| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1 Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan 48824-1224; and 2 Department of Metabolic Diseases, Pfizer Central Research, Groton, Connecticut 06340
 |
ABSTRACT |
|---|
 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Leptin inhibits food intake and increases metabolic rates in adult mice. Neonatal mice need to maximize food intake and also maintain high thermoregulatory metabolic rates to optimize survival, suggesting that leptin may function differentially in neonatal versus adult animals. The efficacy of exogenous leptin to alter these two physiological functions during development was thus examined in C57BL/6J lean (+/+ or ob/+) and ob/ob (leptin-deficient) mice. Intraperitoneal leptin administration (1 mg/kg body wt) to lean and ob/ob pups from 7 to 10 days of age did not affect milk intake, oxygen consumption, body weight, or epididymal fat pad weights. Intracerebroventricular injection of 1 µg leptin to 9-day-old pups also failed to influence milk intake or oxygen consumption. Because neither lean nor ob/ob pups responded to exogenous leptin, high endogenous plasma leptin concentrations per se in these lean mice do not explain their resistance to leptin. Leptin administered intracerebroventricularly also failed to alter milk/food intakes of 17-day-old pups but markedly increased oxygen consumption of these older mice. By 28 days of age, intracerebroventricular leptin inhibited food intake. The well-defined actions of leptin to reduce food intake and enhance metabolic rates do not develop synchronously. The ability of leptin to accelerate metabolic rates is acquired early in life and independent of its anorectic action, which may promote survival of neonates.
milk intake; oxygen consumption; intracerebroventricular injection
| |
INTRODUCTION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
THE OB gene product leptin is synthesized and released from adipocytes and is a key component of the signaling pathway to the hypothalamus to maintain energy balance (9, 28). Abnormalities of the ob regulatory system can lead to profound obesity. This is evident in ob/ob mice where the ob gene is mutated, resulting in a truncated protein and the obese phenotype (28). Elevated food intake and lowered thermoregulatory and diet-induced metabolic rates are characteristic of ob/ob mice. Acute or chronic administration of recombinant leptin to these adult ob/ob mice reverses these irregularities (9, 10, 13, 19, 20, 24). Injecting leptin into adult lean mice results in similar but less dramatic effects (19).
Although the effects of leptin on body energy homeostasis are now well established in adult mice, relatively little is known about the time frame during development when this leptin-hypothalamic signaling pathway becomes operational to regulate energy homeostasis. During neonatal development, animals need to maximize food intake to support growth and also maintain high thermoregulatory metabolic rates to optimize survival. These physiological requirements would seem to contraindicate a role for leptin in neonatal development, but plasma leptin concentrations are high in neonates (2, 6, 22). Preliminary data from one litter of rat pups suggest that neonates may be resistant to the food intake suppressive effects of leptin (23). Leptin administration did, however, elevate metabolic rates in neonatal rats in the study by Stehling et al. (23). These observations raise questions about the developmental sequence of the leptin-hypothalamic signaling pathway to regulate food intake and energy expenditure in young animals. The present study was therefore undertaken to examine the developmental pattern for emergence of effects of leptin administration on food intake and oxygen consumption in neonatal lean and ob/ob mice. Comparisons of lean and ob/ob mice were included to reveal whether the presence of high plasma leptin in lean neonates (which is absent in ob/ob mice) influences the ontogeny of leptin actions on food intake and energy expenditure.
