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Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215
Address all correspondence and requests for reprints to: Jeffrey S. Flier, M.D., Beth Israel Deaconess Medical Center, Division of Endocrinology, Research North, 99 Brookline Avenue, Boston, Massachusetts 02215. E-mail: jflier{at}caregroup.harvard.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-MSH, CART or CRH. These results suggest that the dose response
characteristics of leptin on hypothalamic target neurons at the level
of mRNA expression are variable, with some neurons (e.g.
NPY) responding across a broad dose range and others
(e.g. POMC and CART) showing a limited response within
the low range. These results further suggest that the central targets
of leptin that mediate the transition from starvation to the fed state
may be distinct from those that mediate the response to overfeeding and
obesity. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-MSH (a product of the POMC gene),
CRH, and cocaine and amphetamine-regulated peptide (CART)] are each
decreased by leptin deficiency in ob/ob mice and starvation,
and increased after leptin treatment (2, 7, 8, 9). The anorexigenic effect
of leptin may therefore be mediated by stimulation of -MSH, CRH, and
CART (2, 7, 8, 9), as well as inhibition of NPY (2, 4). Although the above findings have provided insights into potential mechanisms of leptin action in the brain, most studies have been carried out in rodents with total leptin deficiency or insensitivity, or have involved treatment with supraphysiologic doses of leptin. Consequently, it is not known which hypothalamic neurons and which physiologic pathways respond to alterations in leptin levels across its dose-response range, i.e. from low levels during fasting, to elevated levels in the fed state, and to even higher levels characteristic of obesity. To identify hypothalamic targets of leptin in two of these distinct phases of its physiologic dose-response range, we examined the expression of hypothalamic neuropeptides and an array of physiologic effects in two paradigms. The first, which was intended to mimic the rise in leptin above the normal range, as would occur with overfeeding and early obesity, involved constant sc leptin infusion to ad libitum (ad lib)-fed rats. The second, which was designed to examine the effect of leptin on the adaptation to fasting, involved fasting with or without constant sc leptin infusion, such that the characteristic fall in leptin levels with fasting was prevented.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Leptin infusion in ad lib-fed rats
Food intake and body weight were measured during the light and
dark cycles on 3 consecutive days in three groups of rats (n =
5/group). Blood was obtained by tail bleeding within 1 min of handling,
during the light (0800–1000 h) and dark (1800–2000 h) cycles, for
measurement of leptin and corticosterone. Preliminary studies showed
that plasma corticosterone levels were not inappropriately elevated
when blood was obtained by this technique from rats acclimatized
to daily handling (data not shown). The rats were anesthesized with
methoxyfluorane (Metofane, Schering Plough, Union,
NJ); and osmotic pumps (model 2ML2; Alza Corp., Palo Alto,
CA), filled aseptically with recombinant murine leptin (Eli Lilly & Co., Indianapolis, IN) or PBS (pH 7.4) were implanted sc.
Leptin was infused at a rate of 2 µg/h or 4 µg/h in two groups of
rats (n = 5/group), and food intake and body weight were monitored
on alternate days. Control rats were infused with PBS. Blood was
obtained by tail bleeding, on days 7 and 14 of leptin or saline
infusion, for measurement of leptin and corticosterone.
After the period of leptin or saline infusion, the rats were anesthesized with sodium pentobarbital (50 µg/kg BW ip) at 1600–1800 h of the light cycle. Blood was obtained, via cardiac puncture, for hormone measurement; and the rats were perfused with diethylpyrocarbonate-treated PBS followed by 10% neutral buffered formalin. Brains were dissected, immersed in the same fixative overnight, cryoprotected with 20% sucrose-PBS, and stored at -80 C until processing. Frozen 30-µm coronal sections were cut on a sliding microtome and processed for detection of messenger RNAs (mRNAs) for NPY, CRH, POMC, CART, i.e. peptides implicated in leptin action (2, 7, 8, 9), and the long form leptin receptor (OBRb) by in situ hybridization histochemistry, as described previously (10, 11, 12).
