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1 Program for Neuroscience and 2 Department of Veterinary and Comparative Anatomy, Physiology, and Pharmacology, Washington State University, Pullman, Washington 99164-6520
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
GENERAL METHODS
GENERAL DISCUSSION
REFERENCES
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Leptin, the product of the obese gene, reduces food intake and body weight in rats and mice, whereas administration of the gut-peptide CCK reduces meal size but not body weight. In the current experiments, we report that repeated daily combination of intracerebroventricular leptin and intraperitoneal CCK results in significantly greater loss of body weight than does leptin alone. However, leptin plus CCK treatment does not synergistically reduce the size of individual 30-min sucrose meals during this period, and the effect of leptin-CCK combination on daily chow intake, while significant, is small compared with the robust effects on body weight loss. This synergistic effect on body weight loss depends on a peripheral action of CCK and a central action of leptin. These data suggest a previously unsuspected role for CCK in body weight regulation that may not depend entirely on reduction of feeding behavior and suggest a strategy for enhancing the effects of leptin in leptin-resistant obese individuals.
satiety; obesity; meal size; food intake; adiposity
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
GENERAL METHODS
GENERAL DISCUSSION
REFERENCES
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MULTIPLE FACTORS CONTROL THE size of meals, including signals generated from the gut in response to consumed nutrients and signals proportional to body weight or adiposity. The meal-related signal CCK is a peptide secreted from the intestine in response to specific nutrients in the gut (3, 18, 19). There is compelling evidence that CCK can potently reduce the size of individual meals (reviewed in Ref. 37); however, there has been little evidence to suggest that CCK contributes to the regulation of body weight. Rather, previous studies have suggested that CCK is not able to reduce body weight, even while reducing meal size (27, 48, 50).
The inability of exogenous CCK to reduce body weight potently in rodents is in contrast to the effects of the hormone leptin, which can produce profound loss of body fat (20, 21, 34). Whereas leptin treatment reduces meal size (10, 16, 24), increased activity and metabolic changes also are necessary for the full expression of body weight loss in leptin-treated animals (20, 27).
We previously have reported that a single treatment of leptin followed by CCK in mice did not reduce 30-min meal intake compared with CCK alone, but did reduce total daily caloric intake significantly more than leptin alone (29). We also reported that a single injection of leptin into either the lateral or the third cerebral ventricle (intracerebroventricularly), when followed 2-3 h later by intraperitoneal CCK, significantly reduced feeding during the subsequent 48 h and produced significantly greater loss of body weight than leptin alone. In other words, CCK and leptin acted synergistically to reduce body weight (29). This enhanced body weight loss following leptin plus CCK does not appear to depend on reduced meal size (28, 29). The present experiments were undertaken to determine 1) whether the synergistic loss of body weight following leptin plus CCK is sustained over several days (5-9) of repeated treatment and 2) whether leptin and CCK act in the brain or in the periphery to mediate leptin-CCK synergy on body weight.
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GENERAL METHODS |
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TOP
ABSTRACT
INTRODUCTION
GENERAL METHODS
GENERAL DISCUSSION
REFERENCES
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Male Sprague-Dawley rats (300-350 g; Simonsen Laboratories,
Gilroy, CA) were housed individually in hanging wire cages on a 12:12-h
light-dark cycle with lights on at 7:30 AM. Unilateral 23-gauge stainless steel cannulas were implanted stereotaxically into
the lateral ventricle at the coordinates 
1.0 mm from bregma, ±1.5 from midline, 3.9 from dura. Cannula
placement and patency were assessed by measuring water intake following
intracerebroventricular ANG II (30 µg/2 µl) both prior to the start
of treatment and after collection of data was completed.
Rats that drank <5 ml of water in the 30 min following
intracerebroventricular ANG II were excluded. Animals that showed any
sign of illness throughout the experiment were also excluded from
further treatment, and previous data from these animals were not
included in analysis.