| |
MATERIALS AND METHODS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Animals
Litters of lean (+/+ and ob/+) and ob/ob male pups were obtained from our colony of C57BL6J-ob/+ mice. Care of the mice was according to institutional guidelines. Dams were fed a nonpurified stock diet (Rodent Diet 8640; Teklad, Madison, WI). They were housed in solid-bottom cages with wood shavings for bedding at 24°C and were maintained on a 12:12-h light-dark cycle (lights on at 0700). Litter size was adjusted to six male pups per litter within a few days of birth. Pups were weaned at 21 days of age and were fed the stock diet, except in one trial in which a liquid diet was fed.Experimental Protocol
Experiment 1. The effects of repeated intraperitoneal injections of leptin on growth of neonatal mice were tested. Three littermate pups from each of four litters were injected intraperitoneally at 1000 with leptin (1 mg/kg body wt), and three received vehicle from day 7 to day 10 of birth. This dose of leptin has previously been shown to reduce body weight in adult ob/ob mice (20). Body weights were recorded daily. Oxygen consumption was measured on days 8 and 10, 3 h after injection of leptin. Milk intake was measured on day 9. Mice were killed on day 11.Experiment 2. Because intraperitoneal administration of leptin failed to influence milk intake, oxygen consumption, body weight, or fat pad weights of 7- to 11-day-old mice (experiment 1), we next tested the effects of intracerebroventricular injections of leptin on food intake and oxygen consumption of 9- and 17-day-old mice. Older mice (postnatal days 28 and 35) were used in select trials to demonstrate the age-associated changes in response to leptin. A dose of 1 µg was administered intracerebroventricularly. We have previously demonstrated that this dose of leptin effectively reduced food intake and increased metabolic rates in adults (19).
A liquid diet (AIN-93 M liquid diet; Dyets, Bethlehem, PA) was also offered to 8- to 9-wk-old lean mice to simulate the form of food consumed by neonates (i.e., milk). Mice were adapted to this diet for 4 days and then were injected intracerebroventricularly with 1 µg leptin. Food intake was recorded every hour for 3 h and then after 24 h.
Plasma Hormone and Glucose Measurements
Mice were decapitated in the fed state 24 h after the last injection of vehicle or leptin. Leptin was measured by RIA using a mouse leptin RIA kit obtained from Linco Research (St. Charles, MO). Plasma corticosterone concentrations were determined by an RIA procedure, as described earlier (18). Plasma glucose was measured by a glucose oxidase method using the trinder reagent (Sigma Chemicals, St. Louis, MO).Intracerebroventricular Injection
Mice were lightly anesthetized with ether before intracerebroventricular injections of leptin were made in 2 µl of vehicle (artificial cerebrospinal fluid) directly into the lateral ventricle with a 26-gauge needle, as described earlier (19).Oxygen Consumption and Milk Intake
Oxygen consumption was measured by placing mice singly in a chamber in a water bath maintained at 25 or 30°C. Soda lime was used to absorb expired carbon dioxide from the chamber (19). Mice were adapted to the chambers for 5 min before measuring oxygen consumption.To measure milk intake, dams were separated from pups for 4-6 h as indicated in RESULTS. Before returning the dam, pups were reflexively micturated by gentle stroking of the perineum and were weighed to the nearest 0.01 g. To reduce the likelihood that availability of milk was a limiting factor, only four pups were replaced per dam. Body weight gain during 1-3 h of suckling was utilized to estimate milk intake (17, 25).
Genotyping
Neonatal obese (ob/ob) and lean mice (ob/+ or +/+) were identified by genotyping DNA, since ob/ob and lean mice are visually indistinguishable until ~3 wk of age. DNA was extracted from blood cells remaining after separating plasma. The genotyping strategy utilized the Dde I restriction site generated by the ob mutation. Briefly, a portion of target DNA, obtained from blood cells via phenol-chloroform extraction and containing the mutation site, was amplified by PCR. Oligonucleotide primers were designed to flank the site of the ob mutation that was recognized by Dde I. The primers used were 5'-CTGGCAGTCTATCAACAGGTCC-3' and 5'-TGTGGAGTAGAGTGAGGCTTCC-3'. The size of the PCR product was verified by running an aliquot of DNA on an agarose gel. The remaining PCR product was digested with Dde I (Boehringer Mannheim), and the digested fragments resolved on a 4% nusieve (FMC Bioproducts) agarose gel.Statistics
Means ± SE are shown. Data were analyzed by ANOVA using phenotype, age, or test injections as main effects (27). Statistical analyses were performed using the Statview program or the SAS package.| |
RESULTS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Detection of the ob C to T mutation by PCR amplification and subsequent digestion of the amplified product with Dde I yielded products whose sizes could be distinguished on a nusieve agarose gel. Because the ob mutation created a Dde I restriction site that is not present in +/+ mice, ob/ob mice could be readily distinguished from homozygote lean +/+ or heterozygote lean ob/+ mice by the number and size of fragments generated.