Leptin infusion in fasted rats
Six groups of male Sprague Dawley rats (n = 5/group) were
housed and fed ad lib, as described above. Alzet miniosmotic
pumps (model 2ML1) containing murine leptin (4 µg/h) were implanted
sc in two groups of rats. The others received PBS infusion. The choice
of pumps was designed to infuse leptin or PBS for a total duration of 7
days. Starting from day 4 (after pump implantation), one group each of
leptin and PBS-treated rats (n = 5/group) were deprived of food
for approximately 70 h (initiated at lights off at 1800 h).
The rats were anesthesized with ip sodium pentobarbital injection on
day 7 (1600–1800 h). A control group of PBS-treated rats was allowed
ad lib access to food throughout the infusion period. After
obtaining blood by cardiac puncture, for hormone measurements, the rats
were perfused, and brains were processed for detection of mRNA for
neuropeptide, as described above.
Another group of leptin- and PBS-treated rats (n = 5/group) was deprived of food for 70 h, as described above, and was allowed ad lib access to chow after the period of fasting (and PBS or leptin infusion). Food intake and body weight were measured daily for 3 days. Daily blood samples were obtained during the refeeding period, by tail incision, for leptin measurement. A control group of rats (n = 5) received PBS infusion and was fed ad lib throughout the duration of the experiment.
Hormone measurements
Plasma hormones were measured by RIA using kits for leptin and
insulin (Linco Research, Inc., St. Charles, MO),
corticosterone and T4 (ICN Biomedicals, Inc., Costa Mesa, CA), and testosterone (DPC, Los
Angeles, CA), as described previously (4, 13). Leptin was measured in
duplicate 10-µl plasma samples, obtained from tail bleeds or cardiac
puncture, in one half of the reaction volume recommended by the
manufacturer. The detection limit of leptin was 0.5 ng/ml; intraassay
variation (cv), 4.2%; and interassay cv, 3.8%. Corticosterone was
measured in duplicate 5-µl samples obtained by tail bleeding or
cardiac puncture; detection limit, 25 ng/ml; intraassay cv, 5.4%; and
interassay cv, 4.8%. Insulin, T4, and testosterone were
measured on duplicate plasma samples (100 µl, 10 µl, and 100 µl,
respectively) obtained by cardiac puncture. The detection limits and
intraassay and interassay variations were as follows: insulin =
0.1 ng/ml, 4.2%, and 5.3%); T4 = 0.5 µg/dl, 4.6%,
and 4.3%; and testosterone = 0.2 ng/ml, 4.5%, and 6.5%,
respectively. The effects of leptin and PBS infusion on the hormone
concentrations among various treatment groups were compared by ANOVA
and Fisher protected least-significant difference (PSLD) test (Statview
512, Abacus, Berkley, CA). Differences between nocturnal and diurnal
leptin and corticosterone leptin levels were compared by two-tailed
t test. P < 0.05 was considered
significant.
Image analysis
Brain sections from various treatment groups in each experiment
were processed for in situ hybridization under the same
conditions (10, 11, 12). After posthybridization washing and air drying,
brain sections from leptin- or saline-treated rats in each experiment
were matched and exposed to film (Biomax MR, Eastman Kodak Co., Rochester, NY) under the same conditions. The relative
levels of NPY, POMC, CART, CRH, and OBRb mRNA in the hypothalamus were
analyzed on film autoradiograms by laser densitometry using ImageQuant
software (Molecular Dynamics, Inc., Sunnyvale, CA).
