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Am J Physiol Regul Integr Comp Physiol 275: R478-R484, 1998;
0363-6119/98 $5.00
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Vol. 275, Issue 2, R478-R484, August 1998

Neural site of leptin influence on neuropeptide Y signaling pathways altering feeding and uncoupling protein

Catherine M. Kotz1,2, Jacqueline E. Briggs2, James D. Pomonis3, Martha K. Grace4, Allen S. Levine1,2,4,5, and Charles J. Billington2,4

Minnesota Obesity Center, Departments of 1 Food Science and Nutrition, 5 Psychiatry, 2 Medicine, and 3 Neuroscience, University of Minnesota, Saint Paul 55108; and 4 Veterans Affairs Medical Center, Minneapolis, Minnesota 55417

    ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

Inhibition of a signal that produces positive energy balance involving neuropeptide Y (NPY) projection from arcuate nucleus (Arc; site of NPY synthesis) to paraventricular nucleus (PVN; site of NPY release) is one potential mechanism of leptin action. NPY in the PVN increases feeding and decreases uncoupling protein (UCP) activity in brown fat, whereas leptin decreases NPY biosynthesis in the Arc, which presumably decreases PVN NPY. It is hypothesized that decreased NPY activity is necessary for the satiety and thermogenic effects of leptin. To test this, we first determined the effect of leptin on feeding in two paradigms: satiated rats and food-deprived rats. Leptin was effective in decreasing feeding in the satiated rats but ineffective in the food-deprived rats. Next, we determined that leptin decreases NPY and increases UCP gene expression. Finally, we injected leptin intracerebroventricularly before specific PVN NPY microinjection. We found that repletion of NPY in PVN by specific NPY microinjection reverses the feeding-inhibitory and thermogenic effects of centrally administered leptin, the first functional evidence indicating that leptin acts on the Arc-PVN feeding-regulatory pathway.

paraventricular nucleus; arcuate nucleus; gene expression; food intake; brown adipose tissue

    INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

STRONG EVIDENCE NOW supports the concept that leptin, secreted by adipose tissue, provides an important source of information about the size of adipose stores to the central energy regulatory processors in the brain (24, 40). The serum concentrations of leptin are highly correlated with adipose stores (30, 33). Peripheral or central leptin administration results in decreased feeding in normal and genetically obese mice but not in db/db (diabetic) mice (6, 15, 24, 37). Central leptin also decreases feeding in normal rats (27, 31, 38). Leptin receptor is expressed at many brain sites, although current evidence suggests that the most important functional site for leptin signal reception is in the arcuate nucleus (Arc) of the hypothalamus (29, 31, 37). Messenger RNA for leptin receptors are located in hypothalamic brain areas involved in energy balance, including the Arc and dorsomedial and ventromedial nuclei (23, 31). Leptin receptor mRNA is also present in areas outside the hypothalamus, including the choroid plexus, pyriform cortex, cerebral cortex, thalamus, and hippocampus (31).

Inhibition of a signal that produces positive energy balance involving neuropeptide Y (NPY) projection from Arc to the paraventricular nucleus (PVN) is one potential mechanism of leptin action for which evidence has been found (31, 37). Leptin receptors (23, 31) and a high concentration of NPY cell bodies (1, 21) are found in the Arc. The PVN receives neural projections from the Arc and is densely populated with NPY-containing presynaptic nerve terminals and NPY postsynaptic receptors (2, 7). NPY administration intracerebroventricularly and into the PVN increases feeding (8, 20, 35, 36) and decreases brown adipose tissue (BAT) thermogenic capacity (4, 5, 18). Intracerebroventricular leptin has the opposite effects: decreased feeding (6, 15, 24, 27, 30, 33, 37) and increased energy expenditure (16) as indicated by increased norepinephrine turnover in BAT (9) and increased uncoupling protein (UCP) mRNA in BAT (28, 39).

