeed decrease in the face of an isoproterenol infusion.

To control for the hyperinsulinemia during the isoproterenol infusion, a coinfusion of somatostatin was used. Little data are available on the effect of somatostatin on leptin. It could be exerting an indirect effect on adipocytes via inhibition of other hormones, or it could directly effect leptin. These experiments were also able to examine the effect of somatostatin on leptin.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study subjects

Study subjects were recruited from the community. Most of these patients have already been described in a protocol examining the effect of isoproterenol on lipoprotein lipase (18). All were at maximum body weight, had been weight stable for at least 3 months, and were taking no medications. Written informed consent was obtained from all subjects before the study. Screening blood tests including electrolytes, renal and liver function tests, serum glucose, complete blood count, fasting lipids (triglycerides, cholesterol, high density lipoprotein cholesterol, and low density lipoprotein cholesterol), and thyroid function tests were all normal.

Subjects were asked to consume a standardized diet (45% carbohydrate, 40% fat, and 15% protein) for 2 days before the study. They were admitted to the University of Colorado Health Sciences Center General Clinical Research Center the evening before the study and underwent an overnight fast. All studies were begun by 0800 h in the morning and concluded by 1200 h.

Study protocol

The study protocol is summarized in Fig. 1Go.



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  		Figure 1. Experimental protocol. Subjects were assigned to one of five groups: 1) subjects infused for 120 min with isoproterenol a rate of 24 ng/kg/min (ISO24); 2) subjects infused for 120 min with isoproterenol a rate of 8 ng/kg/min (ISO8); 3) subjects infused for 120 min with somatostatin/insulin/GH (SRIH added to control for potentially confounding effects of isoproterenol-induced hyperinsulinemia) followed by coinfusion for next 120 min with 8 ng/kg/min isoproterenol (ISO8 + SRIH); 4) subjects infused for 240 min with somatostatin/insulin/GH alone (SRIH); and 5) control subjects infused for 120 min with saline (NS).

 
ISO24. Subjects were infused with isoproterenol at 24 ng/kg/min over 120 min. This procedure has been previously described (18). Briefly, isoproterenol hydrochloride (Isuprel, Sanofi Winthrop Pharmaceuticals, New York, NY) was diluted to 1 µg/mL in 0.9% NaCl solution with 0.5 mg/mL ascorbic acid (Cenolate, Abbott Lab, North Chicago, IL) added for stability. Isoproterenol was infused with an IVAC 560 Variable Pressure Volumetric Pump (IVAC Corp., San Diego, CA) through an 18-gauge iv catheter placed in an antecubital vein. Pulse and blood pressure were monitored every 10 min throughout the infusion, and 5-lead electrocardiographic tracings were monitored continuously. Blood was drawn from each subject before the infusion and at 10, 20, 40, 80, and 120 min into the infusion.

ISO8. The ISO8 subjects were infused with isoproterenol at 8 ng/kg/min a manner described above. Blood was drawn from each subject before and 120 min into the infusion.

ISO8 + SRIH. To control for the potential effects of isoproterenol-induced hyperinsulinemia, a pancreatic clamp was used as previously described (19). Subjects were infused for 120 min with somatostatin (120 ng/kg/min), insulin (0.07 mU/kg/min), and GH (3 ng/kg/min). Isoproterenol (8 ng/kg/min) was added to the infusate for the next 120 min. Blood was drawn before the SRIH infusion, just before the start of the isoproterenol infusion (i.e. at 120 min), and 120 min after isoproterenol infusion (i.e. 240 min from start of SRIH infusion).

SRIH. Control subjects were infused with the SRIH cocktail as described above. However, rather than the addition of isoproterenol infusion at 120 min, SRIH alone was continued for the subsequent 120 min.

Saline controls. Saline control subjects were infused with 0.9% saline over 120 min at the same rate used for the delivery of 24 ng/kg/min isoproterenol. Blood was drawn from each subject before the infusion and 120 min into the infusion.

Assays

Leptin was assayed using a human leptin RIA (Linco Research, St. Charles, MO). The intra- and interassay coefficients of variance for the leptin assay were 7.7% and 6.8%, respectively. Additionally, serum glucose, insulin (20), free fatty acids (FFA) (21), glycerol (22), and plasma triglycerides were measured (23).

Statistic analyses

Statistical analysis were performed using SigmaStat for Windows Version 2.0 (Jandel Scientific, San Rafael CA). Initial comparisons of pre- and intrainfusion rates were made using a Student’s paired t test. If normality or equal variance failed, a Wilcoxon signed rank test was done. When multiple comparisons were done, a Bonferonni correction was used. Significance was set at P < 0.05. Data are presented as mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The characteristics of the subjects are given in Table 1Go. There were no differences in subject groups with respect to age, body mass index, or baseline plasma leptin. The groups were not matched with respect to gender, however because data are paired, this should not introduce error into the analysis. The females did have higher leptin than the males at baseline (9.1 ± 1.2 and 3.4 ± 0.7 ng/mL, respectively, P < 0.001).