Experiment 1
Seven- to 11-day-old mice. At 11 days of age, lean and ob/ob mice had similar body weights and epididymal fat pad weights (Table 1). Likewise, genotype did not affect oxygen consumption or milk intake at this age (data not presented). Plasma glucose concentrations were also similar, and corticosterone concentrations were equally low in these lean and ob/ob mice. Lean neonates at 11 days of age exhibited a four- to fivefold elevation in circulating leptin concentrations compared with adult mice (Table 1). With the RIA procedure used, plasma leptin-like immunoreactivity in ob/ob mice was <1 ng/ml at all ages examined (Table 1).
|
Treatment of either lean or
ob/ob
pups with leptin failed to influence food intake or oxygen consumption.
Values from lean and
ob/ob
pups were thus pooled for ease of comparison. Body weights of mice
injected daily with 1 mg leptin/kg body wt or saline intraperitoneally from postnatal days 7 to
10 were similar (Fig.
1). Epididymal fat pad weights of
control (n = 12) and leptintreated
(n = 12) mice measured on
day 11 were 7.3 ± 1.1 and 7.2 ± 1.3 mg, respectively. Dams were removed from litters for 6 h and
then returned. Consistent with the failure of leptin administration to
influence body weight or fat pad weight, milk intakes, measured as an
increase in body weight after suckling for 2 h, were also unaffected by
leptin [0.05 ± 0.03 and 0.07 ± 0.03 g increase in body
weight in control (n = 8) and
leptin-treated (n = 8) pups,
respectively]. Likewise, oxygen consumption measured at 25°C
3 h after leptin administration on days
8 and 10 was
unaffected by leptin treatment. Control and leptin-treated mice
consumed 24 ± 2 and 25 ± 1 ml
oxygen · h
1 · mouse1
at 8 days of age, and 35 ± 5 and 38 ± 1 ml
oxygen · h1 · mouse1
at 10 days of age, respectively.
|
Experiment 2
Nine-day-old mice. Because peripheral leptin administration failed to alter energy intake or expenditure in young mice, the ability of intracerebroventricular administration of leptin to alter milk intake and oxygen consumption was tested next. Milk intake and oxygen consumption values for these lean (+/+, ob/+) and ob/ob pups were pooled as in experiment 1, because genotype effects were not significant (P > 0.05) at this age [n = 14 mice/treatment group from seven litters, i.e., 9 lean (+/+ and ob/+) mice and 5 ob/ob mice]. To assess milk intake of pups at 9 days of age, mice were separated from dams for a period of 4 h. To account for interlitter variation, equal numbers of mice within a litter were injected intracerebroventricularly with vehicle or 1 µg leptin, and the dams were returned to their home cages. Body weights (4.5 ± 0.25 and 4.5 ± 0.30 g, respectively) increased by 0.20 ± 0.03 and 0.17 ± 0.03 g in control and leptin-treated mice (P < 0.05) after 1 h; no further increases were observed at 2 or 3 h. Oxygen consumption was measured in these 9-day-old mice 3 h after vehicle or leptin injection. Oxygen consumption of control and leptin-treated mice at 30°C was 20 ± 1 and 22 ± 3 ml · h1 · mouse1, respectively.
To determine whether these 9-day-old mice possessed thermogenic
capacity to regulate metabolic rates, individual lean mice were exposed
to temperatures of 25 or 30°C for 5 min. Oxygen consumption was
higher (P > 0.05) at 25°C than
at 30°C (25 ± 1 and 19 ± 1 ml oxygen
consumed · h1 · mouse1
at 25 and 30°C, respectively; n = 8 mice/group).
