Chronic central administration of ghrelin reverses the effects of leptin

Abstract

OBJECTIVE: To determine whether chronic central administration of ghrelin can block the effects of leptin on food intake, adiposity, and plasma concentrations of metabolic parameters and hormones.

DESIGN: Intracerebroventricular (ICV) infusions of leptin (5 μg/day) for 7 days, with or without ghrelin (1.2 μg/day), in rats. Rats administered leptin plus ghrelin were divided into ad lib-fed and food-restricted groups.

MEASUREMENT: Body weight and food intake were monitored daily. Following killing on day 8, epididymal fat weight and fasting plasma concentrations of glucose, insulin, leptin, ghrelin, IGF-1, and adiponectin were determined.

RESULTS: ICV infusion of leptin decreased food intake by 39% and fat weight by 41%. Leptin decreased plasma concentrations of glucose, insulin, and leptin and increased plasma ghrelin levels. Central coadministration of ghrelin blocked the effects of leptin. Most of the effects of ghrelin were diminished by food restriction but ghrelin effect on adiposity and plasma insulin concentrations remained in food-restricted rats.

CONCLUSION: Chronic central administration of ghrelin reversed the effects of leptin, primarily by altering food intake, but ghrelin may have regulatory effects on adiposity and plasma insulin levels independent of feeding effect.

Introduction

Ghrelin, a stomach-derived hormone, has a potent orexigenic effect when administered to humans and rodents,1, 2 and repeated administration of ghrelin has been shown to increase adiposity in rodents.3, 4 The ghrelin receptor is expressed in the arcuate nucleus (ARC) and ventromedial nucleus (VMH) of the hypothalamus,5 important sites for the regulation of food intake and energy metabolism. Ghrelin increases food intake by activating neuropeptide Y (NPY) neurons, resulting in the increased production of NPY.1, 6

One of the principal mediators signaling adiposity to the hypothalamus is leptin.7 Levels of plasma leptin have been shown to increase in proportion to fat mass,8 whereas central or peripheral administration of leptin inhibits food intake and reduces body weight.9 The long form of the leptin receptor (ob-Rb) is abundantly expressed in the ARC.10 In contrast to ghrelin, leptin inhibits NPY neurons10 and stimulates neurons producing anorexigenic proopiomelanocortin (POMC).11 Thus in the context of energy homeostasis, leptin and ghrelin have opposite effects on hypothalamic neurons.

In addition to regulating food intake, leptin and ghrelin have multiple metabolic actions through the central nervous system. Central administration of leptin suppresses insulin secretion from the pancreas,12 increases glucose uptake in peripheral tissues, and modulates hepatic glucose production.13, 14, 15, 16 Chronic intracerebroventricular (ICV) administration of ghrelin has been reported to increase the 24-h respiratory quotient without altering energy expenditure or locomotor activity.3 It is not clear, however, if these alterations are associated with the changes in body weight and fat mass resulting from ICV administration of ghrelin. It is also not clear whether ghrelin can antagonize the metabolic actions of leptin. We therefore sought to determine if chronic ICV administration of ghrelin could block the effects of leptin on food intake, adiposity, peripheral blood metabolic parameters, and hormonal levels. We also investigated the effect of ICV ghrelin administration on metabolic parameters in food-restricted animals to determine whether the metabolic effects of ghrelin are mediated by a mechanism separate from its effects on food intake.

Methods

Peptides

Biologically active rat ghrelin was purchased from Phoenix Pharm. Inc. (Mountain View, CA, USA). Mouse leptin was obtained from R&D Systems Inc. (Minneapolis, MN, USA).

Animals

Male Sprague–Dawley rats weighing 300–350 g were maintained at ambient temperature (22±1°C) and with 12:12-h light–dark cycles (lights on 0700 h) with free access to water and rat chow unless otherwise indicated. All procedures were approved by the Institutional Animal Care and Use Committee at the Asan Institute for Life Sciences, Seoul, Korea.

Surgery

Animals, anesthetized by intraperitoneal (i.p.) injection of 100 mg/kg ketamine and 20 mg/kg xylazine, were implanted with permanent 26-gauge stainless-steel cannulae (Plastics One Inc., Roanoke, VA, USA) into the third cerebral ventricle (ICV) as previously described.17 Following a 7 day-recovery period, correct positioning of each cannula was confirmed by a positive dipsogenic response to ICV administration of angiotensin II (150 ng/rat). Positive dipsogenic response was defined as the consumption of 5 ml of water within 1 h of injection.