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  		Table 1. Characteristics of subjects

 
At baseline, FFA levels were similar in all groups (Table 2Go). With the ISO24 infusion, there was a 113% increase in FFA (P < 0.001). The ISO8 resulted in a 43% increase in FFA (P = 0.05). When SRIH was infused, there was an increase in FFA (combining the ISO8 + SRIH and the SRIH groups over the first 120 min FFA went from 794 µEq/L ± 63 to 1068 ± 69, P = 0.003). However with SRIH alone, no significant change occurred in the FFA levels either from basal to 120 min (P = 0.17) or from 120–240 min (P = 0.13). Nonetheless, in the ISO8 + SRIH there was a 38% increase in FFA from basal to 120 min (during the SRIH only infusion, P = 0.01) and a 78% increase in FFA from 120–240 min (during the SRIH and ISO8 infusion, P < 0.001). There was also a 40% increase in FFA in the NS group (P = 0.04).


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  		Table 2. Effect of isoproterenol and SRIH on FFA and insulin

 
Insulin levels increased 83% with ISO24 infusion (P < 0.001) and 54% with ISO8 infusion (P < 0.05). With the addition of SRIH, insulin levels were clamped to prevent the isoproterenol-induced rise in insulin. There was however a slight fall in insulin at 120 min in the ISO8 + SRIH group. All other insulin levels with SRIH were stable (Table 2Go). Glycerol increased 99% in the ISO24 infusion (P < 0.001). Otherwise, no changes in glycerol levels occurred.

Figure 2AGo shows the effect of ISO24 on leptin. There was a 27% decrease in leptin from basal (10.8 ± 2.3 ng/mL) to 120 min (7.9 ± 1.7; P < 0.001). This decrease was seen despite an increase in plasma insulin levels (4.8 ± 0.4 µU/mL to 8.8 ± 0.6; P < 0.001). Figure 2BGo shows that the effect of ISO24 on leptin occurred in a time-dependent manner and reached an apparent steady state by 120 min. When subjects were given ISO8, leptin also decreased 16% from 4.9 ± 0.9 to 4.1 ± 1 (P = 0.03, Fig. 2CGo). Saline infusion resulted in a downward trend in leptin (5.7 ± 2 to 4.6 ± 1.6, P = 0.10). When the NS group was separated by gender, females had a trend for higher leptin than males both before and 120 min into the saline infusion (8.7 ± 2.7 and 1.8 ± 0.8 (P = 0.09) at time = 0 and 7.0 ± 2.0 and 1.5 ± 0.9 (P = 0.08) at 120 min).



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  		Figure 2. Effect of isoproterenol on leptin. With infusion of high-dose isoproterenol (24 ng/kg/min, ISO24) there was a 27% decrease in leptin (A). This decrease was seen despite an increase in plasma insulin levels. Additionally, the effect of ISO24 occurred in a time- dependent manner, with an apparent steady state being reached by 120 min (B). Infusion of isoproterenol at 8 ng/kg/min (ISO8) also resulted in a decrease in leptin (C). However, the decrease in leptin was less than was seen with ISO24 infusion (16% vs. 27%).

 
To control for the relative hyperinsulinemia, a pancreatic clamp with SRIH was used (Fig. 3Go). When SRIH was infused, there was a significant decrease in leptin (again combining the ISO8 + SRIH and the SRIH groups over the first 120 min, leptin fell 19% from 6.2 ± 1.2 to 5.0 ± 1.0, P < 0.001). In the SRIH alone group, despite the fall in leptin over the first 120 min (7.1 ± 2.8 to 5.5 ± 2.3, P = 0.05), no further fall in leptin was seen over the next 120 min (5.5 ± 2.3 to 5.4 ± 2.1). However in the ISO8 + SRIH group, in addition to the initial fall in leptin over the first 120 min (5.8 ± 1.3 to 4.8 ± 1.1, P = 0.003), there was an additional 15% fall in leptin over the next 120 min (4.8 ± 1.1 to 4.1 ± 0.9, P = 0.02). Leptin was greater in females than males at all time points. Basal leptin levels were 10.4 ± 1.9 in females vs. 3.4 ± 1.3 in males (P= 0.02), 8.9 ± 1.5 vs. 2.7 ± 0.7 (P = 0.001) after the first 120 min, and 7.5 ± 1.3 vs. 2.4 ± 0.6 after the next 120 min. Females had a 17% decrease in leptin over the first 120 min (P = 0.04) and a 19% decrease over the next 120 min (P = 0.04). Males had a 25% decrease in leptin over the first 120 min (P = 0.05) and a 13% decrease over the next 120 min (P = 0.19).