Seventeen- to eighteen-day-old mice. By 17-18 days of age, effects of genotype on body weight, fat pad weight, and plasma corticosterone are clearly evident (Table 1). Circulating leptin was slightly greater at 18 days of age than in adult lean mice but significantly lower (P < 0.05) than in 11-day-old mice.
The ability of intracerebroventricular leptin to regulate milk/food intake and metabolic rates of 17-day-old mice was tested next. At this age, pups are in transition from consuming milk to solid food. Mice were separated from dams for 4 h, injected with vehicle or leptin, and replaced with dams, and weight gain was measured after suckling for 2 h. Leptin treatment failed to reduce milk intake in either lean mice (increases in body weight in vehicle and leptin-treated mice were 0.17 ± 0.07 and 0.17 ± 0.02 g, respectively; n = 11-14 mice/group) or ob/ob mice (0.18 ± 0.03 and 0.19 ± 0.09 g increase in vehicle and leptin-treated ob/ob mice, respectively; n = 6-7 mice/group) at this age.
We also examined the effect of leptin on solid food intake at this age.
Mice were separated from dams for 4 h, injected with leptin
(1 µg icv), individually housed without the dam, and presented with
preweighed solid food. The
ob/ob
pups consumed more (P < 0.05) solid
food than lean pups, but leptin failed to reduce intakes of stock diet
in either
ob/ob
or lean mice at this age (Fig.
2).
|
At 17 days of age,
ob/ob
pups have lower metabolic rates (P < 0.05) than their lean siblings. Augmentation of oxygen consumption by
intracerebroventricularly administered leptin was observed in both lean
and
ob/ob
mice at 30°C (Fig. 3) on postnatal
day 17 (P < 0.05). This increase in oxygen
consumption by leptin in lean mice was apparent even at 25°C
(P < 0.05).
|
Young adult mice. Body weights, epididymal fat pad weights, and plasma corticosterone concentrations are higher in ob/ob mice than in lean mice at 29 and 36 days of age (Table 1). Circulating leptin concentrations of lean mice at these two ages were very similar and approached adult levels but were lower than observed at 11 days of age. Plasma glucose concentrations were higher in these mice than in the neonates, in part at least likely caused by consumption of the high-carbohydrate stock diet rather than milk.
Mice were deprived of food for 4 h before intracerebroventricular
injection of vehicle or leptin. On postnatal days
28 and 35,
intracerebroventricular leptin (1 µg) decreased food intake of both
lean and
ob/ob
mice (Fig. 4). Food intake remained
depressed for 24 h. Oxygen consumption measured 3 h after
intracerebroventricular leptin injection was enhanced in both lean and
ob/ob
mice at these ages (Fig. 5).
|
|
Adult mice. Adult (8-9 wk old)
lean mice were fed a liquid diet for 4 days to simulate the form of
food consumed by the neonates (i.e., milk). They maintained body weight
on this diet. Body weights before and after consuming the liquid diet
for 4 days were 20.1 ± 0.5 and 21.4 ± 0.5 g, respectively. They
were deprived of food for 4 h, injected intracerebroventricularly with
vehicle or 1 µg leptin, and then refed the liquid diet. Mice injected
intracerebroventricularly with leptin consumed less diet within the
first hour than did vehicle-treated mice (Fig.
6). This decrease in energy intake persisted for 24 h (Fig. 6). Epididymal fat pad weights measured 24 h
after intracerebroventricular injection were 300 ± 2 and 180 ± 4 mg in vehicle and leptin-treated groups, respectively, indicating
that leptin efficiently reduced body fat stores in these mice, which
were fed a liquid diet.
|
| |
DISCUSSION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
The present study was conducted to determine effects of exogenous leptin on food intake and metabolic rates in neonatal mice. The salient findings from this study are 1) plasma leptin concentrations in 11-day-old lean mice were markedly higher than in older mice; 2) peripheral or intracerebroventricular injections of leptin to either lean or ob/ob mice before 2 wk of age were without effect on milk intakes or metabolic rates; 3) intracerebroventricular leptin administration to 17-day-old lean and ob/ob mice increased metabolic rates but failed to modify milk/food intakes; and 4) by 28 days of age, lean and ob/ob mice acquired the ability to decrease food intake in response to leptin. This developmental transition from unresponsiveness to leptin, to a leptin-induced increase in metabolic rate without a reduction in food intake, to the response pattern characteristic of adult animals appears to be independent of endogenous leptin concentrations because lean and leptin-deficient ob/ob mice responded similarly.
