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Physiologic effect of leptin on insulin secretion is mediated mainly through central mechanisms¹

Division of Pediatric Endocrinology, Montefiore Medical Center, Institute for Aging Research and Diabetes Research and Training Center, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA

²Correspondence: Institute for Aging Research, Department of Medicine, Belfer Bldg. #701, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA. E-mail: barzilai{at}aecom.yu.edu

SPECIFIC AIMS

Leptin, an adipocyte-derived hormone, mediates its effects on body weight and energy expenditure through its receptors in the hypothalamus. However, leptin receptors are also present peripherally in many tissues, and the relative role of central vs. peripheral receptors in various physiologic effects of leptin remains to be elucidated. Several in vitro studies on pancreatic islets and in vivo studies have demonstrated that leptin decreases glucose-stimulated insulin secretion in a dose-dependent fashion. This effect of leptin to decrease glucose-stimulated insulin secretion may play a role in the transition of insulin resistance associated with obesity to frank type 2 diabetes. Here we ask whether leptin’s effect on glucose-mediated insulin secretion is mediated through central hypothalamic receptors or the peripheral leptin receptors on the pancreatic ß cells, and if the melanocortin pathway is involved in mediating these effects downstream of leptin receptors.

PRINCIPAL FINDINGS

1. Small doses of leptin infused into the third ventricle decreases glucose-stimulated insulin secretion in a dose-dependent manner (Fig. 1)
Hyperglycemic clamp studies were done in awake, unstressed rats through intravenous (IV) and arterial catheters. The vascular catheters and intra-cerebroventricular (ICV) catheter in the third ventricle were placed under anesthesia 1 or 2 wk before the day of the study. Upon recovery from the surgery, all rats (n=32) were subjected to 5 h of moderate hyperglycemia (11 mM). 25% glucose was infused IV to raise the plasma glucose concentration acutely to 11 mM and maintained at that level for the remainder of the study. At 120 min, rats were administered 3 µL boluses of saline (n=5, control) or leptin (20 or 30 ng, n=5 for each dose) at 0.8 µL/min through ICV. Compared with saline, ICV leptin decreased glucose-stimulated insulin levels significantly (31.6±2.8 vs. 14.9± 2.3 saline vs. 30 ng leptin, respectively; P<0.005). With 20 ng of leptin ICV, glucose-stimulated insulin levels was decreased by one-third and was between that observed with saline and a high dose of leptin ICV (31.6± 2.8 vs. 22.7± 2.1 with saline vs. 20 ng leptin, respectively; P<0.05), demonstrating a dose response (Fig. 1) . This was associated with parallel decreases in C peptide levels and no change in the corticosterone levels. To examine whether these effects were similar to that achieved with physiological leptin levels, we infused IV leptin at 0.3 µg·kg^–1·min^–1. This rate of infusion achieved physiological plasma leptin levels of 17 ng/mL. At these levels glucose-mediated insulin levels decreased by one-third compared with saline (31.6±2.8 vs. 22.6±1.13 with saline vs. leptin, respectively; P<0.05). This response with the low dose leptin was similar to that achieved by 20 ng of leptin administered ICV.

View larger version (26K): [in this window] [in a new window]   Figure 1. Effect of ICV and IV leptin on serum insulin levels during a hyperglycemic clamp. Serum glucose was maintained at 11 mmol/L during hyperglycemic clamps from 0 to 300 min in saline- and leptin-treated groups. ICV leptin (20 or 30 ng) or saline was infused at 120 min of the clamp. Insulin secretion was significantly decreased in a dose-dependent fashion in the ICV leptin-treated groups (P<0.005) in the 30 ng group and (P<0.05) in the 20 ng group compared with saline. A significant decrease in insulin secretion (P<0.05) was also seen in the IV leptin group vs. saline.

2. High doses of peripheral leptin fail to decrease glucose-stimulated insulin secretion in the presence of central melanocortin receptor antagonist (Fig. 2)
A 5 h hyperglycemic clamp (11 mM) was performed in the presence of the centrally infused nonspecific melanocortin receptor antagonist SHU 9119 or saline ICV. A 3 µL bolus (0.66 nmol) of SHU 9119 was followed by a continuous infusion at 0.19 µL/min for 5 h (1.33 nmol/5 h) through ICV cannula from time 0 throughout the period of hyperglycemia clamp. In the ICV saline group, the rats received 5 µg·kg^-1·min^-1 of leptin from 120 min until the end of the study. In the SHU 9119 group, at 120 min, rats were assigned to receive either leptin (5 µg·kg^-1·min^-1) or saline by IV infusions until the end of the study. With this rate of IV leptin infusion, plasma leptin levels of 350 ng/mL were achieved. In the saline ICV group, leptin produced a 30% in the glucose-stimulated insulin levels compared with SHU9119 ICV group (14.3±1.4 vs. 21.8±2.6 in saline vs. SHU 9119 ICV, P<0.05). Insulin levels at 120 min were not significantly different between the saline and SHU 9119 ICV groups and were comparable to those observed in the studies above, suggesting that this blockage did not cause marked changes in glucose-mediated insulin secretion. In the SHU 9119 group, plasma insulin levels continued to be similar in leptin and saline IV groups for the rest of the study; infusion of leptin did not result in significant differences in glucose-stimulated insulin secretion (21.8±2.6 vs. 20.5±2.0, leptin and saline, respectively; n.s).