Rats were adapted to the following daily schedule prior to treatment. Pelletted rodent chow (Harlan Teklad Diet 8664, 3.3 kcal/g) was removed each day at 7:45 AM, and the rats were weighed. After recovery from surgery and prior to the beginning of treatment, they were accustomed to 30-min access to 15% sucrose (0.6 kcal/ml) every day beginning at 11:45 AM for 10 days until a stable daily intake was observed. On treatment days, an injection of 0.9% sterile saline or leptin was given at 8:30 AM, and a second injection of either saline or CCK-8 was given 3 h later at 11:30 AM, immediately prior to sucrose presentation. Chow was returned each day after the sucrose test at 1:00 PM. Treatment always began on day 0 after body weight and chow were collected. Therefore, the first sucrose test in the presence of drug occurred on day 0, whereas the first body weight and daily chow intake data taken after onset of treatment were assessed at the start of day 1.
Murine leptin (PeproTech, Rocky Hill, NJ) was diluted in sterile distilled water for intracerebroventricular injection. The biologically active octapeptide of CCK, CCK-8, was diluted to 2 µg/ml or 0.5 µg/ml in sterile 0.9% saline for intraperitoneal injection or to 0.66 µg/3 µl sterile 0.9% saline for intracerebroventricular injection.
Data were analyzed for each day by one-way ANOVA with alpha level set at P < 0.05, followed by Tukey's post hoc comparisons. The Tukey's procedure made pairwise comparisons between all groups and adjusted for the total number of comparisons made. This test is also fairly stringent and was chosen to minimize the occurrence of Type II errors given the large overall number of pairwise comparisons.
Experiment 1
Previously, we reported that a single combination of intracerebroventricular leptin and intraperitoneal CCK elicits significantly greater body weight loss than does leptin alone (29). We hypothesized that this synergistic loss of body weight would be maintained over an extended course of treatment. In other words, we expected the loss of body weight elicited by leptin plus CCK to remain significantly greater than the weight loss following leptin alone throughout the duration of the treatment period.Methods. Rats were divided into four weight-matched groups and baseline body weight and food intake data were collected prior to treatment according to the daily schedule described above. During the 5 consecutive days of the treatment period (days 0-4), rats were injected with 2 µg leptin or saline into the lateral cerebral ventricle (intracerebroventricular) at 8:00 AM. At 11:00 AM, rats were injected intraperitoneally with either 2 µg/kg CCK-8 or saline. The final number of rats was 26 (saline/saline n = 7; saline/CCK n = 7; leptin/saline n = 5; leptin/CCK n = 7).
Results. Rats that were treated with CCK alone each day for 5 days had no change of body weight relative to saline-saline controls. A
low dose of leptin alone reduced body weight relative to saline;
however, this trend was not significant (P = 0.06 on days
5 and 6). Rats that were treated with leptin plus CCK lost significantly more body weight than rats that received saline-saline by
day 2 (P < 0.01) and had lost significantly more body
weight than leptin-alone rats by day 3 (P < 0.01, Fig. 1). By day 5, 24 h after the
final injections, rats treated with leptin plus CCK had lost four times
more body weight than rats that received saline-saline (P < 0.01) and two times more than those that received only leptin
(P < 0.05). Furthermore, the body weight of leptin plus
CCK-treated rats remained significantly reduced compared with saline
controls until day 11, 7 days after the last injection (P < 0.05).
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Leptin alone reduced daily chow intake to 35% of that of saline
controls (P < 0.001 on day 5). However, the
significant body weight loss of leptin-plus-CCK-treated rats compared
with leptin-alone rats, apparent by day 3, preceded any
significant difference in the daily chow intake of these two groups.
Compared with leptin alone, daily chow intake was reduced significantly
more by leptin plus CCK only on day 5 (P < 0.05).
Daily chow intake of rats treated with CCK alone was not significantly
different from saline-saline controls at any time (Fig.
2).
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CCK alone significantly reduced 30-min sucrose intake compared with
saline on all treatment days (P < 0.01, Table
1). Leptin alone also reduced 30-min
sucrose intake, but this reduction was significant only on day 3 (P < 0.05). The combination of leptin plus CCK did not reduce
sucrose intake significantly more than CCK alone. However, the dose of
CCK used was sufficiently effective that further suppression may not
have been detectable.