On day 8, the animals were anesthetized with i.p. injection of sodium pentobarbital (65 mg/kg), and each was surgically implanted with an Alzet osmotic minipump (Alza Corp. Palo Alto, CA, USA) filled with saline or peptides by insertion under the skin over the dorsal chest. A catheter from the minipump was connected into the ICV cannula through a subcutaneous tunnel.

Study design

Study 1. Chronic ICV administration of leptin with or without ghrelin on food intake, adiposity, and plasma concentrations of metabolic parameters and hormones

Animals with positive dipsogenic responses were randomized into four groups of 6–7 rats each. The control group received ICV infusions of saline for 7 days; the leptin group received ICV infusions of leptin (5 μg/day) for 7 days; the leptin plus ghrelin ad lib group received ICV infusions of leptin (5 μg/day) and ghrelin (1.2 μg/day) for 7 days, and were allowed free access to rat chow; and the leptin plus ghrelin pairfed group received ICV infusions of leptin (5 μg/day) and ghrelin (1.2 μg/day) for 7 days, but were allowed to eat only as much chow as consumed by the leptin group on the previous day. Chow was provided at the beginning of the dark phase, a physiological feeding period. The dose of leptin administered was determined on the basis of the previous study.18 The dose of ghrelin used was determined in our preliminary study, which was able to reverse the leptin effect on food intake. Body weight and food intake were monitored daily at the early light period.

On day 8, the rats were fasted from the early light cycle for 5 h and killed during the mid-light cycle under sodium pentobarbital anesthesia. Epididymal fat tissue was dissected and weighed. Blood was collected from the inferior vena cava, and plasma was quickly separated by centrifugation and stored at −80°C.

Study 2. Chronic ICV administration of ghrelin alone on food intake, adiposity, and plasma concentrations of metabolic parameters and hormones

To further investigate the effect of ghrelin alone on food intake, adiposity, and plasma metabolic parameters and hormones, we performed a separate experiment. Animals with positive dipsogenic responses were randomized into three groups (n=8–9 per group). The control group received ICV infusions of saline for 7 days; the ghrelin/ad lib group received ICV infusions of ghrelin (1.2 μg/day) for 7 days and were allowed free access to rat chow; and the ghrelin/pairfed group received ICV infusions of ghrelin (1.2 μg/day) for 7 days, but were allowed to eat only as much chow as consumed by the control group on the previous day. Pairfeeding was conducted by the same method as of study 1. Body weight and food intake were monitored daily at the early light phase. On day 8, the rats were killed and blood was collected by the same method as of study 1.

Analysis of blood samples

Plasma glucose was determined using a glucose analyzer (YSI 2300; Yellow Springs Instruments, Yellow Springs, OH, USA). Plasma insulin, leptin, IGF-1, and adiponectin concentrations (Linco, St Louis, MO, USA) and plasma ghrelin concentrations (Phoenix Pharm. Inc.) were determined by radioimmunoassay.

Data analysis

Data are presented as mean±s.e. Differences between the groups were analyzed by ANOVA, followed by post hoc least significance difference. We considered values of P<0.05 to be statistically significant.

Results

ICV administration of ghrelin reverses leptin effect on food intake, body weight, and adiposity

Chronic ICV infusion of leptin decreased food intake (Figure 1a). This reduction was significant from the second day of leptin infusion and was sustained throughout the study period. The average food intake in the control group was 24.1 g/day, whereas the average food intake in the leptin group was 14.5 g/day (P<0.05). In contrast, the average food intake in the leptin plus ghrelin ad lib group (22.8 g/day) did not differ significantly from that in the control group.

Figure 1
figure1

Effects of ICV infusion of leptin and leptin plus ghrelin on (a) daily food intake and (b) body weight. Four groups of rats (6–7 per group) were infused for 7 days with saline, leptin, or leptin plus ghrelin. Rats infused with leptin plus ghrelin were ad lib-fed or pairfed to leptin-infused rats. *P<0.05; **P<0.01 vs saline and leptin plus ghrelin ad lib-fed groups. (c) Epididymal fat weights at the end of the study. *P<0.05 vs saline group, P<0.05 vs leptin group. The P-values between indicated groups are also shown.