View larger version (30K): [in this window] [in a new window]   Figure 2. Effect of ICV SHU 9119 and IV leptin on serum insulin levels during a hyperglycemic clamp. Serum glucose was maintained at 11 mmol/L during the hyperglycemic clamp from 0 to 300 min in saline- and leptin-treated groups. In one control group, saline was infused ICV and leptin was infused IV from 120 min until the end of the study. In the SHU 9119 group, SHU 9119 was infused IV throughout the study. IV leptin (5 µg·kg–1·min–1) or saline was infused from 120 min of the clamp until the end of the study. In the presence of SHU 9119, leptin failed to produce any significant decrease in insulin secretion.

CONCLUSIONS AND SIGNIFICANCE

These studies suggest that leptin decreases glucose-mediated insulin secretion through its receptors in the hypothalamus and that the effect is mediated through the melanocortin pathway.

We had earlier demonstrated that acute physiological increase in serum leptin levels in vivo significantly reduces glucose-mediated insulin levels in rats in a dose-dependent fashion. We assumed that this effect of leptin was elicited through the leptin receptors on the ß cells of the pancreatic islets. Here we make three important additional findings and reject our initial assumption. First, very small doses of leptin administered to the third ventricle (ICV) reproduced the effect of IV leptin in a dose response manner (Fig. 1) . This dose of ICV leptin infusion was not associated with any increase in the plasma leptin levels, suggesting that these effects are mediated mainly through the central leptin receptors. Second, the effect of ICV leptin can be mimicked by elevating the peripheral plasma leptin levels to 17 ng/mL. These levels of plasma leptin are often seen in overweight humans who have insulin resistance and an increased risk of diabetes. In these individuals, insulin resistance is initially compensated for by an increase in insulin secretory capacity. However, this compensatory mechanism may fail over time, and a decrease in insulin secretion in either a relative or absolute sense contributes to the actual onset of diabetes. We speculate that the effect of leptin on insulin secretion may favor this decompensation and contribute to the pathogenesis of type 2 diabetes in obese individuals. Third, on blocking the melanocortin receptors, even though the plasma leptin levels were in the range of 350 ng/mL, there was no change in glucose-stimulated insulin secretion. Similar plasma levels of leptin had shown a dramatic decrease in glucose-stimulated insulin secretion in our previous studies in the absence of the melanocortin antagonist. This suggests that the central melanocortin receptors are activated downstream of leptin; in the presence of central melanocortin antagonists, even very high plasma levels of leptin do not affect glucose-stimulated insulin secretion. This also implies that the effect on insulin secretion is not a direct effect of leptin on the ß cells of the pancreatic islets.

In summary, this study establishes that moderate doses of leptin acutely decrease glucose-mediated insulin secretion through a central effect on the hypothalamus and that this effect may be mediated through the melanocortin receptors. It adds to the growing debate on the relative contribution of peripheral vs. central effects of leptin on variety of its actions and the role leptin in the transition of obesity and compensated insulin resistance to type 2 diabetes mellitus.

View larger version (22K): [in this window] [in a new window]   Figure 3. An increase in nutrient intake is associated with an increase in number and size of adipocyte stores and can independently contribute to an increase in plasma leptin levels (1). Leptin acts through the central leptin receptors on the hypothalamus (2) leading to a downstream activation of melanocortin receptors (3), which results in a decrease in glucose-stimulated insulin secretion (4). This effect may be mediated through increased sympathetic activity. Thus, leptin may contribution to the pathogenesis of type 2 diabetes in certain at-risk obese individuals (5). Leptin receptors on the ß cells of the pancreas do not appear to have a physiologically relevant role in the effect of leptin on glucose-stimulated insulin secretion (6).

FOOTNOTES

¹ To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.02-0991fje; to cite this article, use FASEB J. (April 22, 2003) 10.1096/fj.02-0991fje

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