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Discussion. The present data are consistent with our previous reports of synergy between CCK and leptin in mice (29) and rats (29). Interestingly, the enhanced reduction of body weight following leptin plus CCK compared with leptin alone may not depend exclusively on reduced food intake. The relatively small difference between the chow intake of the leptin group and the leptin plus CCK group and the absence of apparent synergy on 30-min intake suggest that the CCK-leptin interaction on body weight might not depend entirely on CCK's well-described ability to reduce meal size. That is, the combination of leptin plus CCK may enhance body weight loss through mechanisms other than or in addition to feeding behavior, such as increased metabolic rate, thermogenesis, or decreased efficiency in the absorption and storage of ingested nutrients.
Experiment 2
The effects of intraperitoneal CCK to reduce meal size are likely mediated via a peripheral, endocrine, or paracrine action of CCK on CCK-A receptors (reviewed in Ref. 37). The satiety signal ascends to the brain stem via small, unmyelinated fibers of the vagus nerve that synapse in the nucleus of the solitary tract (NTS) (30, 36, 38, 44). Reduction of meal size by peripheral CCK injection is abolished by destruction of the abdominal vagal sensory innervations by either vagotomy (42, 43) or intraperitoneal capsaicin treatment (30, 36). Hence, a peripheral site of action for control of meal size by CCK seems well established.Nonetheless, centrally acting and centrally produced CCK also have been implicated in the control of feeding (9 and reviewed in Ref. 37). For example, CCK has been reported to reduce meal size when administered directly into the cerebral ventricles of rats (39) and sheep (7). Furthermore, the synergy between leptin and CCK we observed previously (29) and in experiment 1 might not rely on the same substrates that mediate CCK's reduction of meal size. In other words, it is possible that CCK injected into the periphery acts directly in the brain to mediate leptin-CCK synergy on body weight. Therefore, in experiment 2, we gave the same dose of CCK, which we had previously given intraperitoneally, directly into the lateral cerebral ventricle to determine whether centrally administered CCK could mediate significant leptin-CCK synergy.
Methods. Rats were divided into four weight-matched groups, and baseline body weight and food intake data were collected prior to treatment according to the daily schedule described above. During the 7 consecutive days of the treatment period (days 0-6), rats were injected with 2 µg leptin or saline into the lateral cerebral ventricle (intracerebroventricularly) at 8:30 AM, and then at 11:30 AM rats were again injected intracerebroventricularly into the lateral ventricle with either 2 µg/kg (0.66 µg) CCK-8 or saline immediately prior to sucrose presentation. The final number of rats was 42 (saline/saline n = 11; saline/CCK n = 10; leptin/saline n = 10; leptin/CCK n = 11).
Results. In contrast to the results of experiment 1,
when CCK was given peripherally, CCK injected into the lateral
ventricle did not enhance body weight loss when paired with daily
leptin treatment. Seven consecutive days of treatment with a low dose of leptin alone or leptin plus CCK reduced body weight relative to
saline on days 6-10 (P < 0.05) and
6-13 (P < 0.05, Fig.
3), respectively. However, there was no
significant difference between the body weight loss of leptin alone and
leptin plus CCK rats at any time. Rats that were treated with CCK alone
exhibited no change of body weight relative to saline-saline controls
(Fig. 3).
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Both leptin alone and leptin plus CCK reduced daily chow intake
compared with saline on days 3-7 (P < 0.05).
However, there was no significant difference between the daily intake
of leptin alone and leptin-plus-CCK-treated rats at any time, nor was
there a difference between CCK alone and saline-saline controls (Fig. 4).
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A dose of CCK (2 µg/kg), which potently reduced sucrose intake when
given in the periphery (Table 1), had no effect on 30-min sucrose
intake when given directly into the lateral ventricle (Table
2). There also was no effect of leptin
alone or leptin plus CCK on 30-min sucrose intake compared with either
saline or CCK-alone, respectively.
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Discussion. The same dose of CCK that elicited significant synergy when given intraperitoneally (experiment 1) was not sufficient to mediate leptin-CCK synergy on body weight when given directly into the brain. This result strongly suggests that CCK given into the periphery acts in the periphery and not in the brain to elicit significant leptin-CCK synergy. It is plausible that the peripheral action of CCK in leptin-CCK synergy may be mediated by the vagus nerve, as is the effect of CCK on meal size; however, further experiments are needed to test this hypothesis directly. Furthermore, whereas these results suggest that centrally produced and released CCK does not elicit significant enhancement of body weight loss during leptin treatment, they cannot exclude this possibility.