Autoradiograms from 4 rats in each treatment group were analyzed. The
number of sections analyzed per region in each rat and the approximate
levels (figures) in the atlas of Paxinos and Watson (14) were as
follows: retrochiasmatic area: 2 sections/rat (level 25);
arcuate hypothalamic nucleus: 6 sections/rat; 2 from each level:
rostral (level 27/28), mid (level 29/30), caudal
(level 32/33); paraventricular hypothalamic nucleus: 6
sections/rat; and 2 from each level: rostral (level 24), mid
(level 25), caudal (level 26). At each
rostrocaudal level, a rectangle was drawn to enclose the nucleus of
interest in a particular brain region, and the absorbance of the
autoradiographic signal was measured. The rectangle was then reproduced
to the same dimension and used to measure absorbances in similar
regions in matched sections from other rats. Absorbance values
corresponding to the content of neuropeptide mRNA per region were
corrected for background (nonspecific signal) by subtracting the
absorbance in a region on the same brain section not known to
express that product. Statistical comparisons of integrated densities
per brain region among various treatment groups was performed by ANOVA
and Fisher PSLD test (Statview 512, Abacus). P
< 0.05 was considered significant.
Brain sections were dipped in photographic emulsion and processed for microscopy (10, 11). The slides were examined under bright- and darkfield optics with a Carl Zeiss Axioplan light microscope. Photomicrographs were produced by capturing images with a Kodak digital camera (Eastman Kodak Co.) mounted directly on the microscope and an Apple Macintosh Power PC computer, and combined into plates using Adobe Photoshop software. Figures were printed on an Eastman Kodak Co. 8650 dye sublimation printer.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, A–C). Plasma leptin increased 1.5- to 2-fold within 1 week of constant
sc leptin infusion and remained elevated thereafter. In addition to
mean leptin levels being elevated, the infusion protocol prevented the
diurnal variation in leptin levels (Fig. 1). Plasma corticosterone
levels were 52% higher during the dark cycle than the light cycle
(P < 0.05) in ad lib-fed rats infused with
PBS (Table 1). In contrast, chronic
leptin infusion at rates of 2 µg/h and 4 µg/h attenuated the
nocturnal rise in corticosterone (Table 1). Leptin infusion did not
affect the levels of insulin, T4, or testosterone (Table 1).
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). A dose effect of leptin to reduce
weight gain was observed after 8 days of infusion and persisted through
the duration of the experiment (Fig. 2A). Nocturnal food intake was
decreased by leptin after 3 days (P < 0.05) (Fig. 2B).
There was a dose effect of leptin to reduce nocturnal feeding after
7–9 days; however, unlike body weight, the additional reduction in
nocturnal food intake in response to the higher leptin dose was gone
after 10 days (Fig. 2B). Nocturnal food intake was reduced by 25% in
response to both 2 µg/h and 4 µg/h leptin at the end of the
infusion period (Fig. 2B). Chronic elevation of plasma leptin did not
affect food intake during the light cycle (data not shown).
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, A–C;
and 4). On the other hand, leptin
infusion did not affect the expression of CRH, POMC, and CART mRNA
(Fig. 4). There was no significant alteration in the level of OBRb mRNA
in the hypothalamus in response to chronic leptin infusion in fed rats
(data not shown).
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). Leptin infusion prevented the fall in
plasma leptin that accompanies fasting but did not result in a further
decrease in body weight (Table 2). Fasting caused marked decreases in
insulin (50%), T4 (46%), and testosterone (74%) (Table 2). Maintenance of plasma leptin levels during fasting prevented the
fall in T4 and testosterone but did not affect the fall in
insulin (Table 2). Plasma corticosterone increased 3-fold, from 268
ng/ml to 815 ng/ml, in response to fasting, and it was not
significantly affected by leptin treatment (Table 2).
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illustrates the changes in
food intake, body weight, and plasma leptin in response to ad
lib feeding during the postfast period. There was significant
attenuation of weight gain and feeding in the rats that received leptin
infusion while fasting. In contrast, rats infused with PBS had a marked
increase in food intake, rapid weight gain, and elevated plasma leptin
levels within 24–48 h of initiation of refeeding.
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, A–C; and
7). There was a marked increase in NPY
mRNA in the dorsolateral region of the arcuate hypothalamic nucleus
(Fig. 6B). POMC (Figs. 6, D–F; and 7) and CART mRNA (Figs. 6, G–H;
and 7) levels decreased by 25% (P < 0.05) in the
arcuate hypothalamic nucleus. In addition, CART mRNA levels were
reduced significantly, by 20%, in the dorsomedial hypothalamic nucleus
in response to fasting (data not shown). POMC and CART mRNA levels in
the retrochiasmatic area were not altered by fasting or maintenance of
leptin within physiologic levels during fasting (data not shown).