Leptin could inhibit NPY effects on appetite and energy balance by suppressing NPY biosynthesis, by reducing NPY receptor binding, or by signaling to the neuroregulatory units on which NPY is having its effect. In addition, recent evidence suggests that there are other energy regulatory signals originating in Arc and projecting to PVN that may also be modified by leptin (13, 17). In this investigation, we reasoned that if the primary site of leptin action is in the Arc, then administration of NPY into the PVN should be unaffected by administration of intracerebroventricular leptin. On the other hand, if leptin also has important appetite and energy metabolism modulatory effects at other brain sites or through other mechanisms, then the effects of NPY administered into PVN should be modified by leptin. To examine this leptin-NPY interaction, we performed a series of studies. In the first two experiments, we measured the satiety effect of intracerebroventricular leptin in rats with presumed differing endogenous activity of PVN NPY: the food-deprived rat (high PVN NPY levels) (study 1) and the nondeprived, spontaneously feeding rat (normal PVN NPY levels) (study 2). Alterations in PVN NPY levels due to food deprivation have been reported previously by several investigators (3, 25, 26). In the next experiment, we tested the effect of intracerebroventricular leptin given before repletion of NPY in the PVN by specific microinjection of exogenous NPY in the PVN. Finally, we determined the time course of one dose of intracerebroventricular leptin on Arc NPY gene expression and UCP gene expression in BAT.

    MATERIALS AND METHODS
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

Animals

Male Sprague-Dawley rats (Harlan, Madison, WI) weighing 250-350 g were individually housed in conventional cages with a 12:12-h light-dark photoperiod (lights on at 0700) in a temperature-controlled room (21-22°C). Teklad verified lab chow and water were allowed ad libitum.

Drugs

Murine leptin was generously supplied by Amgen (Thousand Oaks, CA). Porcine NPY was purchased from Peninsula Laboratories (Belmont, CA). All drugs were dissolved in 0.9% phosphate-buffered saline (pH = 6.7) just before use.

Specific Experimental Protocols

Experiment 1. Twenty-four-hour food-deprived rats were injected intracerebroventricularly with graded doses of leptin. Rats were fitted with intracerebroventricular cannulas as previously described (18). Animals were food deprived for 24 h, then injected with leptin (0.1, 1, 5, or 10 µg/5 µl icv) or saline at 0 h (0900). Food intake was measured at 1, 2, 4, 24, 48, and 72 h after injection. Data were analyzed for main effects by a two-factor repeated-measures ANOVA (treatment × time). When there was a significant main effect, data within each time period were analyzed by a one-factor ANOVA followed by Fisher's least-significant difference t-test to compare individual treatment means; n = 12 rats per group. This study was carried out over 5 study days, each 1 wk apart, after animals were at or above baseline body weight. Data were combined after it was determined that there was no effect of day on feeding response in the control groups (F4,12 = 0.567, P = 0.6471).

Experiment 2. To determine the effect of leptin and duration of leptin action in rats with presumed normal endogenous NPY levels, i.e., nondeprived, spontaneously feeding rats, intracerebroventricularly cannulated rats were injected with 10 µg leptin or saline at 1700, 2 h before the start of the dark (normal feeding) cycle. Food intake measurements were carried out over 136 h, just less than 6 days. Male Sprague-Dawley rats (300-430 g, n = 17) were fitted with intracerebroventricular cannulas as previously described (18). After 10 days of recovery, animals were injected with leptin (10 µg/5 µl icv) or saline at 0 h (1700). Food intake and body weights were measured at 0, 16, 40, 64, and 136 h. This study was designed as a repeated-measures test such that each rat received both treatments once on separate days with 1 wk between treatments. Data from 2 study days were combined after it was determined that there was no effect of day on feeding response in the control groups (F1,15 = 0.189, P = 0.6703). Both treatments were represented on each study day. Data were analyzed for main effects by a two-factor (treatment × time) repeated-measures ANOVA. When there was a significant main effect, data within each time period were analyzed by a one-factor ANOVA followed by Fisher's least-significant difference t-test to compare individual treatment means.