Experiment 3
Leptin receptors are present both in the periphery and the central nervous system (CNS) (6, 8, 11, 15, 31, 40, 45). Central sites of leptin action apparently elicit effects complementary to, but distinct from, peripheral leptin actions (5, 23, 32). We hypothesized that the leptin-CCK synergy we observed previously and in experiment 1 is elicited by leptin acting directly in the brain. However, it remained possible that the leptin given into the lateral ventricle diffused out of the brain and acted at some peripheral site. Therefore, in experiment 3, we administered leptin by intraperitoneal injection, at the same dose as is effective in eliciting leptin-CCK synergy when it is given intracerebroventricularly.Methods. Male rats were divided into four weight-matched groups, and baseline body weight and food intake data were collected prior to treatment according to the daily schedule described above. During the 5 consecutive days of the treatment period (days 0-4), rats were injected intraperitoneally with 2 µg leptin or saline in 0.3 ml at 8:30 AM, and then at 11:30 AM rats were again injected intraperitoneally with either 2 µg/kg CCK-8 or saline immediately prior to sucrose presentation. The final number of rats was 23 (saline/saline n = 6; saline/CCK n = 6; leptin/saline n = 5; leptine/CCK n = 6).
Results. There was no significant effect of either 2 µg
leptin or 2 µg/kg CCK injected intraperitoneally on body weight, nor was there a significant effect of leptin plus CCK (Fig.
5). There was also no significant effect of
any treatment on daily chow intake (data not shown). Both CCK alone and
CCK plus leptin reduced sucrose intake compared with saline on all
treatment days (P < 0.01; Table
3). At no time was the reduction of 30-min
sucrose intake following leptin and CCK different from that following CCK alone.
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Discussion. The results of experiment 3 support the hypothesis that leptin acts in the brain to mediate the synergy on body weight and food intake observed in experiment 1 and in previous reports (28, 29). The importance of centrally acting leptin is consistent with the hypothesized role of central leptin receptors in the integration of the regulation of body weight (12, 13). However, although the low dose of leptin used in these experiments did not act in the periphery, this does not exclude the possibility of important peripheral interactions between leptin and CCK. Endogenous leptin-CCK synergy may involve both central and peripheral sites of leptin action. These results do exclude the possibility that the low-dose leptin given in experiment 1 and in our previous report (29) acts directly on peripheral tissues such as leptin-sensitive vagal afferents suggested to play a role in short-term leptin-CCK synergy in mice (2, 46, 47).
Experiment 4
Exogenous CCK reduces food intake over a wide range of doses (reviewed in Ref. 37). Therefore, in experiment 4, we gave two different doses of CCK (2 and 0.5 µg/kg) to determine whether a lower CCK dose is capable of mediating leptin-CCK synergy.Methods. Male rats were divided into five weight-matched groups, and baseline body weight and food intake data were collected prior to treatment according to the daily schedule described above. During the 9 consecutive days of the treatment period (days 0-8), rats were injected intracerebroventricularly with 2 µg leptin in 3 µl or saline at 8:30 AM, and then at 11:30 AM rats were injected intraperitoneally with either 2 µg/kg CCK-8, 0.5 µg/kg CCK-8, or saline immediately prior to sucrose presentation. The final number of rats was 32 (saline/saline n = 8; saline/CCK high n = 6; leptin/saline n = 6; leptin/CCK high n = 6; leptin/CCK low n = 6).
Results. Both low- and high-dose CCK synergistically enhanced
the reduction of body weight following leptin treatment. The synergistic enhancement of weight loss by leptin-CCK combination was
comparable for both doses of CCK used. A low dose of CCK (0.5 µg/kg)
plus leptin was as effective for enhancing leptin's body weight
reducing effects as leptin plus a 2-µg/kg CCK dose (Fig. 6). Furthermore, rats that received leptin
plus either a low (0.5 µg/kg) or high (2 µg/kg) dose of CCK lost
significantly more body weight than rats that received saline or leptin
alone (P < 0.05). By contrast, rats that were treated with
intracerebroventricular saline and the high dose of CCK each day for 9 days had no change of body weight relative to saline-saline controls
(Fig. 6). Nine days of treatment with a low dose of leptin alone
slightly reduced body weight relative to saline; however, this
reduction did not reach significance (P = 0.36 on day
9; Fig. 6).