ICV administration of leptin for 7 days resulted in a 12% reduction in body weight. On day 7, the average weight in the control group was 356.7±7.6 g, while the average weight in the leptin group was 315.2±9.7 g (P<0.005, Figure 1b). Epididymal fat weight was also significantly lower in the leptin group (1.6±0.3 g) than in the control group (2.6±0.1 g, P<0.05, Figure 1c). While body weight in the leptin plus ghrelin ad lib group on day 7 (354.7±5.0 g) was not significantly different from that in the control group (Figure 1b), epididymal fat weight in the leptin plus ghrelin ad lib group (3.6±0.2 g) was significantly greater than that of the leptin (P<0.005) and control groups (P<0.05, Figure 1c).

Rats in the leptin plus ghrelin pairfed group consumed the same amount of food (average intake, 14.0 g/day) as that consumed by the leptin group (14.5 g/day) throughout the 7-day study period (P=NS, Figure 1a). At the end of the study, body weight in the leptin plus ghrelin pairfed group was similar to that of the leptin group (Figure 1b), but epididymal fat weight was higher in leptin plus ghrelin pairfed group (2.3±0.2 g) than in the leptin group (P<0.05, Figure 1c).

Effects of ICV administration of leptin with or without ghrelin on plasma levels of metabolic parameters and hormones

Fasting plasma concentrations of glucose, insulin, and leptin were lower, and plasma ghrelin concentrations were higher in the leptin group than in the control group (Figure 2a–d). Coadministration of ghrelin completely reversed the effects of leptin on plasma insulin, leptin, and ghrelin concentrations, but did not reverse the effects of leptin on plasma glucose levels (Figure 2a–d). While chronic ICV administration of leptin decreased plasma IGF-1 levels, this was not reversed by coadministration of ghrelin (Figure 2e). In contrast, plasma adiponectin concentrations were not altered by ICV administration of leptin, in either the presence or absence of ghrelin (Figure 2f).

Figure 2
figure2

Plasma concentrations of (a) glucose, (b) insulin, (c) leptin, (d) ghrelin, (e) IGF-1, and (f) adiponectin following ICV infusion for 7 days with saline, leptin, or leptin plus ghrelin. *P<0.05, **P<0.005 vs saline group. P<0.05 vs leptin group. The P-values between indicated groups are also shown. C; saline-infused control group, L; leptin-infused group, L+G ad lib; leptin and ghrelin-infused and ad lib-fed group, L+G pairfed; leptin and ghrelin infused and pairfed to leptin group.

Plasma glucose and leptin levels in the leptin plus ghrelin pairfed group were reduced to the levels of the leptin group (Figure 2a and c). Ghrelin-induced changes in plasma insulin and ghrelin levels were not completely reversed by food restriction (Figure 2b and d). In contrast, plasma IGF-1 and adiponectin concentrations were unaltered by food restriction (Figure 2e and f).

Effect of ICV-administered ghrelin on food intake, body weight and adiposity

Food intake increased in rats that received chronic ICV infusion of ghrelin compared to rats that received saline throughout the study period (Figure 3a). Body weights in the ghrelin/ad lib group were higher compared with the control group from the 4th study day to the end of the study (Figure 3b). Epididymal fat weight was also significantly higher in the ghrelin ad lib group (3.2±0.2 g) than in the control group (2.5±0.1 g, P<0.01, Figure 3c).

Figure 3
figure3

Effects of ICV ghrelin infusion on (a) daily food intake and (b) body weight. Three groups of rats (8–9 per group) were infused for 7 days with saline or ghrelin. Rats infused with ghrelin were ad lib fed or pairfed to saline-infused rats. *P<0.05; **P<0.01 vs saline and ghrelin pairfed groups. (c) Epididymal fat weights at the end of study. *P<0.05, **P<0.01 vs saline group, P<0.05 vs ghrelin ad lib-fed group.

The ghrelin pairfed group consumed the same amount of food as that consumed by the control group (Figure 3a). At the end of the study, body weight in the ghrelin pairfed group was similar to that of the control group (Figure 3b), but epididymal fat weight was higher in the ghrelin pairfed group (2.9±0.1 g) than in the control group (P<0.05, Figure 3c).