Experiment 3. In the next study, we sought to determine whether intracerebroventricular leptin would influence the postreceptor effects of exogenous PVN NPY administration: feeding stimulation and brown fat inhibition. To do this, we prepared doubly cannulated rats: one cannula placed into the PVN for NPY administration and one placed intracerebroventricularly for leptin administration. Male Sprague-Dawley rats (275-300 g, n = 40) were fitted with two cannulas, one into the PVN and one into the right lateral ventricle as previously described (18); n = 7-8 rats/group. Rats were injected with leptin (5 µg/5 µl icv) at 0 and 12 h and NPY (0.5 µg/0.5 µl, PVN) at 0, 6, 12, 18, and 24 h. At 0 and 12 h, the intracerebroventricular injections were given just before PVN injections, with at least a 30-s delay between injections. Food intake was measured at 1, 2, 4, 6, 12, 18, 24, and 26 h. At 26 h, animals were killed and tissues were taken for analysis. UCP mRNA in BAT was determined as previously described (19). This study was conducted on two separate days, 1 wk apart, and data were combined after it was determined that there was no effect of day on feeding in the control groups (F1,5 = 0.023, P = 0.8846). Data were analyzed by a one-factor ANOVA followed by Fisher's least-significant difference t-test to compare means.

Experiment 4. To verify that leptin alters NPY gene expression in the Arc concurrently with changes in feeding and BAT UCP gene expression, rats were injected intracerebroventricularly with leptin or saline at 0800 (0 h) and again at 2000 (12 h). Male Sprague-Dawley rats (275-300 g, n = 53, 6-9 per group) were fitted with intracerebroventricular cannulas (right lateral ventricle) as previously described (18). Rats were injected with leptin (5 µg/5 µl icv) or saline at 0 and 12 h. Food intake was measured at 12, 24, 36, 48, 60, and 72 h. At 24, 48, and 72 h, animals were killed and tissues were taken for analysis. UCP mRNA in BAT and Arc NPY and beta -actin mRNA were determined as previously described (19). Data were analyzed for main effects by a two-factor ANOVA (treatment × time). When there was a significant main effect, data within each time period were analyzed by a one-factor ANOVA followed by Fisher's least-significant difference t-test to compare individual treatment means. Correlation coefficients were determined using regression analysis to describe the relationship between NPY/beta -actin mRNA levels and UCP mRNA levels.

    RESULTS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

Experiment 1

In the two-factor ANOVA, there was no main effect of treatment (F4,55 = 1.601, P = 0.1870), but there was a main effect of time interval (F2,110 = 8.553, P = 0.0004). In the one-factor ANOVA of each time interval, post hoc testing indicates that the 5- and 10-µg doses of leptin significantly decreased feeding within the 24-48 h postinjection period (-12%, P = 0.0237, and -19%, P = 0.0005, respectively; Table 1). No dose of leptin had any effect on feeding induced by food deprivation in the first 24 h after injection (feeding was similarly unaffected at 1, 2, and 4 h postinjection; data not shown) or in the 48-72 h postinjection period (Table 1). However, cumulative food intake at 72 h was still significantly lowered by 5 and 10 µg leptin (-8%, P = 0.0486, and -10%, P = 0.019, respectively).