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There was no significant difference between the daily chow intake by
leptin-alone rats and the intake by rats treated with leptin plus
either dose of CCK, despite the large difference in body weight loss
among these groups. A low dose of leptin alone did not significantly
reduce daily chow intake compared with saline controls (Fig.
7). However, daily chow intake was reduced
by leptin plus a low dose of CCK compared with saline controls on
days 1 and 5 (P < 0.05) and by leptin plus a high
dose of CCK on days 4 and 6 (P < 0.05). The
daily chow intake of rats treated with CCK alone was never
significantly different from saline-saline controls (Fig. 7).
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A high dose (2 µg/kg) of CCK alone significantly reduced sucrose
intake compared with saline (P < 0.05; Table
4). Leptin plus a high or low dose of CCK
also reduced intake compared with saline (P < 0.05), but at
no time did leptin plus either dose of CCK significantly reduce intake
compared with CCK (2 µg/kg) alone.
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GENERAL DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
GENERAL METHODS
GENERAL DISCUSSION
REFERENCES
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We report here that a single daily intraperitoneal injection of CCK octapeptide synergistically enhances the efficacy of a low intracerebroventricular dose of leptin to reduce body weight. This effect depends on a peripheral action of CCK and a central action of leptin. The robust effect of repeated CCK plus leptin to enhance weight loss observed in experiment 1 was replicated in experiment 4 and is consistent with our previous report of CCK-leptin synergy on body weight following a single treatment of these two peptides (29). In addition, the results of experiment 4 indicate that an even lower dose of CCK (0.5 µg/kg) given into the periphery is sufficient to mediate synergistic body weight loss.
The experiments in this report do not support the existence of an especially robust leptin-CCK synergy on food intake (Fig. 7). In our previous work using a similar paradigm in mice, we observed an effect of leptin-CCK combination on total daily caloric intake (29). Previously we also have observed a significant leptin-CCK synergy in rats on reduction of daily chow intake as well as on body weight, although the effect on food intake was not as robust as the effect on body weight (29). However, in the present experiments, there was not a reliable difference between the food intake of the leptin alone and the leptin plus CCK-treated rats, even when the data were analyzed as cumulative intake over several days. Rather, the results of these studies suggest that while there is some effect of leptin and CCK on long-term food intake, this effect is far less robust than the greater effects of leptin-CCK combination on body weight. Thus leptin-CCK synergy might promote body weight loss through mechanisms largely independent of feeding behavior, such as increased resting metabolic rate, thermogenesis, or decreased efficiency of absorption and storage of ingested nutrients.
Recently, several reports have indicated that CCK and leptin probably interact in multiple ways. Bado et al. (1) reported that leptin immunoreactivity is present in the stomach and is depleted, concomitant with a rise in plasma leptin levels, following refeeding after a fast or treatment with very large doses of exogenous CCK. Furthermore, two groups have reported short-term synergy between leptin and CCK to reduce feeding behavior (2, 14). A synergistic suppression of chow intake lasting <6 h has been reported in fasted mice when leptin and CCK are given simultaneously into the peritoneal cavity (2). This short-term interaction was apparent following a low dose of peripheral leptin (2) and may be mediated by leptin-sensitive vagal afferents and involve enhanced neuronal activity in the hypothalamus (46, 47). In addition, there have been recent reports of enhanced CCK-mediated satiety during a 30-min Ensure meal 1 h after intracerebroventricular leptin (3.5 or 10 µg) in rats, concomitant with synergistically enhanced c-fos expression in dorsal hindbrain nuclei and hypothalamus (14). This experiment used a large group of rats (n = 18) in a repeated-measures design (14) and thus had greater statistical power than the present experiments.
