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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 9 3230-3235
Copyright © 1998 by The Endocrine Society

Original Studies

Different Central and Peripheral Responses to Leptin in Rhesus Monkeys: Brain Transport May Be Limited1

Jon J. Ramsey, Joseph W. Kemnitz, Ricki J. Colman, David Cunningham and Andrew G. Swick

Wisconsin Regional Primate Research Center (J.J.R., J.W.K., R.J.C.), Institute on Aging (J.J.R.), and Department of Medicine (J.W.K.), University of Wisconsin, Madison, Wisconsin 53715-1299; and Department of Molecular Sciences (D.C.) and Metabolic Diseases (A.G.S.), Pfizer Central Research, Groton, Connecticut 06340

Address all correspondence and requests for reprints to: Jon J. Ramsey, Wisconsin Regional Primate Research Center, University of Wisconsin, 1223 Capitol Court, Madison, Wisconsin.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The purpose of this experiment was to determine the effect of leptin administration on food intake and energy expenditure in rhesus monkeys. Four adult male rhesus monkeys, cannulated in the left lateral cerebral ventricle, were used for all phases of this experiment. Food intake was measured following intracerebroventricular injections of vehicle or three doses (500 ng, 2 µg, and 22 µg) leptin. Leptin administration resulted in a dose-dependent decrease in food intake (P < 0.05), with food intake decreased by an average of 54% at 22 µg leptin. Energy expenditure was also measured at two intracerebroventricular doses of leptin. Energy expenditure was not different (P > 0.10) between placebo and leptin injections at either dose. Food intake was also measured following iv injection of 3 mg leptin. In this case, leptin did not alter (P > 0.10) food intake, despite increasing serum leptin levels by as much as 100-fold. These results suggest that leptin is a potent inhibitor of food intake in rhesus monkeys, but this effect requires elevation of leptin concentrations in the cerebrospinal fluid or critical brain sites. The transport system for movement of leptin across the blood-brain barrier may limit the influence of circulating leptin on food intake in monkeys.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE cloning of the mouse obese gene (1) and subsequent synthesis of leptin, the protein product of the gene, led to speculation that this protein may be useful as a treatment for obesity. Leptin administration to ob/ob mice has been shown to decrease body fat and normalize body weight by decreasing food intake and increasing energy expenditure (2, 3, 4). Similarly, leptin administration decreases food intake in rodents that are not genetically obese, including wild-type mice (2, 3, 4), diet-induced obese mice (4), and arctic ground squirrels (5). Subcutaneous injection of leptin to lean Zucker rat pups has also been shown to increase energy expenditure (6). These results have led to speculation that leptin administration could be useful for treatment of obesity in humans. However, studies with rodents (7, 8) and humans (8, 9) have shown that circulating leptin levels are highly correlated with body fat content, suggesting that peripheral leptin deficiency is not responsible for most cases of obesity.

It has been hypothesized that the brain is the major target organ of leptin action. Consistent with this idea, the active form of the leptin receptor has been shown to be densely concentrated in the hypothalamic region of the brain (10, 11, 12), suggesting that transport across the blood-brain barrier could limit access of leptin to hypothalamic leptin receptors and thus regulate activity of circulating leptin. This is supported by the observation that obese humans have a lower cerebrospinal fluid (CSF)/blood leptin ratio than lean individuals (13, 14). In contrast, the concept of blood brain-barrier restrictions to leptin activity is not consistent with studies that reported leptin to be active when administered peripherally to lean and obese rodents. It is possible that leptin transport into the brain is more tightly regulated in humans (and nonhuman primates) as compared with rodents. To test this idea, the effect of intracerebroventricular (ICV) and iv leptin administration on food intake was determined in rhesus monkeys. Additionally, the effect of ICV injections of leptin on energy expenditure was also evaluated.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Leptin preparation