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  		Figure 3. Effect of SRIH with and without subsequent isoproterenol infusion on leptin. With infusion of SRIH, leptin levels were decreased. When both groups were combined for first 120 min, leptin fell from 6.2 ± 1.2 to 5.0 ± 1.0 (P < 0.001). Over second 120 min, leptin remained stable in SRIH + saline infusion. However, with addition of 8 ng/kg/min isoproterenol to SRIH infusion, leptin further decreased.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Isoproterenol decreases leptin in adipocyte cultures, and this study now shows a similar in vivo effect in humans as well. The isoproterenol is most likely causing a decrease in leptin through stimulation of ß-adrenergic receptors and increases in intracellular cAMP, as has been shown in cell culture and in animal models (14, 15, 16, 17, 24, 25). The differential effect of isoproterenol on leptin (i.e. ISO24 having a greater decrease in leptin than ISO8) could be because of the degree of ß-stimulation or could be attenuated by the resultant hyperinsulinemia. Although the stimulatory effect of insulin on leptin messenger RNA and protein was clear in 3T3-L1 adipocytes and primary adipocytes (9, 14, 26, 27, 28), in humans several studies have shown no short-term effect of hyperinsulinemia on leptin (11, 12, 29, 30, 31, 32). However, if insulin does have an effect on leptin in vivo in humans, it is possible that insulin may inhibit the isoproterenol-mediated decrease in leptin. Specifically, it would be expected that with the ISO24 the isoproterenol response would predominate and leptin would decrease, whereas in the ISO8 group the response to insulin would be able to modulate the isoproterenol effect so that less of a change in leptin would occur. The experiments with SRIH however argue against this conclusion. With 8 ng/kg/min isoproterenol infusion, leptin levels fell a similar amount whether the isoproterenol-induced hyperinsulinemia was blocked with SRIH or not. Thus taken together, these data support much of the other human data suggesting less of a role for insulin in the direct regulation of leptin.

The saline group showed a decrease in leptin, albeit not significant. There are several possible explanations for this. It should be noted that the NS group also had a rise in FFA over the infusion. Although the mechanism for decreases in leptin following ß-stimulation remains to be established, one possibility is because of a stimulation of lipolysis. If the increase in FFA is taken as a marker of increased lipolysis, then it is not unexpected that the NS group had a fall in leptin. As further support of this concept, when the change in leptin is correlated with the change in FFA for all of the studies described above, a weak but significant relationship exists (r = 0.29, P = 0.03). Despite the correlation between FFA and leptin, no significant change in FFA was seen in the SRIH alone group, even though a decrease in leptin occurred. Therefore, although lipolysis may play a role in the regulation of leptin, other mechanisms may be occurring with SRIH’s regulation of leptin.

The effect of SRIH to decrease leptin was unexpected, and there are several potential mechanisms for this effect. First, there could be a direct effect of somatostatin on adipocytes. Specific somatostatin binding sites have been characterized on adipocytes, but no somatostatin receptor subtype characterization has been done (33). If the hypothesis that increased lipolysis decreases leptin is used as an explanation, then several supporting studies exist that have described a lipolytic effect both during infusion (34, 35) and in adipocyte culture (36, 37). The lipolytic effect of SRIH seen in this experiment (i.e. the increase in FFA seen with SRIH infusion) is also consistent with the literature. However if this direct effect of somatostatin on leptin is indeed the mechanism of action, then it is a novel mechanism as SRIH receptors act via decreasing and not increasing cAMP (38).

SRIH could also be acting indirectly in this study by changing other potentially leptin regulatory hormones. Included among these are insulin-like growth factor I (IGF-I), GH, and cortisol. Although the effect of GH alone on leptin is unknown, because it was replaced at a low-dose stable infusion in this study, it is unlikely that GH caused a decrease in leptin. IGF-I, another possible regulator of leptin, was not replaced (or measured) in this study. However because IGF-1 has a very long half life, it is unlikely there was a significant decrease in IGF-I over the period of these infusions. Finally, glucocorticoids increase leptin in both rat and human adipocytes (9, 14). Short-term hypercortisolemia has been shown to increase leptin in humans (39). The effect of hypocortisolemia on leptin is unknown. However because SRIH infusion does not change cortisol (40), it is unlikely that this was the mechanism of the decrease in leptin. Overall, it is unlikely that the effect of SRIH on leptin was caused by the change in another hormone.

In summary, these experiments show that high-dose isoproterenol infusion (ISO24) decreased leptin, as did the low-dose isoproterenol infusion (ISO8). A SRIH infusion also decreased leptin over the first 120 min but no further over the next 120 min, whereas the addition of low-dose isoproterenol to SRIH infusion (ISO8 + SRIH) resulted in a further decrease in leptin over the second 120 min. It is most likely that the mechanism of the isoproterenol effect was through ß-adrenergic stimulation of lipolysis, whereas the mechanism for the effect of SRIH on leptin remains to be further clarified.


   Acknowledgments
 
We thank Tere Marcell for the technical assistance in the measurement of leptin.


   Footnotes
 
1 This work was presented in part at the North American Association for the Study of Obesity Annual Meeting, October 13, 1996, Breckinridge, Colorado. This study was supported by the National Institutes of Health Grant DK-22356, General Clinical Research Center Grant RR-00051 and Clinical Nutrition Research Unit Grant DK-48520. Back

Received May 19, 1997.

Revised August 6, 1997.

Accepted August 26, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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