Leptin infusion prevented the rise in arcuate hypothalamic NPY mRNA
expression (Figs. 6, A–C; and 7) and the fall in POMC (Figs. 6, D–F;
and 7) and CART mRNA (Figs. 6, G–H; and 7) expression during fasting.
CRH mRNA expression in the paraventricular hypothalamic nucleus was not
affected by starvation or leptin infusion (Fig. 7).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-MSH),
CART, and CRH (2, 7, 8, 9). Although these findings have contributed
toward understanding of the mechanisms underlying leptin action in the
brain, such studies have not determined the specific responses of
hypothalamic targets across the dose range for leptin. Specifically, it
is not known whether the actions of leptin during the transition from
the starved to fed state are sensed by similar groups of neurons, as
when its levels are further elevated by overfeeding. Here, we show, for
the first time, that leptin has distinct effects on the expression of
hypothalamic neuropeptides, regulation of hormone levels, and feeding
behavior within these two phases of the leptin dose-response curve. To study the response to leptin at the low end of the dose-response curve, leptin was administered, by constant sc infusion, to fasted rats, with the goal of maintaining plasma leptin at levels observed in ad lib chow-fed rats, and the expression of various hypothalamic neuropeptides implicated in feeding behavior was examined. Maintaining plasma leptin prevented the increase in NPY mRNA levels and the fall in POMC and CART mRNAs in the arcuate hypothalamic nucleus that are seen with fasting. The design of this study, in which leptin infusion prevented the fall in plasma leptin without producing supraphysiologic levels, allows us to conclude that the fall of leptin with fasting is sufficient to produce these effects. In contrast to the fasting paradigm, constant sc leptin infusion, which increased plasma leptin in ad lib-fed rats to levels observed with overfeeding or moderate obesity, suppressed NPY mRNA below that of the fed state but did not affect the expression of putative anorexigenic peptides. Thus, whereas increased leptin levels produced a dose-related decrease in NPY mRNA expression in the arcuate hypothalamic nucleus, POMC and CART mRNA levels were not affected. These are the first results, to our knowledge, of the capacity of leptin-responsive hypothalamic neurons to respond to a modest rise in leptin levels above the normal fed range.
Studies have reported that CRH mRNA expression is reduced or unchanged
in the paraventricular hypothalamic nucleus as a result of fasting or
food restriction (15, 16, 17). Furthermore, CRH has been proposed as a
potential central mediator of the anorectic action of leptin, along
with -MSH and CART (2, 7, 8, 9). However, in the present study, we did
not detect any change in CRH mRNA levels in the paraventricular
hypothalamic nucleus in response to fasting or a rise in leptin.
Based on the regulation of hypothalamic neuropeptides and feeding
behavior by leptin in the fasted state, we speculate that low leptin
levels stimulate hyperphagia and weight gain in the postfast period, at
least in part, by increasing NPY levels and decreasing the expression
of the anorexigenic peptides -MSH and CART in the arcuate
hypothalamic nucleus. During the postfast period, leptin levels would
be expected to increase as a result of hyperphagia, leading to a
decrease in NPY levels, an increase in -MSH and CART levels,
and a reduction in food intake and stabilization of body weight at the
prefast level. At the other end of the dose-response curve, mild
chronic hyperleptinemia resulted in a dose-related decrease in body
weight gain and food intake in ad lib-fed rats. It is likely
that the reduction in nocturnal feeding and weight gain in ad
lib-fed rats in response to chronic elevation in leptin is
mediated, at least in part, by a fall in NPY mRNA levels. The lack of
effect of chronic leptin elevation on POMC, CART, and CRH mRNA levels
suggests that hypothalamic neurons expressing these putative
anorexigenic peptides are not as sensitive, as NPY neurons, to a
chronic rise in leptin in the fed state, at least at the level of mRNA
expression. However, because NPY-deficient mice respond normally to
inhibition of food intake by leptin (18), other targets must exist. The
inhibitory action of rising leptin levels on feeding may be mediated by
peptides, such as agouti-related peptide, which we did not assess in
this study (2, 19), or by as-yet-undefined targets in the hypothalamus
or other brain regions. In addition, actions of leptin may involve
effects apart from changes in neuropeptide gene expression.