Administration of leptin to mice before 2 wk of age failed to influence either milk intake or oxygen consumption. The dose of leptin administered peripherally (i.e., 1 mg/kg body wt) in the present study has been reported to decrease food intake and body weight of adult lean mice (20). It is possible that high concentrations of leptin binding protein (12) in plasma of neonates may limit transport of leptin from the periphery to the central nervous system. This potential limitation was circumvented by directly administering leptin into the lateral cerebral ventricle. Because the amount of leptin administered centrally to these small neonates (i.e., 1 µg) was the same as given to older and larger mice (present study and Refs. 14 and 19), it seems unlikely that the dose of leptin administered was a limiting factor. It is possible that our approaches to measure milk intake (i.e., the suckle-weigh method) and energy expenditure (i.e., measurement of respiration for a relatively short period) were not sufficiently sensitive to detect subtle leptin-induced changes in these neonates. However, because leptin treatment also failed to alter fat pad mass in these mice, leptin must exert minimal effects, if any, on food intake and energy expenditure of 9-day-old neonatal mice. Stehling et al. (23) have observed that leptin administration blocks the early morning torpor-like state characteristic of rat pups at 8 days of age but does not further elevate metabolic rates during the maximal phase of the circadian cycle. Further support for the ineffectiveness of leptin to significantly alter energy balance in neonatal mice is obtained from ob/ob mice. Leptin-deficient ob/ob mice exhibit only subtle differences in body weight and fat pad mass compared with lean littermates before 2 wk of age (Table 1), suggesting that the absence/presence of endogenous leptin plays a minimal role in regulation of energy balance in these neonatal mice. We also conclude that this apparent leptin resistance cannot be attributed to the high plasma leptin concentrations characteristic of lean neonates because the leptin-deficient ob/ob pups were equally insensitive to leptin action.
The ineffectiveness of leptin to regulate food intake and energy expenditure in neonatal mice does not preclude an active role for leptin in other metabolic processes at this stage of development (1, 15, 26). Alternatively, the capability of leptin synthesis and secretion may developmentally precede emergence of functional leptin receptors coupled to regulation of body energy balance and other metabolic processes. Plasma leptin concentrations are severalfold higher in neonates than observed in adults (Refs. 2, 6, 22, and present study). This spike in leptin concentrations occurs when fat deposits are minimal (Table 1). It remains to be resolved whether this elevation in leptin is caused by an enhanced synthesis and secretion of leptin from adipocytes of these neonates or from an impaired capacity to clear leptin from their circulation. Further studies are needed to evaluate these possibilities as well as to characterize the development of the leptin receptor system in neonates.
At ~2 wk of age, pups begin to leave the microenvironment of the nest and search for solid food. Their nutritional demands are high to sustain a rapid rate of growth at the same time that thermoregulatory thermogenesis must be sufficient to maintain body temperature when isolated from the litter. This is also the stage of development when leptin-deficient ob/ob mice exhibit a hypometabolic response to cold stress and begin to accumulate body fat at an accelerated rate, suggesting the emergence of a role for leptin in maintenance of thermoregulatory thermogenesis at this stage of development (4). Indeed, administration of leptin caused pronounced increases in the metabolic rates of lean and ob/ob pups at 17 days of age. This maturation of the leptin signal transduction system between 9 and 17 days of age to activate thermoregulatory thermogenesis coincides with the development of the hypothalamic-pituitary-adrenal axis to increase corticosterone in these mice (Refs. 3 and 16 and Table 1). Corticosterone might be one of the triggers to couple the leptin signal transduction pathway to metabolic rate regulation. Consistent with this suggestion, removal of corticosterone from adult mice by adrenalectomy prevents leptin-induced increases in metabolic rate (19). This implies that corticosterone is needed for leptin to activate thermogenesis. Interestingly, leptin did not suppress milk or solid food intake in these 17-day-old pups, even though their corticosterone concentrations had increased. This ineffectiveness of leptin to suppress food intake of pups coupled with the concomitant activation of energy expenditure pathways has obvious survival value for these pups as they begin to leave the nest. Stehling et al. (23) also observed that repeated subcutaneous administration of leptin failed to influence milk intake of 9- to 15-day-old rat pups. Additional studies will be required to determine the full extent of corticosterone-leptin interactions in the regulation of food intake and energy expenditure.