                              
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  		Table 1.   Food intake in the 0-24 h, 24-48 h, and 48-78 h time periods after intracerebroventricular injection of saline or leptin in food-deprived animals

Experiment 2

In the two-factor ANOVA there were main effects of treatment and time (F1,32 = 8.878, P = 0.0055, and F3,96 = 5.898, P = 0.0010, respectively) on feeding. In the one-factor ANOVA of each time interval, feeding was significantly decreased by leptin in the 0-16 h and 16-40 h postinjection periods (-22%, F1,16 = 48.726, P = 0.0001, and -25%, F1,16 = 61.118, P = 0.0001, respectively; Fig. 1A). Food intake was back to control levels in the 40-64 h time period, although cumulative feeding response was still significantly lower in the leptin-treated animals after 136 h postinjection (-8%, F1,16 = 31.561, P = 0.0001; Fig. 1B). Thus leptin feeding-suppressive effects in nondeprived rats occurred within the first 40 h after leptin injection, and by 136 h (5.7 days) the rats had not yet compensated for this decreased food intake. Body weight in the leptin-treated animals was lower than controls at 16, 40, 64, and 136 h postinjection, but this decrease in body weight was not significantly different until 64 h after injection (-1.9%, F1,16 = 7.175, P = 0.0165; Fig. 1C). In eight animals followed after 136 h for an additional 48 h, body weight in the leptin-treated rats had reached control levels (data not shown). Although absolute body weight had not changed significantly until the 64 h time point, the change in body weight in the 0-16 h time periods between groups was significant (F1,16 = 13.855, P = 0.0019; Fig. 1D).


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  		Fig. 1.   Effect of intracerebroventricular leptin (10 µg) or saline on spontaneous feeding and body weight. A: periodic feeding response. B: cumulative feeding response. C: body weight. D: body weight change. * P < 0.02 relative to control group (saline).

Experiment 3

There were main effects of treatment on feeding and UCP mRNA levels (F1,13 = 13.331, P = 0.0029, and F1,13 = 7.730, P = 0.0156, respectively). PVN NPY administration significantly increased food intake at all time points (+37% cumulative, P < 0.05; Fig. 2A) and significantly decreased BAT UCP mRNA (-29%, P = .0231; Fig. 2B). Intracerebroventricular leptin significantly decreased 18, 24, and 26 h food intake (-36% cumulative, P < 0.05; Fig. 2A) and significantly increased BAT UCP mRNA relative to controls (+28%, P = 0.0162; Fig. 2B). However, intracerebroventricular leptin did not alter PVN NPY effects on feeding at any time point (Fig. 1A) or BAT UCP mRNA (Fig. 1B).


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  		Fig. 2.   Effect of intracerebroventricular leptin on normal feeding and feeding induced by paraventricular nucleus neuropeptide Y (NPY) (A) and on brown adipose tissue (BAT) uncoupling protein (UCP) mRNA levels (B). Optical density (OD) units are relative arbitrary units. * P < 0.05 relative to control group (saline). Columns with different superscripts indicate that representative values are significantly different from each other (P < 0.05).

Experiment 4

There were main effects of treatment on feeding, NPY mRNA, and UCP mRNA (F1,91 = 28.232, P = 0.0001; F1,37 = 4.345, P = 0.0441; and F1,37 = 14.792, P = 0.0005, respectively; Fig. 3, A-D). There were main effects of time interval on feeding (F2,91 = 18.496, P = 0.0001; Fig. 3B) but not on NPY or UCP mRNA (F2,37 = 1.516, P = 0.2328, and F2,37 = 2.160, P = 0.1297, respectively; Fig. 3, C-D). Feeding was most potently and significantly reduced by intracerebroventricular leptin in the 0-24 and 24-48 h time periods (-46%, P = 0.0002, and -45%, P = 0.0001, respectively; Fig. 3B). Feeding was only slightly reduced (-10%) in the 48-72 h time period (Fig. 3B). However, intracerebroventricular leptin resulted in a significant decrease in cumulative feeding at 72 h after injection (-37%, P = 0.0011; Fig. 3A). We normalized our data for generalized changes in gene expression by dividing NPY mRNA levels by beta -actin mRNA levels such that data is expressed as NPY mRNA/beta -actin mRNA. In an ANOVA including all time points, the overall effect of leptin on Arc NPY/beta -actin mRNA was a significant decrease (-27%, P = 0.0440; Fig. 3D). NPY/beta -actin mRNA levels in the Arc were significantly reduced by leptin at 48 h (-43%, P = 0.0349; Fig. 3D) but not at 24 or 72 h (Fig. 3D). Intracerebroventricular leptin also significantly increased BAT UCP mRNA levels at 48 h (+61%, P = 0.0131; Fig. 3C). BAT UCP mRNA levels were not normalized for changes in beta -actin mRNA because both NPY and leptin alter BAT tissue growth, and beta -actin levels change when cellularity is altered. In a regression analysis including all data, NPY mRNA/beta -actin mRNA was inversely and significantly correlated with BAT UCP mRNA (P = 0.0056, r = 0.465).