Mammals have the ability to match caloric intake to expenditure, such that overfeeding triggers a compensatory decrease in food intake and weight loss to restore energy balance. Involuntary overfeeding by gastric infusion has been shown to suppress voluntary food intake and body weight in rats (16, 20). An increase in hypothalamic CRH and POMC mRNA levels, during the period of overfeeding, has been proposed to mediate the ensuing hypophagic response (16, 20). In contrast to CRH and POMC, hypothalamic NPY mRNA expression was not altered by overfeeding (16). It has been suggested that the aforementioned regulation of hypothalamic neuropeptide expression in the overfed state may be mediated by a rise in leptin; however, leptin was not measured in that study (16). Unlike the effect of overfeeding, chronic leptin elevation in the current study decreased NPY mRNA without affecting CRH and POMC mRNA levels. The hypothalamic neural responses to chronic leptin infusion in the current study might differ from the response to involuntary overfeeding as a result of several important distinctions between these two states. For example, the state of afferent signals from the gut is different in overfeeding vs. leptin administration.
The observation that a modest rise in plasma leptin, within the dose range associated with mild to moderate obesity, has marked inhibitory effects on food intake and body weight gain in ad lib chow-fed rats is in agreement with a study by Halaas et al. (21). In that study, a 1.4- to 5-fold increase in plasma leptin, from constant sc leptin infusion, decreased body weight by 5–15% and increased energy expenditure in ad lib-fed mice. Although we did not measure the latter in our experiment, it is likely that the reduction in weight gain in rats was partly attributable to increased thermogenesis (1, 2, 3). These responses to leptin infusion contrast with earlier reports that wild-type rodents have decreased sensitivity to peripheral leptin injection (22, 23, 24). It is likely that the bioavailabilty of leptin is suboptimal when administered by bolus injection.
The ability of a chronic mild elevation in plasma leptin, from sc infusion, to exert marked effects on feeding and body weight contrasts with the failure of much greater increases in endogenous leptin levels to decrease food intake and adiposity in diet-induced obesity (25, 26, 27). Although hyperleptinemia in diet-induced obesity is thought to represent a state of leptin resistance, the mechanisms underlying the lack of response to rising endogenous leptin levels are not known (1, 2, 3). A possible explanation for the lack of response to rising endogenous leptin levels, compared with recombinant leptin, is the difference in potency between the two proteins. It is also possible that alterations in leptin transport into the brain or inhibition of leptin action by molecules such as SOCS-3 (a member of the suppressor of cytokine signaling family) may alter the sensitivity to endogenous leptin (1, 2, 28). Further studies will be required to understand the molecular mechanisms underlying the apparent failure of negative feedback regulation by high leptin levels in diet-induced obesity.
Effects of leptin at the low end of the dose-response curve on the neuroendocrine axis were studied by administering leptin by constant sc infusion, to increase plasma levels from low (fasted) to the normal fed range. In agreement with a previous study in which leptin was administered by bolus ip injection, leptin infusion prevented the fall in T4 and testosterone but did not alter insulin levels (4, 29). The observation that maintenance of plasma leptin within the physiologic range prevents the fall in T4 and testosterone further extends the view that the fall in leptin is the critical mediator of the adaptation of thyroid and gonadal axes to fasting (1, 4, 29). We have previously reported that suppression on the thyroid axis, by falling leptin levels during fasting, is mediated by decreased expression of TRH (29). Moreover, ablation of the arcuate hypothalamic nucleus with monosodium glutamate prevents the leptin-mediated regulation of thyroid hormones during fasting (30). Because NPY and POMC neurons in the arcuate hypothalamic nucleus are direct leptin targets and, in turn, regulate the hypophysiotropic TRH axis, it is likely that the effect of leptin on the thyroid axis is mediated, at least in part, through action on these neurons (30). As with the thyroid axis, results in rodents and nonhuman primates suggest that the suppression of reproductive hormones during fasting is mediated by central action of leptin in the pituitary or the brain (31, 32).