Perspectives
Early in life, gastrointestinal tract distension regulates food intake (5, 8, 21). As the pups develop, a complex regulatory system integrating signals from metabolic fuels and the neuroendocrine system evolves to regulate food intake (11). Between 17 and 28 days of age, mice acquire the ability to incorporate the leptin signal transduction system into the overall food intake regulatory system. In fact, in adult mice, the impact of leptin on food intake predominates over the impact on metabolic rate to control fat stores. A dose of leptin that may lower food intake by 50% or more causes considerably less pronounced increases in metabolic rates (19). Leptin appears to primarily support maintenance of metabolic rate characteristic of the fed state in adult mice. Leptin administration increases metabolic rates of food-restricted (7) or fasted adult lean mice (19) but has minimal effects on metabolic rates of fed lean mice (19). This strategy to control body fat reserves in adulthood would, if activated in neonates, likely impair their survival.Leptin actions are developmentally regulated to optimize growth and survival of neonates. Pups acquire the ability to increase metabolic rates and thereby maintain body temperature in response to leptin coincidental with their movement from the nest but, importantly, do not initially depress food intake in response to leptin. This disconnect enables neonates to thermoregulate and simultaneously maximize growth and development. Developmentally regulated shifts in the coupling of the leptin signal transduction system to food intake and metabolic rate regulation play an important role in the transition from neonate to adulthood.
| |
ACKNOWLEDGEMENTS |
|---|
We thank Jason C. Lindsey for assistance with the first experiment, Chris Oberg for preparation of the graphs, and Gissela Pfeifer for assistance with manuscript preparation.
| |
FOOTNOTES |
|---|
This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-15847 and by the Michigan State University Agricultural Experiment Station.
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: D. R. Romsos, Dept. of Food Science and Human Nutrition, Michigan State Univ., East Lansing, MI 48824-1224 (E-mail: dromsos{at}pilot.msu.edu).
Received 18 February 1999; accepted in final form 12 May 1999.
| |
REFERENCES |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
1.
Ahima, R. S.,
D. Dushay,
S. N. Flier,
D. Prabhakaran,
and
J. S. Flier.
Leptin accelerates the onset of puberty in normal female mice.
J. Clin. Invest.
99:
391-395,
1997[Medline].
2.
Ahima, R. S.,
D. Prabhakaran,
and
J. S. Flier.
Postnatal leptin surge and regulation of circadian rhythm of leptin by feeding.
J. Clin. Invest.
101:
1020-1027,
1998[Medline].
3.
Allen, C.,
and
J. W. Kendall.
Maturation of the circadian rhythm of plasma corticosterone in the rat.
Endocrinology
80:
926-930,
1967[Medline].
4.
Boissonneault, G. A.,
M. J. Hornshuh,
J. W. Simons,
D. R. Romsos,
and
G. A. Leveille.
Oxygen consumption and body fat content of young lean and obese (ob/ob) mice.
Proc. Soc. Exp. Biol. Med.
157:
402-406,
1978[Medline].
5.
Cramer, C. P.,
and
E. M. Blass.
Mechanisms of control of milk intake in suckling rats.
Am. J. Physiol.
245 (Regulatory Integrative Comp. Physiol. 14):
R154-R159,
1983.
6.
