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Original Studies |
Dipartimento di Medicina Interna e Scienze Biomediche, Facoltà di Medicina, Università di Parma (P.C., R.V., S.C., V.C.), 43100 Parma; and Unità di Endocrinologia, Ospedale di Codogno (L.C., G.S.), Codogno, Italy
Address all correspondence and requests for reprints to: Dr. Paolo Chiodera, Dipartimento di Medicina Interna e Scienze Biomediche, Università di Parma, Via Gramsci 14, 43100 Parma, Italy.
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Abstract |
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These findings led us to evaluate the secretory pattern of leptin in 12 obese patients in similar experimental conditions. In all patients basal leptin levels were significantly higher than those in normal weight subjects. In 6 obese subjects, the infusion of OT alone (1, 2, or 4 mIU/min) was unable to change serum leptin levels. In the remaining 6 obese subjects, dex administration significantly increased serum leptin levels; however, the leptin response to dex was not modified by the concomitant infusion of 1, 2, or 4 mIU/min OT.
These data show inhibition by elevated circulating OT levels of glucocorticoid-induced, but not basal, leptin secretion in normal weight subjects, suggesting a possible role for OT in the regulatory control of leptin. Furthermore, the results obtained in obese subjects indicate that this regulation is disrupted in obesity.
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Introduction |
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Oxytocin (OT) is probably involved in this regulation. In fact, OT not only participates in the control of food intake at the hypothalamic level (5), but it also plays an important role in the regulation of adipose tissue metabolism (6) through specific receptors (7). Like GH (8), OT shows both insulin-like and antiinsulin-like effects in adipocytes (9, 10). Furthermore, OT shares similar activities on key enzymatic mechanisms [i.e. increase in phosphorylation of an acid-soluble 22-kDa protein (11) and increase in phospholipid methyltransferase activity (12)] with ß-adrenergic agents (2) and forskolin (12), which are well known inhibitors of leptin secretion (2, 13).
In the present study we examined whether OT is involved in the regulation of leptin secretion. For this purpose, the plasma leptin response to dex under feeding conditions was studied in healthy normal weight men in the presence or absence of a constant systemic infusion of OT. Further experiments in other normal weight subjects under similar experimental conditions tested the effect of OT infusion alone on circulating leptin levels. Finally, the same experiments were performed in obese patients.
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Materials and Methods |
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Each subject underwent five different tests, which were performed in random order at least 7 days apart. On the experimental day, subjects consumed 2000 Cal (55% carbohydrate, 15% protein, and 30% fat): breakfast (700 Cal) at 0800 h, lunch (960 Cal) at 1200 h, and afternoon snack (340 Cal) at 1400 h. All tests followed a similar procedure; tests started after a 10-h overnight fast. At 0700 h on the days of the experiment, two iv cannulas were placed into two different veins. One cannula was kept patent with a slow saline (0.9% NaCl) infusion and was used for blood sampling. The other was used for drugs or normal saline administration.
Dex test
Subjects were injected with an iv bolus of 4 mg dex over 1 min after withdrawal of a basal sample at 0730 h. Additional blood samples were taken every 60 min for 10 h. This procedure was in accordance with the method described by Laferrère et al. (4).
Dex plus OT test
Dex injection was followed by the constant infusion of 1, 2, or 4 mIU/min OT (Syntocinon, Novartis Farma, Origgio, Italy) for 10 h. These doses and route of administration of OT were chosen because in previous studies (14) they resulted in plasma OT levels comparable to or slightly higher than values found after OT-releasing stimulations such as breast suckling (15) or insulin-induced hypoglycemia (16). In the dex test an equal amount of normal saline was infused instead of OT.
Normal saline test
A bolus injection of normal saline was followed by a constant infusion of saline for 10 h.
The effect of OT alone on serum leptin levels was tested in six additional healthy nonobese subjects (mean weight, 66.1 ± 1.5 kg; mean height, 175 ± 1.4 cm; mean body mass index, 23.1), aged 22–30 yr, and in six obese patients (mean weight, 105.8 ± 5.0 kg; mean height, 173 ± 1.9 cm; mean body mass index, 36), aged 27–33 yr. All subjects were tested in similar experimental conditions as described above.
OT test
OT was infused as described for the dex plus OT test after a bolus injection of normal saline instead of dex.
Normal saline test
A bolus injection of normal saline was followed by a constant infusion of saline for 10 h.