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  		Fig. 3.   Effect of intracerebroventricular leptin on cumulative food intake (A), periodic food intake (B), BAT UCP gene expression (C), and arcuate nucleus NPY gene expression (D) at 24, 48, and 72 h after injection. * P < 0.05 relative to control group (saline).

    DISCUSSION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

The present data support the hypothesis that the effect of leptin on energy homeostasis is due to a decrease in NPY biosynthesis in the Arc. Food-deprived animals have increased endogenous NPY peptide in the PVN (3, 25, 26), a parallel situation to PVN administration of exogenous NPY, and leptin did not affect feeding in either of these settings (Table 1 and Fig. 2). Additionally, the effect of intracerebroventricular leptin in nondeprived animals occurs much earlier than in food-deprived animals, suggesting that in food-deprived animals, high endogenous PVN NPY levels, and other changes in the appetite regulatory systems, are able to counteract leptin-induced decreases in NPY biosynthesis. This suggests that leptin does not influence NPY receptor binding or NPY postreceptor effects. In studies of ob/ob mice, intracerebroventricular NPY-induced feeding was similarly not affected at 2 h postinjection of intracerebroventricular leptin, although NPY-induced feeding was decreased by leptin after 4 h (34). The earlier effect in ob/ob mice may reflect a possible increased sensitivity to Ob protein. Seeley et al. (32) reported that leptin administered into the third ventricle in normal rats decreased deprivation-induced feeding. However, in that study, leptin was administered at the start of the deprivation period and again at the end of the deprivation period. In our study, leptin was administered only at the end of the deprivation period, just before food was returned to the cages. The influence of leptin on NPY biosynthesis during the deprivation period in the Seeley study likely resulted in food-deprived rats without the increased endogenous PVN NPY levels normally associated with food deprivation. Thus decreased NPY levels due to leptin treatment during food deprivation may have induced satiety in the leptin-treated rats after food was returned (32).

The feeding-suppressive effect of leptin during spontaneous feeding may likely be due to a decrease in NPY biosynthesis (Figs. 1 and 3). Centrally administered leptin did not alter the postreceptor effects of NPY administered into the PVN (Fig. 2), yet intracerebroventricular leptin alone resulted in decreased feeding and increased BAT UCP mRNA (Figs. 2 and 3). These two effects are opposite to NPY effects on feeding and UCP gene expression, indicating that leptin is modulating NPY activity. The inability of intracerebroventricular leptin to influence exogenous PVN NPY administration effects on feeding or BAT UCP mRNA supports the hypothesis that leptin's influence on NPY occurs at the level of biosynthesis and not at NPY receptor-binding or at postreceptor effects. Were leptin to alter NPY receptor binding and/or NPY postreceptor effects, one would expect to see blockade of PVN NPY effects by intracerebroventricular leptin.