The rise in leptin from low to normal levels did not prevent activation of the hypothalamic-pituitary-adrenal (HPA) axis, as was observed in response to ip leptin injection (4). Studies have shown that leptin blunts the activation of the HPA axis during fasting and in response to restraint stress or ACTH stimulation (4, 33). Moreover, leptin directly inhibits glucocorticoid secretion by adrenal cortical cells (34, 35). However, supraphysiologic doses of leptin were used in most of these studies. The failure of maintenance of plasma leptin levels, within the near-physiologic range, to prevent the fasting-induced rise in corticosterone in the present study suggests that the hypophysiotropic CRH neuron is less sensitive to changing leptin levels. Whether achievement of leptin levels slightly higher than those attained here would prevent the activation of the HPA axis will require further study.
In contrast with fasted rats, chronic elevation of leptin above the ad lib-fed range did not affect T4 and testosterone levels. Circadian rhythms of leptin and glucocorticoids are temporally related to the feeding cycle in rodents and humans (4, 13, 36, 37). In ad lib-fed rats, leptin expression peaks several hours after maximal feeding in the dark cycle, and the nadir of leptin precedes the nocturnal rise in corticosterone (4, 38). Chronic leptin infusion prevented the normal fall in leptin in ad lib-fed rats and, therefore, enabled us to determine whether the corticosterone rhythm and light-dark feeding patterns may be regulated by leptin. Interestingly, chronic elevation of leptin prevented the nocturnal rise in corticosterone and reduced nocturnal feeding; however, maximum food intake still occurred during the dark cycle. These findings suggest that diurnal leptin variations may influence the diurnal corticosterone rhythm; however, it is unlikely to be the primary drive for the feeding cycle under ad lib-fed conditions.
Taken together, the differential effects of leptin on neuropeptide expression and hormone levels under ad lib-fed and fasted conditions suggest that there are distinct thresholds for leptin action on hypothalamic neuronal targets. This view is supported by a recent study by Ioffe et al. (39), in which expression of different levels of leptin from the prenatal period had variable effects on feeding, thermogenesis, adiposity, and neuroendocrine function in postnatal ob/ob mice. For example, expression of one half of the mean plasma leptin levels observed in wild-type mice fully corrected neuroendocrine abnormalities, including infertility, partially blunted hyperphagia, and weight gain, but it did not amelioriate thermoregulatory abnormalities in transgenic ob/ob mice. On the basis of these and other data, Friedman and colleagues (2, 39) proposed that distinct neural targets responded to low vs. high leptin levels. NPY was proposed to mediate the effects of low leptin, whereas anorexigenic peptides (such as POMC and CART) were proposed to respond to leptin levels above the normal range (2). In contrast, our results show that NPY is responsive to both low and high leptin, whereas POMC and CART respond to low leptin and not to a chronic rise in leptin levels.
Our results provide new insights into the role of leptin as a hormone signal for both the adaptation to fasting, as well as caloric excess. Because starvation is a greater threat than food excess, the greater sensitivity of hypothalamic neural mechanisms to a reduction in leptin, as adipose energy stores decline [as evidenced by both an increase in the expression of NPY (orexigenic) and a decrease in the expression of POMC and CART (anorexigenic)] may be necessary to trigger responses aimed at energy conservation and promoting food intake. The dual role of leptin in energy homeostasis, i.e. responses to starvation and overfeeding, is likely to involve differential dose-responses on hypothalamic neurons expressing peptides involved in the regulation of feeding behavior, thermogenesis, and neuroendocrine function.
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Footnotes |
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Received March 30, 1999.
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P < 0.05, compared with PBS-treated fasted rats.