Devaskar, S. U.,
C. Ollesch,
R. A. Rajakumar,
and
P. A. Rajakumar.
Developmental changes in ob gene expression and circulating leptin peptide concentrations.
Biochem. Biophys. Res. Commun.
238:
44-47,
1997[Medline].
7.
Döring, H.,
K. Schwarzer,
B. Nuesslein-Hildesheim,
and
I. Schmidt.
Leptin selectively increases energy expenditure of food-restricted lean mice.
Int. J. Obes. Relat. Metab. Disord.
22:
83-88,
1988.
8.
Friedman, M. I.
Some determinants of milk ingestion in suckling rats.
J. Comp. Physiol. Psychol.
89:
636-647,
1975.
9.
Friedman, J. M.
Leptin, leptin receptors, and the control of body weight.
Nutr. Rev.
56:
S38-S46,
1998[Medline].
10.
Halaas, J. L.,
K. S. Gajiwala,
M. Maffei,
S. L. Cohen,
B. T. Chait,
D. Rabinowitz,
R. L. Lallone,
S. K. Burley,
and
J. M. Friedman.
Weight-reducing effects of the plasma protein encoded by the obese gene.
Science
269:
543-546,
1995
11.
Henning, S. J.,
S.-S. P. Chang,
and
E. G. Gisel.
Ontogeny of feeding controls in suckling and weanling rats.
Am. J. Physiol.
237 (Regulatory Integrative Comp. Physiol. 6):
R187-R191,
1979.
12.
Houseknecht, K. L.,
C. S. Mantzoros,
R. Kuliawat,
E. Hadro,
J. S. Flier,
and
B. B. Kahn.
Evidence for leptin binding to proteins in serum of rodents and humans: modulation with obesity.
Diabetes
45:
1638-1643,
1996[Abstract].
13.
Hwa, J. J.,
A. B. Fawzi,
M. P. Graziano,
L. Ghibaudi,
P. Williams,
M. Van Heek,
H. Davis,
M. Rudinski,
E. Sybertz,
and
C. D. Strader.
Leptin increases energy expenditure and selectively promotes fat metabolism in ob/ob mice.
Am. J. Physiol.
272 (Regulatory Integrative Comp. Physiol. 41):
R1204-R1209,
1997
14.
Hwa, J. J.,
L. Ghibaudi,
D. Compton,
A. B. Fawzi,
and
C. D. Strader.
Intracerebroventricular injection of leptin increases thermogenesis and mobilizes fat metabolism in ob/ob mice.
Horm. Metab. Res.
28:
659-663,
1996[Medline].
15.
Kiess, W.,
T. Siebler,
P. Englaro,
J. Kratzsch,
J. Deutscher,
K. Meyer,
B. Gallaher,
and
W. F. Blum.
Leptin as a metabolic regulator during fetal and neonatal life and in childhood and adolescence.
J. Pediatr. Endocrinol. Metab.
11:
483-496,
1998[Medline].
16.
Leeper, L. L.,
R. Schroeder,
and
S. J. Henning.
Kinetics of circulating corticosterone in infant rats.
Pediatr. Res.
24:
595-599,
1988[Medline].
17.
Lin, P.-Y.,
D. R. Romsos,
and
G. A. Leveille.
Food intake, body weight gain and composition of the young obese (ob/ob) mouse.
J. Nutr.
107:
1715-1723,
1977.
18.
Mistry, A. M.,
N-G. Chen,
Y.-S. Lee,
and
D. R. Romsos.
Consumption of a glucose diet enhances the sensitivity of pancreatic islets from adrenalectomized genetically obese (ob/ob) mice to glucose-induced insulin secretion.
J. Nutr.
125:
503-511,
1995.
19.
Mistry, A. M.,
A. G. Swick,
and
D. R. Romsos.
Leptin rapidly lowers food intake and elevates metabolic rates in lean and ob/ob mice.
J. Nutr.
127:
2065-2072,
1997
20.