Effect of ICV-administered ghrelin on plasma levels of metabolic parameters and hormones

Fasting plasma insulin concentrations were higher in both ghrelin ad lib and ghrelin pairfed groups than in the control group (Figure 4b). Plasma leptin levels were also higher in the ghrelin ad lib group than in the control group, but decreased in the ghrelin pairfed group to the levels of the control group (Figure 4c).

Figure 4
figure4

Plasma concentrations of (a) glucose, (b) insulin, (c) leptin, (d) ghrelin, (e) IGF-1 and (f) adiponectin following ICV infusion with saline or ghrelin for 7 days. *P<0.05, **P<0.01 vs saline group. P<0.05 vs ghrelin ad lib-fed group. C; saline-infused control group, G ad lib; ghrelin-infused and ad lib-fed group, G pairfed; ghrelin-infused and pairfed to the control group.

There was no significant difference in plasma glucose, ghrelin, IGF-1, and adiponectin levels between the three groups (Figure 4a, d–f).

Discussion

We have shown here that chronic ICV administration of leptin significantly reduced food intake, body weight gain, and visceral fat mass in rats. This finding is in agreement with previous studies demonstrating that leptin causes anorexia and weight loss through a central mechanism.9, 19 We also showed that chronic coadministration of ghrelin could completely block the effects of leptin on food intake, body weight, and visceral adiposity, indicating that leptin and ghrelin act on a common pathway regulating food intake and body weight.

Chronic central administration of ghrelin has been shown to induce adiposity by stimulating food intake and by increasing the respiratory quotient.3 We showed here that ICV administration of ghrelin increased food intake and body weight and completely blocked leptin-induced decreases in food intake and body weight. We also found that ICV ghrelin administration increased epididymal fat and prevented loss of epididymal fat induced by ICV leptin treatment. Restricted food intake reversed the effects of ghrelin on body weight but ghrelin’s effect on epididymal fat mass was not completely abolished by food restriction. These findings suggest that mechanisms other than hyperphagia may mediate ghrelin-induced increases in fat weight.

Besides its critical role in body weight regulation, leptin is involved in the central regulation of glucose metabolism.13, 14, 15, 16 We found that chronic central administration of leptin decreased fasting plasma glucose concentrations, a finding consistent with previous results showing that chronic central administration of leptin decreased fasting plasma glucose levels in normal and diabetic rats.20 Centrally administered leptin has also been shown to stimulate glucose uptake to the peripheral tissue13, 14 and to increase glucose turnover,15 which may result in decreased plasma glucose levels. In contrast, coadministration of ghrelin did not reverse the reduction in glucose levels caused by chronic leptin administration. Moreover, chronic ICV administration of ghrelin alone did not change plasma glucose levels.

Leptin and ghrelin may also be involved in the central regulation of insulin secretion. Central infusion of leptin was recently shown to suppress glucose-stimulated insulin secretion acutely through a central melanocortin receptor,12 and we observed that chronic ICV administration of leptin decreased plasma insulin levels. Ghrelin has been found to stimulate insulin secretion directly from cultured pancreas islets,21 and we found that chronic ICV administration of ghrelin increased plasma insulin levels and reversed the leptin-induced reduction in insulin levels. We also observed that the effect of ghrelin on plasma insulin levels was not completely attenuated by food restriction. Taken together, these data suggest that ghrelin has a stimulatory effect on insulin secretion through both central and peripheral mechanisms.

We also showed that ICV administration of leptin reduced fasting plasma leptin levels by about 70%. This reduction may reflect loss of adipose tissue. However, it was greater than that expected from loss of body weight (12%) or visceral fat mass (39%), suggesting the likely existence of a negative feedback loop between the central leptin signal and leptin production by adipose tissue. In line with this finding, plasma leptin concentrations and leptin mRNA expression in adipose tissue increased in Zucker fatty rats, which have an inactive leptin receptor.22 Moreover, leptin has been shown to stimulate sympathetic outflow to the peripheral organs including adipose tissue,23 and catecholamines have been found to decrease leptin secretion in vitro and in vivo.24, 25 We observed, however, that centrally administered ghrelin increased plasma leptin levels and blocked the leptin-induced decrease in plasma leptin levels, but that this effect was almost abolished by food restriction. These results suggest that ICV administration of ghrelin does not have a specific effect on leptin production or secretion.