The recombinant human leptin used for this experiment was greater than 95% pure as determined by silver-stained SDS-PAGE. Following purification, the leptin was treated with polymixin B agarose to remove endotoxin. The final endotoxin concentration was 6–12 EU/mg protein (or <0.025 endotoxin units (EU)/kg for the 22 µg ICV dose), as determined by the limulus amebocyte lysate assay. Even at the highest dose, the endotoxin level was well below the upper limit for intrathecal administration (viz. 0.2 EU/kg) established by the United States Food and Drug Administration. The authenticity of the final preparation was confirmed by both N-terminal sequence analysis and mass spectroscopy. Analytical size exclusion chromatography revealed a single peak with a retention time typical of a 16-kDa globular protein. In addition, the spectra generated from far ultraviolet circular dichroism analysis was typical of a folded protein with high helical content, whereas thermal and denaturant unfolding suggested a very high degree of conformational stability. Furthermore, the specificity of the anorectic effect was supported by the observation that the preparations of leptin were active when administered ICV (1 µg) to ob/ob mice, but inactive in db/db mice.

Experimental design and animals

Four adult, male rhesus monkeys (Table 1Go), born and raised at the Wisconsin Regional Primate Research Center, were used for this study. All phases of the experiment were approved by the Institutional Animal Care and Use Committee at the University of Wisconsin-Madison. The animals were individually caged to allow accurate measurement of food intake. The cages were constructed of stainless steel with inside dimensions of 89 cm wide x 86 cm deep x 86 cm high. The cages were fitted with food hoppers and water spigots that allowed the animals continuous access to water. The animals were maintained on a 12 h light/12 h dark cycle with lights on between 0600 and 1800 h, and room temperature was maintained at approximately 21 C. Each animal was fed a preweighed amount of monkey biscuits (5038; PMI Feeds, St. Louis, MO) at 0800 h each morning. Before the start of the experiment, food allotments for each animal were determined, which prevented excessive waste and yet normally resulted in food remaining after 24 h. At 0800 h, food remaining in the cage was collected and weighed, and the animals were given another preweighed allotment of food. Food intake was measured daily during all phases of the experiment.


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  		Table 1. Age and body composition1 of four monkeys treated with leptin

 
At least 3 weeks before the start of the experiment, all animals had a cannula (model 201–25, David Kopf Instruments, Tujunga, CA) stereotaxically implanted in the left lateral cerebral ventricle adjacent to the foramen of Munro while under halothane anesthesia. Cannulas were placed 18 mm anterior to ear bar zero, 3 mm left of the midline, and lowered to 18–20 mm below the dura. The cannulas were attached to the skull using stainless steel screws and dental acrylic. Cannula placement was verified by observing water consumption following angiotensin injection in the cannula or visualizing the ventricle with the injection of a radiopague dye.

Food intake and energy expenditure were measured following ICV injections (40 µL) vehicle (phosphate buffer) or leptin at doses of 500 ng and 22 µg. Additionally, food intake measurements were made following ICV injections of vehicle and 2 µg leptin. The doses used in this experiment were selected after dose tests in the monkeys had shown that these amounts of leptin consistently decreased food intake without any signs of harmful side effects. One animal was removed from the ICV portion of the experiment following the 500-ng injection phase because of cannula problems. The monkeys were given ICV injections of vehicle, leptin, and vehicle on consecutive days. Measurements of food intake and energy expenditure were completed on the same day.

A peripheral injection of 3 mg leptin was given to all four animals 2 weeks after the completion of the ICV portion of the experiment. On the first day, the animals were given an iv injection of vehicle, and blood samples were collected at 5 min and 6 h following injection. A single iv leptin injection was then given on the second day, and blood samples were again collected at 5 min and 6 h following injection. On the third day, only food intake measurements were collected for each animal. All blood samples were collected from the saphenous vein into Vacutainer tubes. Blood samples were analyzed for leptin using a RIA kit (Primate Leptin RIA Kit, LINCO, St. Louis, MO) that does not differentiate between rhesus and human leptin.

Indirect respiration calorimetry

Oxygen consumption and carbon dioxide production were measured by indirect respiration calorimetry. The monkeys were placed in the calorimetry chambers and allowed to adapt to their surroundings for at least 2 days before the start of calorimetry measurements. The calorimetry chambers had inside dimensions of 75 cm wide x 75 cm deep x 80 cm high, and the animals were able to see and hear other animals the entire time that they were in the chambers.