However, we previously observed no significant synergy between peripheral leptin and CCK on 30-min Ensure intake in a similar repeated-measures design with a large group size (n = 16) in which the different treatments were given in a randomized, counterbalanced order (29). In eight separate experiments using several different doses of CCK and leptin, we have not observed significant enhancement of CCK's reduction of intake during a single 30-min meal in either mice (29) or rats (present experiments and 29). Wildman et al. (49) also have reported the absence of enhanced CCK action on single-meal intake following leptin treatment using a similar design. The dose of CCK (2 µg/kg) we have used has a robust effect on meal size and may have precluded detection of greater reductions. Furthermore, we have observed both an independent effect of leptin on single meal intake (Table 1) and trends toward decreased sucrose intake following leptin plus CCK compared with CCK (Table 1). However, these trends were not consistently observed (Table 4), suggesting that if leptin plus CCK treatment does reduce individual meal size, this effect is not robust. Thus we have observed long-term enhancement of leptin's suppression of body weight by CCK with no concomitant effect on short-term intake. Therefore, we suggest that the short-term interaction(s) between leptin and CCK on feeding (2, 14) may be related, but are not necessarily essential to, the long-term body-weight effects of CCK-leptin combination.
The present experiments also provide some insight into the possible mechanisms by which CCK and leptin act to mediate this synergy. CCK appears to act in the periphery. It will be of considerable interest to determine whether this interaction is dependent on the same peripheral neural substrates that appear to mediate CCK's effects on meal size. For example, leptin-CCK synergy may be abolished by capsaicin treatment or vagotomy or attenuated by prior treatment with a CCK-A receptor antagonist or lesion of the NTS.
Leptin appears to act within the CNS to mediate leptin-CCK synergy on body weight. Leptin receptors in the hypothalamus have been extensively investigated (6, 8, 11-13, 15, 31, 40, 41, 45), and several neuropeptide systems have been suggested to mediate effects downstream from hypothalamic leptin receptor activation (12, 13). These pathways may also mediate leptin actions important to leptin-CCK synergy. For example, could leptin-CCK synergy be elicited without activation of leptin receptors on the neuropeptide Y (NPY)/agouti-related peptide (AgRP) containing cells in the arcuate nucleus?
The synergistic interaction between leptin and CCK is most likely integrated at one or more sites within the CNS. Recently, Broberger and colleagues (4) have suggested the parabrachial nucleus (PBN) in the pons as a potential site for integration of short- and long-term satiety signals because of a dense projection of NPY/AgRP neurons from the arcuate to the PBN. The NTS, which receives synaptic termination from CCK-activated vagal afferents (35), also provides a dense projection to the PBN (22, 25, 33). Both the NTS and the arcuate nucleus display intense leptin-receptor immunoreactivity (45). The PBN may also supply ascending input to the hypothalamus related to feeding behavior or body weight regulation, as CCK immunoreactive cell bodies in the PBN project to the ventromedial hypothalamus (17). However, the PBN is only one of several potential sites of integration that can be proposed based on our current understanding of the neural events initiated by leptin and CCK. The eventual identification of the neural mechanisms underlying leptin-CCK synergy promises to extend our understanding of the roles of CCK and leptin in both feeding and body weight regulation.
Perspectives
A more complete understanding of the factors that enter into the calculus of the regulation of body weight requires that we identify the key endogenous signals and determine their interaction. The synergistic body weight loss following leptin-CCK combination suggests that interactions between such signals are probably critical to the understanding of the control of food intake and the regulation of body weight. Consideration of these interactions may extend beyond the search for pharmacological "magic bullets" and move us toward a more realistic and informed approach to the complex pathogenesis of obesity.| |
ACKNOWLEDGEMENTS |
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This work was supported by National Institute of Neurological Disorders and Stroke Grant NS-20561 to R. C. Ritter. C. A. Matson is the recipient of the Poncin Scholarship.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: C. A. Matson, Dept. of VCAPP, Washington State Univ., Pullman, WA 99164-6520 (E-mail: caesia{at}vetmed.wsu.edu).
Received 8 June 1999; accepted in final form 17 September 1999.
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GENERAL DISCUSSION
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P < 0.05).
Lep-plus-CCK-treated rats also reduced body weight significantly
compared with Sal controls by day 2 and remained significantly
underweight until day 11, 7 days after treatment was
discontinued (* P < 0.05). Although Lep alone also reduced
body weight compared with Sal controls, this reduction did not reach
significance (P = 0.06 on days 5 and 6). CCK
alone had no effect on body weight change compared with Sal. ICV,
intracerebroventricular; IP, intraperitoneal.