In all tests, a basal sample was taken before drug or saline injection at 0730 h. Additional blood samples were taken every 60 min for 10 h. Blood samples were used for the measurement of leptin, glucose, and insulin. Glucose was evaluated with a glucose autoanalyzer (Instrumentation Laboratory, Milan, Italy). Serum leptin was measured by RIA, using commercial kits (Mediagnost, Tubingen, Germany). The intra- and interassay coefficients of variation were 5% and 8%, respectively; the sensitivity of the method was 0.1 ng/mL. In our laboratory, the normal range is 6.2–8.1 ng/mL. Insulin levels were determined by RIA (Pantec, Milan, Italy). The intra- and interassay coefficients of variation were 5% and 6%, respectively. The sensitivity of the method was 26.7 pmol/L.
ANOVA was used to test for differences among the mean responses. Multiple comparisons were performed using Fisher’s protected least significant difference procedure. Values are reported as the mean ± SE.
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Results |
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(A and B); values
obtained for obese subjects are shown in Fig. 2 (A and B). In each group, serum insulin
levels at all corresponding time points in all tests were similar. Each
group showed similar blood glucose levels in the dex and dex plus OT
tests; in these tests, blood glucose values were significantly higher
than those in the saline test (P < 0.05; Figs. 1A and 2A).
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) and
obese (Fig. 3B) subjects showed similar circulating leptin
concentrations at all time points examined during the 10-h infusions of
OT (1, 2, or 4 mIU/min) or normal saline alone. However, in the obese
group, leptin levels were significantly higher than those in normal
weight subjects (P < 0.01).
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; obese subjects, Fig. 2C). In the normal weight
subjects, the dex-induced leptin rise did not change when dex
administration was followed by a 1 mIU/min OT infusion, whereas it was
completely abolished when 2 or 4 mIU/min OT were given [Fig. 1C; dex
plus OT (2 or 4 mIU/min) vs. dex test, P <
0.02; NS vs. saline test]. In contrast, in obese patients
OT infusion did not change the dex-induced leptin rise at any
dose used (1, 2, or 4 mIU/min; Fig. 2C). No side-effects were noticed in any subject after dex administration or OT infusion.
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Discussion |
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In contrast, OT completely inhibited dex-induced leptin secretion when it was infused at the rate of 2 mIU/min in normal weight subjects. Previous studies (14) have shown that the infusion of OT at this rate (2 mIU/mL) produces circulating OT levels within the range of values found after primary stimuli [i.e. breast suckling (15) or insulin-induced hypoglycemia (16)]. This phenomenon was not observed when lower doses (1 mIU/min) of OT were given, suggesting that the inhibitory effect of OT on leptin secretion might be exerted during physiological or pathological conditions, where both OT and glucocorticoid secretion are stimulated, such as stress or hypoglycemia.
Laferrère et al. (4), found synergistic stimulatory effects of feeding and dex on serum leptin levels, suggesting that endocrine (possibly insulin) and/or metabolic factors associated with food ingestion interact with dex in the stimulatory action on leptin secretion. In fact, dex was unable to stimulate leptin secretion in fasting subjects (4).
At present, we do not know where OT exerts its inhibitory activity on dex-induced leptin secretion. In fact, our in vivo model cannot establish whether OT action takes place in the digestive apparatus, where OT could interact with the endocrine/metabolic changes induced by food digestion, or directly at the adipose tissue level. OT is known to modify gastrointestinal function by inhibiting gastric motility (17); on the other hand, complex interactions in the control of adipocyte metabolism are described between OT and other hormones regulating leptin production from adipose tissue (see introduction). In vitro studies of the effect of OT on glucocorticoid-stimulated leptin production in adipocytes are needed to clarify this issue.
From a speculative point of view, the possible OT involvement in the regulation of corticosteroid-stimulated leptin secretion is intriguing. Both OT and leptin have been implicated in the modulation of food intake. A variety of studies suggest that OT may be a mediator of the anorexigenic action of leptin. In fact, leptin directly activates the paraventricular nucleus (18), where OT is produced; furthermore, leptin stimulates CRH (19, 20), which is believed to inhibit food intake through oxytocinergic pathways in the central nervous system and at the gastric level (21). In the light of these observations, the inhibition by OT of corticosteroid-stimulated leptin secretion might be supposed to play a role in the regulatory loop described by Spinedi and Gaillard (22) between the hypothalamo-pituitary-adrenal axis and circulating leptin. Further studies are needed to substantiate this hypothesis.
The additional findings in obese subjects confirm that in obesity basal serum leptin levels are higher than normal, and leptin secretion is sensitive to dex stimulation. On the other hand, OT was unable to modify the leptin response to dex, suggesting that in obesity the control mechanism of OT on leptin secretion is abolished.
Received November 23, 1999.
Revised May 19, 2000.
Accepted June 30, 2000.
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