Pelleymounter, M. A.,
M. J. Cullen,
M. B. Baker,
R. Hecht,
D. Winters,
T. Boone,
and
F. Collins.
Effects of the obese gene product on body weight regulation in ob/ob mice.
Science
269:
540-543,
1995
21.
Phifer, C. B.,
C. R. Sikes,
and
W. G. Hall.
Control of ingestion in 6-day-old rat pups: termination of intake by gastric fill alone?
Am. J. Physiol.
250 (Regulatory Integrative Comp. Physiol. 19):
R807-R814,
1986.
22.
Rayner, D. V.,
G. D. Dalgliesh,
J. S. Duncan,
L. J. Hardie,
N. Hoggard,
and
P. Trayhurn.
Postnatal development of the ob gene system: elevated leptin levels in suckling fa/fa rats.
Am. J. Physiol.
273 (Regulatory Integrative Comp. Physiol. 42):
R446-R450,
1997
23.
Stehling, O.,
H. Döring,
J. Ertl,
G. Preibisch,
and
I. Schmidt.
Leptin reduces juvenile fat stores by altering the circadian cycle of energy expenditure.
Am. J. Physiol.
271 (Regulatory Integrative Comp. Physiol. 40):
R1770-R1774,
1996
24.
Weigle, D. S.,
T. R. Bukowski,
D. C. Foster,
S. Holderman,
J. M. Kramer,
G. Lasser,
C. E. Lofton-Day,
D. E. Prunkard,
C. Raymond,
and
J. L. Kuijper.
Recombinant ob protein reduces feeding and body weight in the ob/ob mouse.
J. Clin. Invest.
96:
2065-2070,
1995.
25.
Wilson, L. M.,
M. L. Stewart,
and
E. P. McAnanama.
Milk intakes of genetically obese (ob/ob) and lean mouse pups differ with enhanced milk supply.
Physiol. Behav.
46:
823-827,
1989[Medline].
26.
Yu, W. H.,
M. Kimura,
A. Walczewska,
S. Karanth,
and
S. M. McCann.
Role of leptin in hypothalamic-pituitary function.
Proc. Natl. Acad. Sci. USA
94:
1023-1028,
1997
27.
Zar, J. H.
Biostatistical Analysis. Englewoods Cliffs, NJ: Prentice Hall, 1984.
28.
Zhang, Y.,
R. Proenca,
M. Maffei,
M. Barone,
L. Leopold,
and
J. M. Friedman.
Positional cloning of the mouse obese gene and its human homologue.
Nature
372:
425-432,
1994[Medline].
This article has been cited by other articles:
|
|
 |
|
  K. Huang, R. Rabold, E. Abston, B. Schofield, V. Misra, E. Galdzicka, H. Lee, S. Biswal, W. Mitzner, and C. G. Tankersley Effects of leptin deficiency on postnatal lung development in mice J Appl Physiol, July 1, 2008; 105(1): 249 - 259. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T.-L. Li, L.-C. Chiou, Y. S. Lin, J.-R. Hsieh, and L.-L. Hwang Electrophysiological study on the effects of leptin in rat dorsal motor nucleus of the vagus Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2007; 292(6): R2136 - R2143. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Bowen, T. D. Mitchell, and R. B. S. Harris Method of leptin dosing, strain, and group housing influence leptin sensitivity in high-fat-fed weanling mice Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2003; 284(1): R87 - R100. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. J. A. Janssen and J. F. M. Smits Autonomic control of blood pressure in mice: basic physiology and effects of genetic modification Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2002; 282(6): R1545 - R1564. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Y. W. Chan, J. Nasir, C.-A. Gutekunst, S. Coleman, A. Maclean, A. Maas, M. Metzler, M. Gertsenstein, C. A. Ross, A. Nagy, et al. Targeted disruption of Huntingtin-associated protein-1 (Hap1) results in postnatal death due to depressed feeding behavior Hum. Mol. Genet., April 15, 2002; 11(8): 945 - 959. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. E. Truett, J. A. Walker, and R. B. S. Harris A developmental switch affecting growth of fatty rats Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2000; 279(6): R1956 - R1963. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