Air was drawn through the chambers and flow rate was measured by a mass flowmeter (FMA-408; Omega, Stamford, CT). The chamber exhaust was continuously sampled at a rate of 100 mL/min (Flow Control R-1; Ametek, Pittsburgh, PA) for analysis of O2 content (Oxygen Sensor N-22 M and Oxygen Analyzer S-3A/I; Ametek, Pittsburgh, PA), CO2 content (Carbon Dioxide Sensor P-61B and Carbon Dioxide Analyzer CD-3A), and temperature and humidity (RH411 Digitial Thermo-Hygrometer; Omega). Outputs from the analyzers and mass flowmeter were recorded every 10 min with the use of a Flash 12 data acquisition system (Strawberry Tree, Sunnyvale, CA) and Diversified Systems 486 PC (Middleton, WI). The chambers were calibrated by burning ethanol lamps and measuring the recovery of oxygen and carbon dioxide in the system.

Energy expenditure was calculated using 16.50 kJ/L oxygen consumed plus 4.63 kJ/L carbon dioxide produced (15). For analysis, energy expenditure was divided into daytime (0600–1800 h), nighttime (1800–0600 h), and 24-h measurements.

Statistical analyses

Food intake differences with ICV treatments were examined by analysis of covariance (SAS system software, SAS Institute, Cary, NC). Energy expenditure and all measurements following iv leptin administration were compared using paired Student’s t test. All values are presented as means ± SE.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
ICV injection of leptin, analyzed across dose, resulted in a significant decrease in food intake (P = 0.006) when compared with injection of vehicle. The decrease in food intake was dose dependent, with the greatest decrease occurring at the highest leptin dose. Dose was shown to have a significant effect on food intake, with the 500-ng and 22-µg doses showing different (P = 0.026) responses to leptin treatment (Fig. 1Go). Leptin administration resulted in an average food intake decrease of 36% at 500 ng (P = 0.131), 33% at 2 µg (P = 0.066), and 54% at 22 µg (P = 0.031). The large SE (Fig. 1Go) associated with the food intake measurements reflected the large differences in response to leptin by individual monkeys. One animal did not show a food intake response to leptin at either the 500-ng or 2-µg dose, whereas food intake was decreased by at least 28% in all other animals at each leptin concentration. Overall, food intake response to leptin was consistent within animal, with individuals that showed a decrease at the 500-ng dose showing a similar or larger leptin response at the other doses. In addition to dose-related changes in 24-h food intake, the duration of response to ICV leptin also appeared to be related to dose (Fig. 2Go). Food intake was reduced for only 1 day following the 500-ng leptin dose, whereas it remained suppressed in some animals for 2 days following the 22-µg dose. The percent body fat of the animals used in this experiment ranged from 13.9–34.1%, however, there was no detectable relationship between body composition and food intake with ICV leptin treatment.



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  		Figure 1. Mean (±SE) values for percent decrease in food intake following 500 ng (n = 4), 2 µg (n = 3), or 22 µg (n = 3) ICV leptin treatments compared with previous vehicle treatment. Bars with different letters (a or b) differ (P < 0.05) as determined by analysis of covariance.

 


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  		Figure 2. Mean (±SE) values for 24-h food intake following ICV injections of vehicle, 500 ng leptin (n = 4), or 22 µg leptin (n = 3) in rhesus monkeys. **, Indicates difference (P < 0.05) between food intake following leptin injection and food intakes following preceding vehicle injection, as determined by analysis of covariance.

 
In addition to food intake measurements, energy expenditure was measured for 24 h following ICV injections of either vehicle or leptin (500-ng and 22-µg doses). Energy expenditure was not different (P > 0.10) between vehicle and leptin ICV injections at either leptin dose or at any period of the day (Fig. 3Go).



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  		Figure 3. Daytime (0600–1800 h), nighttime (1800–0600 h), and 24-h energy expenditure following ICV injection of vehicle, 500 ng leptin (n = 4), and 22 µg leptin (n = 3) in rhesus monkeys. There were no significant differences (P > 0.10) between vehicle and leptin treatment at any time period as tested by paired t test. (V = vehicle, L = leptin)

 
All of the animals used in the ICV portion of the experiment were also given a single iv injection of 3 mg leptin. Peripheral administration of leptin did not significantly (P = 0.63) alter food intake (Fig. 4Go). In addition to food intake measurements, serum leptin concentrations were measured at 5 min and 6 h following the peripheral injection of leptin. Serum leptin concentrations were increased by as much as 100-fold 5 min after iv leptin injection, and these concentrations remained elevated by approximately 4-fold 6 h after the injection (Fig. 5Go), when compared with average leptin concentrations for morning and afternoon measurements in the monkeys following iv injection of vehicle.