In more direct support for the hypothesis that leptin satiety effects are due to decreased NPY biosynthesis, we verified that intracerebroventricular leptin resulted in decreased NPY gene expression in the Arc (Fig. 3D). Others have demonstrated similar decreases in NPY mRNA (29, 31, 37) and have also reported decreased PVN NPY levels after leptin treatment (10). BAT was most potently influenced by intracerebroventricular leptin at 48 h, although alterations were observed by 24 h (Fig. 3C). Cumulative feeding was significantly decreased at all time points (Fig. 3A). However, when broken into time periods, the 0-24 and 24-48 h time periods were the most strongly affected by intracerebroventricular leptin (Fig. 3B). The effect of leptin appears to wane after 48 h, as feeding was decreased by only 10% in the 48-72 h time period.

Of interest is the duration of leptin effects on energy balance. It appears that 48 h after intracerebroventricular leptin administration is the peak in leptin effects on NPY, feeding, and BAT. However, it took more than 3 days for animals to return to baseline body weight, and body weight remained below control levels for more than 6 days after one intracerebroventricular injection of 10 µg leptin (Fig. 1). This is similar to other reports in which leptin-treated rats remain significantly below control body weight more than 6 days after leptin treatment stopped (10, 32). Thus leptin is a potent and long-lasting effector of energy metabolism alterations.

These data provide further evidence that leptin modulates Arc NPY biosynthesis, which results in alterations in feeding and energy expenditure. Recently, Erickson et al. (11) demonstrated that progeny mice of a cross between ob/ob (leptin deficient) and NPY knockouts were less severely obese due to decreased feeding behavior and increased energy expenditure, suggesting that the obesity in ob/ob mice is importantly dependent on enhanced NPY activity. The most direct anatomic evidence that leptin influences NPY biosynthesis in the Arc comes from recent data by two groups of investigators. Mercer et al. (22) and Hakansson et al. (13, 14) have demonstrated in mice that leptin receptor mRNA and preproNPY mRNA are coexpressed on the majority of cells in the Arc. Both leptin and NPY influence synaptic transmission in the Arc of normal rats (12), whereas leptin has no effect on synaptic transmission in Arc neurons from Zucker fatty rats, which have mutated leptin receptors (12).

In summary, leptin administration does not modify feeding and energy metabolism effects produced by exogenous NPY stimulation of the PVN or endogenous neuroregulatory changes associated with food deprivation. However, leptin alone decreases NPY gene expression in the Arc and modifies feeding and energy metabolism. These results point to an interaction of leptin with NPY-synthesizing cells in the Arc. Advancement in knowledge of leptin action in the central nervous system would benefit from future investigations into other neural centers potentially influenced by leptin.

Perspectives

The present data functionally demonstrate that leptin impacts feeding and thermogenesis by acting on the Arc-PVN NPY energy regulatory pathway. In conjunction with other lines of evidence, these data indicate that leptin exerts its effects by reducing NPY biosynthesis and NPY release, whereas NPY receptors in the PVN remain unaffected. Thus, even after leptin treatment, the postreceptor effects of NPY, increased feeding and decreased thermogenesis, remain intact following exogenous NPY administration in the PVN. Although this is not the only feeding-regulatory system with which leptin may interact, it is one of the more well-defined pathways, and the present study refines our knowledge of the interaction between leptin and NPY in the regulation of energy balance. Further studies of leptin interaction with other feeding regulatory systems will enhance knowledge of the neural pathways that may be altered or malfunctioning in obesity. It is only after these pathways are clearly defined that therapeutic approaches can safely be considered.

    ACKNOWLEDGEMENTS

This work was supported by the Minnesota Obesity Center (P30 DK-50456), the Department of Veterans Affairs, the National Institutes of Health (DK-42698), and the National Institute of Drug Abuse (DA-03999).

    FOOTNOTES

Address for reprint requests: C. M. Kotz, Veterans Affairs Medical Center, One Veterans Drive, Research Route 151, Minneapolis, MN 55417.

Received 19 September 1997; accepted in final form 23 April 1998.

    REFERENCES
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

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Am J Physiol Regul Integr Compar Physiol 275(2):R478-R484
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