Although plasma ghrelin level is reciprocally associated with body fat mass26 and is altered by feeding state,3, 27, 28 the mechanism that regulates the biosynthesis and secretion of ghrelin remains to be clarified. We have shown here that plasma ghrelin levels were increased in leptin-treated animals. Intraperitoneal administration of leptin for 5 days was found to increase ghrelin mRNA expression in the gastric fundus.29 Thus, leptin could have a stimulating effect on ghrelin production or secretion through a centrally mediated mechanism. However, elevated plasma ghrelin levels in leptin-treated rats could result from leptin-induced reduction in body weight and fat mass. A short-term study will be warranted to clarify the effect of leptin on ghrelin production or secretion.

In our study, chronic coadministration of ghrelin and leptin decreased leptin-induced elevation in plasma ghrelin levels, while ICV administration of ghrelin alone did not change plasma ghrelin levels. Thus, a reduction in plasma ghrelin levels in the leptin plus ghrelin ad lib-fed group could be due to an increase in food intake and fat mass. Again, higher plasma ghrelin levels in the leptin plus ghrelin pairfed group compared to the leptin plus ghrelin ad lib-fed group could be a secondary change to food restriction.

Since both leptin and ghrelin have been shown to stimulate acutely the secretion of growth hormone,30, 31 we expected that plasma IGF-1 levels would increase following chronic treatment of leptin and/or ghrelin. We found, however, that plasma IGF-1 levels were decreased by chronic ICV administration of leptin and that this was not counteracted by coadministration of ghrelin. Furthermore, chronic ICV administration of ghrelin did not affect plasma IGF-1 levels. Thus, long-term treatment with both peptides does not seem to be an effective treatment modality to increase plasma IGF-1 levels.

Adiponectin, also called AdipoQ or Acrp30, is an abundant serum adipocytokine secreted exclusively by differentiated adipocytes.32 Plasma adiponectin levels are reciprocally related to fat mass,33 and reduced plasma adiponectin levels in obese subjects are related to the development of insulin resistance.34 When we tested the effects of chronic ICV leptin and ghrelin on plasma adiponectin levels, we found that these hormones did not alter plasma adiponectin levels.

Our study may have several limitations. First, we investigated the effect of ghrelin in pairfed animals to exclude the metabolic and hormonal changes secondary to alteration in food intake. However, pairfed animals had meal patterns different from those of ad lib-fed animals, although they consumed the equal amount of food that might affect the plasma levels of metabolic parameters and hormones. Second, since the normal concentrations of leptin and ghrelin in the CSF is 2 order and an order of magnitude lower than the plasma levels, respectively,35, 36 we cannot exclude the possibility that the supraphysiologic concentrations of leptin and ghrelin administered into the cerebroventricle cause leakage of peptide into the systemic circulation and result in unphysiologic effects. Third, ICV administration of leptin and ghrelin is allowed to diffuse freely to several brain lesions with unknown receptor populations so that the effects observed could be nonspecific.

In summary, we have shown that chronic ICV administration of ghrelin could antagonize the effect of ICV leptin on food intake, adiposity, and plasma concentrations of glucose, insulin, leptin, and ghrelin. Food restriction diminished most of the effects of ghrelin. but did not completely reverse ghrelin-induced increases in adiposity and plasma insulin concentrations. Moreover, chronic ICV administration of ghrelin alone increased fat mass and plasma insulin levels even in food-restricted animals. Therefore, an increase in food intake is the main mechanism behind ghrelin effects, but ghrelin may have regulatory effects on adiposity and plasma insulin levels independent of feeding effect.

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Acknowledgements

This work was supported by an NRL grant from the Ministry of Science and Technology (M1-0104-00-0103) and a grant from the Korean Ministry of Health & Welfare (03-PJ1-PG1-CH05-0005) and Asan Institute of Life Sciences (2002-326).

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Correspondence to K-U Lee.

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Kim, M., Namkoong, C., Kim, H. et al. Chronic central administration of ghrelin reverses the effects of leptin. Int J Obes 28, 1264–1271 (2004). https://doi.org/10.1038/sj.ijo.0802647

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Keywords

  • ghrelin
  • leptin
  • intracerebroventricular
  • food intake
  • adiposity
  • metabolic effect

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