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  		Figure 4. Twenty four-hour food intake following vehicle (iv injection of phosphate buffer), leptin (iv injection of 3 mg leptin), and control (no injections) treatment in four rhesus monkeys. There were no significant differences (P > 0.10) between treatments using paired t test.

 


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  		Figure 5. Total serum leptin concentrations in rhesus monkeys (n = 4) following iv injections of vehicle or human leptin: am = values obtained from serum samples taken 5 min after injection, pm = values obtained from serum samples taken 6 h after injection, V = average values for leptin following injection of vehicle, L = average values for leptin following injection of human leptin. Values above bars are means for each experimental phase. SE bars were too small to be seen in all phases except L (am).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Leptin administration to ob/ob mice has been shown to dramatically decrease food intake, contributing to an overall loss in body weight primarily through the loss of fat mass (2, 3, 4, 16, 17). Leptin administration has also been shown to decrease food intake in other rodents, including wild-type mice (2, 3, 4, 18), diet-induced obese mice (4), lean rats (19, 20), and arctic ground squirrels (5). These results have led to speculation that leptin will have similar anorectic effects in species other than rodents, and ultimately provide a useful treatment for obesity in humans. The present study demonstrates that leptin can strongly inhibit food intake in rhesus monkeys. These results suggest that elevated concentrations of CSF leptin have an anorectic effect in a primate species and could promote weight loss through this decrease in food intake.

ICV leptin administration resulted in a potent, dose-dependent decrease in food intake. The decrease in food intake following ICV leptin injection in rhesus monkeys was similar to the results obtained for lean strains of rodents receiving similar absolute ICV leptin amounts (4, 10, 19, 20). This suggests that the monkeys used in this experiment were at least as sensitive to exogenous leptin administration as the previously studied lean rodent strains. The anorectic effect of ICV leptin administration lasted for 1 day with the lowest leptin doses, whereas the highest dose resulted in a 2-day suppression of food intake in some animals. This result is consistent with ICV leptin injection studies in rodents which have shown that a single injection can induce an inhibition of food intake for 2 days (19, 20).

Individual differences in food intake response to ICV leptin administration were observed between monkeys. These differences in response to leptin could reflect either differences in leptin sensitivity or slight differences in cannula location within the left cerebral ventricle, which could effect leptin concentration at target sites. Different strains of mice have been shown to differ in their response to central or peripheral leptin infusions (21), and studies in humans have shown variability in serum leptin concentrations between individuals with similar body fat percentages (9). These results suggest that individuals do show large differences in their sensitivity to leptin. In addition to differences in sensitivity to leptin, slight differences in cannula location within the left ventricle could potentially contribute to the observed responses to leptin administration. Experiments have shown that leptin activates the paraventricular nucleus (22, 23) and ventrobasal (23) region of the hypothalamus. It is possible that slight differences in cannula location could influence leptin concentration around these or other critical sites and thus contribute slightly to the observed differences in response to leptin.

Energy expenditure was not different between placebo and leptin ICV treatments. Considering that food intake was substantially decreased during these measurements, a decrease in the thermic effect of feeding would have been expected. Because thermic effect of feeding is related to energy intake and responsible for 10–15% of total energy expenditure, a 3–8% decrease in energy expenditure would have been predicted with the decreases in food intake observed with leptin treatment. A slight increase in energy expenditure of less than 10% may have obscured this decrease in the thermic effect of feeding. A previous study with lean and obese strains of mice also showed that leptin does not increase energy expenditure but prevents the decrease in energy expenditure following a decrease in food intake (21). Studies have shown that leptin dramatically increases oxygen consumption and energy expenditure (2, 16) in ob/ob mice, but large increases in energy expenditure generally have not been reported with leptin treatment in other strains of mice. These results suggest that large, leptin-associated changes in energy expenditure may be unique to the leptin deficiency disorder in ob/ob mice, whereas in other animal models, leptin may result in only a slight increase (<10%) in energy expenditure that counteracts the decrease in thermic effect of feeding.

In contrast to the ICV results, a single peripheral injection of leptin did not alter food intake despite the fact that serum leptin levels were elevated by as much as 100-fold following the injection. Studies in mice have demonstrated that some animals are resistant to peripheral leptin, but respond to central leptin administration (21, 24). Experiments with human volunteers have shown that obese individuals have a lower leptin CSF/serum ratio than lean individuals, suggesting a saturable transport system from the blood to the CSF (13, 14). In support of this idea, evidence for a saturable leptin-specific receptor for endocytosis across the blood-brain barrier has been found in isolated human brain capillaries (25). The presence of a saturable transport system from the blood to the CSF could explain how large increases in serum leptin concentration with obesity are associated with smaller changes in CSF leptin levels. Failure of iv leptin administration to inhibit food intake in monkeys suggests that saturation of the system for transportation of leptin across the blood-brain barrier may limit the ability of peripheral leptin to regulate food intake. It is also possible that binding proteins may play a role in limiting the action of peripheral leptin. It has been reported that a soluble isoform of the leptin receptor acts as a binding protein and may inhibit leptin interaction with its receptor (26). Binding proteins may play a role in preventing peripheral leptin from interacting with receptors or transport proteins needed for movement into the CSF, however, additional research is needed to determine the role these proteins may play in regulating the action of circulating leptin.

It has been proposed that the primary physiological function of leptin may not be as a signal of adiposity and regulator of food intake, but as a regulator of the neuroendocrine system during starvation (27). Studies in humans (28, 29) and mice (27) have shown that short-term fasting results in a rapid decrease in blood leptin levels, despite the fact that body fat content is only slightly decreased during this time. Leptin administration to fasted mice blunts many of the thyroid, adrenal, and reproductive hormone changes (27) with this condition. It is possible that the body rapidly responds to a decrease in leptin concentrations, whereas it is resistant to leptin concentrations above those measured in the fed state. Increases in leptin transporter numbers may be required for food intake response to high doses of leptin. Our study demonstrates that food intake in rhesus monkeys is rapidly altered by central but not peripheral leptin administration. It is possible that increased leptin receptor concentrations are needed for effective transport of leptin from the blood to the CSF. The obese Koletsky rat has nearly complete absence of leptin receptor messenger RNA in the brain, and has been shown to have greatly reduced ratio of CSF/plasma leptin when compared with lean animals (30). These results suggest that leptin receptor concentrations in critical brain sites play an extremely important role in regulating leptin transport from the blood to CSF. The obese Koletsky rat, however, has similar CSF leptin concentrations as lean rats, indicating that at least some leptin can enter the brain through a pathway separate from the leptin receptor. The failure of this pathway to increase CSF leptin concentrations above normal levels in obese rats with peripheral hyperleptinemia has led to speculation that this pathway is saturated at normal physiological plasma leptin concentrations (30). It is possible that long-term exposure to high peripheral leptin concentrations could influence food intake by inducing leptin receptor synthesis or by some other adaptive mechanism. In the short term, however, the blood brain barrier may prevent rhesus monkeys from responding to leptin levels above those in the fed state.

Overall, ICV doses of as little as 500 ng leptin tended to decrease food intake, whereas a peripheral dose sufficient to elevate serum leptin concentrations up to 100-fold above baseline concentrations and maintain elevated leptin for at least 6 h had no effect on food intake in rhesus monkeys. These results suggest that leptin is a potent regulator of food intake in rhesus monkeys, but is only effective when concentrations are elevated in the CSF. The transport system for movement of leptin across the blood-brain barrier appears to limit the effective regulation of food intake by peripheral administration of leptin to monkeys. Additional research on this transport system will probably be needed before leptin may be successfully used for the treatment of obesity.


   Acknowledgments
 
We thank Drs. D. Fryburg, R. Garofalo, and R. Stevenson for careful review and comments on the manuscript. We also thank J. Spitzer and S. Baum for technical assistance.


   Footnotes
 
1 This research was supported by grants from Pfizer and NIH Grants RR-00167 and AG-11915. Back

Received April 2, 1998.

Revised May 8, 1998.

Accepted May 21, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals