| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Trauma Research, St. Joseph's Hospital and Medical Center, Phoenix, Arizona 85013; and Thermoregulation Laboratory, Legacy Holladay Park Research and Technology Center, Portland, Oregon 97208
 |
ABSTRACT |
|---|
 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Leptin is thought to be involved in febrigenic signaling from the periphery to the brain. Zucker obese rats have a so-called fatty mutation in the leptin receptor gene and express a dysfunctional protein. Studies comparing the fever responses of fatty (fa/fa) rats and of their lean (Fa/Fa and Fa/fa) counterparts yield contradictory results. To resolve these contradictions, we evaluated the effect of fatty mutation on infectious and stress-associated fevers at thermoneutrality (29°C) and in a cool environment (20°C). Zucker fa/fa and Fa/? rats were infused with Escherichia coli lipopolysaccharide (LPS; 10 µg/kg) through a jugular catheter (infectious fever) or with saline through the catheter (control) or received a painful intramuscular injection of saline (stress fever). At thermoneutrality, the colonic temperature (Tc) responses of fatty rats to all stimuli tested were no different from the responses of lean rats. In a cool environment, Tc responses of fatty rats to all stimuli were ~0.5°C lower than those of lean rats. The observed attenuation of LPS-induced and stress-associated fevers in Zucker fatty rats in the cold agrees with the literature data showing that brown adipose tissue (the major heat production effector) is morphologically and functionally defective in these rats. The normal febrile responses of fatty Zucker rats to pyrogenic stimuli at thermoneutrality indicate that fatty mutation does not interrupt febrigenic signaling from the periphery to the brain.
infectious fever; stress fever; lipopolysaccharide; endotoxin; thermogenesis; thermoneutrality; cold exposure; obesity
| |
INTRODUCTION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
FEVER is a common
sign of inflammation, infection, and stress. According to the
definition (38), infectious fever is triggered by a
variety of exogenous pyrogens, such as bacterial lipopolysaccharide (LPS), and further mediated by endogenous pyrogens, including cytokines
[e.g., interleukin (IL)-1
, IL-6, and tumor necrosis factor
(TNF)-
] and prostaglandins (PGs) of the E series. Stress fever
(also known as stress hyperthermia) is evoked by both physical and
psychological stimuli such as restraint, foot shock, or exposure to a
new environment. Like infectious fever, stress fever is mediated by
cytokines and PGs (19, 20). At the effector level, fever is realized via inhibition of heat loss mechanisms and/or activation of
heat production mechanisms (34, 36).
Several lines of evidence suggest that mechanisms of LPS- and
cytokine-induced fevers involve leptin, an IL-6-like protein produced
by adipocytes and responsible for adipose tissue-to-brain signaling
(7, 9). Indeed, exogenous (LPS) and endogenous (IL-1 and
TNF) pyrogens upregulate expression of the leptin gene and increase the
concentration of leptin in the blood (15, 17, 31).
LPS-induced leptin expression is mediated by IL-1 (10). Leptin, in turn, stimulates production of pyrogenic cytokines by
immunocytes (21, 22). Furthermore, Luheshi et al.
(23) demonstrated pyrogenic activity for leptin. The
authors found that intracerebroventricular or intravenous
administration of leptin to rats causes fever, which is mediated by
IL-1 and PGs. It could be expected, therefore, that animals
deficient in leptin or its receptor should respond to pyrogens with
attenuated fevers.
Zucker obese rats have a missense point mutation (fatty) in
the primary leptin receptor gene and express a dysfunctional protein with a glycine-to-proline substitution in position 269 of the ligand-binding domain (4, 26). As a result, the
receptor-mediated transport and intracellular signaling of leptin are
defective in these animals (6, 41). Studies examining the
effect of the fatty mutation on fever yield contradictory
results (3, 8, 27, 30). Rosenthal et al. (30)
observed an attenuation of the early, but not late, stages of an
intramuscular LPS-induced fever in Zucker fatty
(fa/fa) rats compared with their lean
(Fa/Fa and Fa/fa) counterparts. The authors also
reported that the fatty rats responded to a painful
intramuscular injection of saline with an attenuated stress fever.
Dascombe et al. (8) and Busbridge et al. (3)
found that the febrile response to intracerebroventricular IL-1 was
strongly attenuated in Zucker obese rats. Plata-Salamán et al.
(27) found that intracerebroventricular IL-1-induced fever was not inhibited but, to the contrary, strongly exaggerated in
fa/fa rats, whereas intracerebroventricular IL-2- and
IL-6-induced fevers were suppressed, and intracerebroventricular
TNF--induced fever was unaffected. The data showing an attenuation
of fever in obese rats (3, 8, 27, 30) seem to suggest a
functionally important role of leptin receptor in febrigenic signaling;
they also suggest a deficiency of this signaling in fatty
mutants. However, interpretation of these data is convoluted.
All studies reviewed (3, 8, 27, 30) were conducted at an
ambient temperature (Ta) of 22-24°C, i.e., under
conditions of mild-to-moderate cold exposure. Even 24°C is normally
below the lower border of the thermoneutral zone for Zucker rats, both obese and lean (25, 28). At subneutral Tas,
the development of the febrile response requires activation of
thermogenesis in brown adipose tissue, the major heat production
effector in the rat (12). However, brown adipose tissue is
morphologically and functionally defective in fatty animals,
and their thermogenic responses are weak (2, 33). Hence,
the observed attenuation of intracerebroventricular IL-1, IL-2, and
IL-6 fevers (3, 8, 27), stress fever (30),
and the early stages of intramuscular LPS fever (30) might
result from insufficient thermogenesis rather than a deficiency of the
hypothesized leptin receptor-mediated febrigenic signaling.
The present study was conducted to evaluate the effect of fatty mutation of the leptin receptor on LPS-induced fever and stress fever; the latter was caused by a painful intramuscular injection of saline. The responses were studied at thermoneutrality and in a cool environment. The results suggest that fatty mutation leads to a thermogenic insufficiency but does not interfere with febrigenic signaling.
| |
MATERIALS AND METHODS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Animals
Twelve male Zucker fa/fa and eleven Fa/? rats were purchased from Harlan (Indianapolis, IN). At the time of the experiments, all rats were 9-10 wk old. Initially, the animals were housed three per standard "shoebox"; after surgery, they were caged individually. The room was on a 12:12-h light-dark cycle (lights on from 7:00 AM); Ta was maintained at 22°C. Food (Teklad Rodent Diet W 8604, Harlan Teklad, Madison, WI) and water were available ad libitum. The animals were handled and weighed regularly. They also were habituated (5 training sessions, 4 h each) to a cylindrical stock that limited their back-and-forth movements and prevented them from turning around. The same stocks have been used in our laboratory in the past (29). We learned that rats easily adapt to the stocks and often prefer them to the open space of their home cages; they show no signs of stress and have the same body temperature as their freely moving counterparts would have at the same Ta (42). All experiments were performed during the light phase (measurements started at ~9:00 AM). To prevent the development of tolerance, each animal received LPS only once. At the end of the study, the rats were killed with pentobarbital sodium (20 mg/kg iv). The experiments have been approved by the Institutional Animal Care and Use Committee (Protocol 98-07).Surgical Preparation
General information. Each rat was subjected to a two-step surgical operation. During the first step, an acrylic platform was secured to the rat's skull. During the second step, a catheter was implanted into the vena cava superior, the free end of the catheter was placed into a hollow pedestal, and the pedestal was affixed to the platform (see below). Before surgery, each rat received a subcutaneous injection of an antibiotic (enrofloxacin, 12 mg/kg) and was anesthetized with an intraperitoneal injection of ketamine-xylazine-acepromazine cocktail (55.6, 5.5, and 1.1 mg/kg, respectively). During surgery, the animal's body was heated with a Deltaphase Isothermal Pad (Braintree Scientific, Braintree, MA). Postoperatively, the animal was allowed to recover from anesthesia under a heating lamp and transferred to its home cage thereafter.
Step 1. The head of an anesthetized rat was placed into a stereotaxic instrument (model 900, David Kopf Instruments, Tujunga, CA), and a 1.5-cm incision was made over the sagittal suture. Subcutaneous tissues were removed, and the bone was cleansed with hydrogen peroxide (3%) and dried with ethanol (98%). Four miniature stainless steel screws were threaded into the bone. The bone and the screws were covered with dental acrylic to form a round platform (~1 cm in diameter) with a flat surface. After the acrylic hardened, the rat was released from the stereotaxic instrument.
Step 2. The animal was then placed on an operating board (Harvard Apparatus, South Natick, MA), and a 1-cm longitudinal incision was made on the ventral surface of the neck, 1 cm to the right of the trachea. The muscles were retracted, and the right jugular vein was exposed. A silicone catheter (ID 0.5 mm, OD 0.9 mm) containing heparinized (50 U/ml) pyrogen-free saline was passed into the vena cava superior through the right jugular vein. The 15-cm free end of the catheter was pulled under the skin to the head. The wound on the ventral surface of the neck was sutured. The free end of the catheter was rolled into a coil and placed into a polypropylene vial (pedestal). The pedestal was affixed to the platform with dental acrylic and protected with a screwed-on cap. The day after surgery and every other day thereafter, the catheter was flushed with heparinized saline.
Experiments
Instrumentation. For an experiment, each rat was placed into its stock and transferred to a climatic chamber (Forma Scientific, Marietta, OH) set to 50% relative humidity and a Ta of either 29.0°C (neutral for Zucker rats; Refs. 25, 28) or 20.0°C (moderate cold exposure). The exteriorized portion of the intravenous catheter was pulled through a wall port and connected to a syringe. Each animal was instrumented with a thermocouple (inserted 9 cm beyond the anus) to measure its colonic temperature (Tc). The thermocouples from multiple animals were connected to a data logger (Dianachart, Rockaway, NJ) and personal computer. After a 1-h stabilization period, the measurements were begun, and Tc and Ta were sampled every 2 min for the duration of the test.
Protocol. After the baseline Tc was recorded for 1 h, each animal received either an intravenous injection of saline (saline test), an intravenous injection of LPS (LPS test), or a painful intramuscular injection of saline (stress test). In the LPS test, Escherichia coli 0111:B4 LPS (lot no. 35H4086; Sigma, St. Louis, MO; 10 µg/kg) in saline (1 ml/kg) was nonstressfully injected through the catheter from outside the chamber. In the saline test, pyrogen-free saline (1 ml/kg) was injected through the catheter. In the stress test, saline (1 ml/kg) was injected intramuscularly, into the posterior aspect of the thigh (mm. biceps femoris, semitendinosus, and gluteus maximus) with a 23-gauge needle; this injection was associated with unavoidable pain and stress. In each rat, all three tests were conducted. The LPS and saline tests were performed 3 days apart in a counterbalanced order; the stress test was performed 2 wk later. Each test was conducted in a neutral (29°C) or cool (20°C) environment. The rats were observed for 8 h (LPS or saline test) or 2 h (stress test).
Data Processing and Analysis
Measure of the febrile response.
Two measures are often used to assess the height of fever: deep body
temperature (e.g., Tc) at the peak of the response
(Tmax) and the maximal rise in deep body temperature
(
Tmax). The latter is calculated as follows
|
(1) |
Tmaxs, their Tmaxs are
equal as well. Hence, when animals have the same T0, their
febrile responses can be compared by using either Tmax or
Tmax, and the results of the comparison are independent
of the response measure used. However, when two animals have different
T0s and respond to a pyrogen with equal
Tmaxs, their Tmaxs are not equal. In this case, comparison of the two responses gives different results, depending on whether Tmax or Tmax is used.
In a variety of models [intracerebroventricular PGE1- or
PGE2-induced fever (11, 24, 35, 37),
intracerebroventricular cholecystokinin-8-induced fever (35,
37), intravenous LPS fever (34), and yeast
infection-associated fever (18) in rats; intraperitoneal
LPS-induced fever and stress fever in hamsters (5)], it
has been firmly established that Tmax represents a
consistent characteristic of the febrile response. In contrast,
Tmax varies widely, depending on experimental conditions (different T0s due to different Tas, day-night
variations, etc.), and cannot be used as a reliable measure of fever
height. Hence, Tmax (not Tmax) is the
physiologically justified measure [see Feng et al.
(11)]. This measure was used in the present study. For
the triphasic LPS-induced fever (see Ref. 29), three
Tmaxs were determined, one for each febrile phase. For the
monophasic stress fever, one Tmax was determined.
Data analysis. Different procedures were used to compare curves [Tc(time) functions] and individual points (T0s and Tmaxs). The Tc curves were randomized between genotypes (separately for each test) and subjected to 10,000 repetitions of the analysis of variance. An empirical distribution of the F-statistic was created and compared with the original statistic. The Tmaxs (for stress fever and each phase of LPS fever) and T0s were determined in individual curves, averaged across the group, and compared between genotypes by Student's t-test. The data are presented as means ± SE.
| |
RESULTS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Saline Test
At thermoneutrality (Fig. 1, left), Zucker Fa/? and fa/fa rats had similar T0s (37.8 ± 0.1 and 38.1 ± 0.2°C, respectively; P = 0.153). Saline injection did not affect Tc in either strain and evoked no significant difference between the genotypes (P = 0.603). In the cool environment (Fig. 1, right), the T0 of the lean rats (37.9 ± 0.2°C) was substantially higher than that of the fatty rats (37.3 ± 0.1°C; P = 0.010). Throughout the test, Tc of the lean rats gradually decreased and reached ~37.3°C at the end of the observation period. In the obese rats, Tc decreased in a parallel fashion and remained ~1°C lower than in the lean rats throughout the test (P = 0.004).
|
LPS Test
At the neutral Ta (Fig. 2, left), T0s of the lean and obese rats were 38.1 ± 0.1 and 38.3 ± 0.1°C, respectively (P = 0.089). Both genotypes responded to LPS with triphasic fevers. These fevers had a relatively high first phase (lean: Tmax = 39.1 ± 0.1°C; obese: Tmax = 39.1 ± 0.1°C; P = 0.721) and a relatively low third phase (lean: Tmax = 38.8 ± 0.3°C; obese: Tmax = 39.0 ± 0.1°C; P = 0.638), which is typical for Long-Evans and Long-Evans-derived rat strains (16, 29). No febrile phase differed significantly between the genotypes. In the cool environment (Fig. 2, right), the T0 of the lean rats (38.4 ± 0.2°C) was substantially higher than that of the obese animals (37.6 ± 0.1°C; P = 0.003). The first phase of the triphasic LPS fever was suppressed in the obese rats (Tmax = 38.5 ± 0.2°C) compared with the lean (Tmax = 39.0 ± 0.1°C; P = 0.026), but neither the second phase (lean: Tmax = 38.6 ± 0.1°C; obese: Tmax = 38.3 ± 0.3°C; P = 0.325) nor the third phase (lean: Tmax = 38.6 ± 0.3°C; obese: Tmax = 38.6 ± 0.4°C; P = 0.934) was affected.
|
Stress Test
At the neutral Ta (Fig. 3, left), T0s of the lean and obese rats were 37.7 ± 0.1 and 37.9 ± 0.2°C, respectively (P = 0.206). Both genotypes responded to the painful intramuscular injection of saline with rapid rises in Tc; no significant intergenotype differences were found (lean: Tmax = 38.5 ± 0.1°C; obese: Tmax = 38.5 ± 0.1°C; P = 0.920). In the cool environment (Fig. 3, right), the T0 of the lean rats (37.9 ± 0.1°C) was substantially higher than that of the obese animals (37.3 ± 0.2°C; P = 0.015). The stress fever was suppressed in the obese rats (Tmax = 38.1 ± 0.2°C) compared with their lean counterparts (Tmax = 38.8 ± 0.1°C; P = 0.012).
|
| |
DISCUSSION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
To test the hypothesis that fatty mutation of the leptin receptor impairs febrile responsiveness, we studied LPS fever (a model of infectious fever) and stress fever in Zucker fa/fa and Fa/? rats. At thermoneutrality, the two genotypes had comparable Tcs and responded with similar Tc rises to the febrigenic stimuli used, i.e., an intravenous injection of LPS and a mild stressor (intramuscular injection of saline). These findings represent the first attempt to measure the febrile response of fatty rats at a neutral Ta. They demonstrate that the fatty mutation-associated defect in the primary leptin receptor affects neither LPS-induced nor stress-associated fever.
In a cool environment, the T0 of fatty rats was
substantially lower than that of lean rats. These data support previous
studies showing that leptin receptor-deficient rats have a defective
response to cold and are prone to hypothermia at subneutral
Tas (8, 27, 39). Both LPS fever and stress
fever were attenuated in the mutants. These findings are consistent
with data by others who also used Tc (not
Tc; see Data Processing and Analysis) as a
response measure and showed that stress fever (30),
intramuscular LPS-induced fever (30), and
intracerebroventricular IL-1 fever (3, 8) were all
attenuated in fatty Zucker rats at subneutral Tas. In contrast, the only study that used
Tc found a variable effect of fatty mutation
on the febrile response to intracerebroventricular cytokines, from
inhibition to no effect to exaggeration (27). However,
T0 of the obese rats was 0.6°C lower than that of the lean rats (27). When T0s are different, an
attenuation of the Tc response may correspond to any change
of the Tc response, from inhibition to no effect to
exaggeration. Hence, most reports (3, 8, 30) support our
finding that febrile responsiveness of Zucker fatty rats is
inhibited in the cold, while the only remaining study (27)
neither supports nor refutes it.
Why is the febrile response of fatty rats normal at thermoneutrality but inhibited in the cold? Fever occurs because of a decrease in heat loss (the predominant autonomic mechanism is skin vasoconstriction) and/or an increase in heat production (the predominant autonomic mechanism is thermogenesis in brown adipose tissue). Energetically inexpensive effector mechanisms (skin vasoconstriction) are recruited first; if their activation is insufficient to produce an adequate response, then the expensive effectors (thermogenesis) are activated (36). At neutral and supraneutral Tas, skin vasoconstriction is always used by rats to mount a fever; moreover, at these Tas, rats respond to a pyrogen [e.g., intravenous LPS (34), intracerebroventricular PGE1 (37), or intracerebroventricular cholecystokinin-8 (37)] often by using skin vasoconstriction alone, without activation of heat production. At subneutral Tas, skin vasculature is already constricted; no further constriction is possible (28, 34), and rats depend on brown fat thermogenesis to produce the febrile response. Yet, the brown adipose tissue is morphologically and functionally defective in Zucker fatty animals, and their thermogenic responses are weak (2, 33). Therefore, the impaired thermogenesis in Zucker fa/fa rats is likely to account for the inhibition of their febrile responsiveness at subneutral Tas (3, 8, 30, and present data). At neutral Tas, the role of thermogenesis is less important, and its deficiency leads to no change in the fever response.
We conclude that attenuation of the febrile response observed in fatty Zucker rats at subneutral Tas probably reflects impaired thermogenesis in brown adipose tissue. When studied at thermoneutrality, LPS-induced and stress-associated fevers of fatty rats are no different from the responses of lean rats. These data indicate that fatty mutation of the leptin receptor does not interrupt febrigenic signaling.
Perspectives
The present results show that fatty mutation does not interrupt the mediatory cascade of fever. Nevertheless, they do not rule out the possibility that the febrigenic cascade involves the leptin receptor. Until recently, fatty mutation was thought to attenuate or even to prevent leptin receptor-mediated signaling completely in various experimental tests (1, 6, 14, 32, 41). However, recent studies (13, 40) show that this mutation may permit normal functioning of the leptin receptor, at least in some experimental paradigms. Hence, negative results obtained in fatty mutants should be viewed with caution. Further investigations involving pharmacological blockade or genetic deletion of the leptin receptor are warranted.| |
ACKNOWLEDGEMENTS |
|---|
We thank S. Patel (Phoenix Country Day School, Scientific Enrichment Program) and L. Was (Univ. of Arizona, Undergraduate Biology Research Program) for technical assistance, Dr. L. Homer for help with data analysis, Drs. V. Kulchitsky and D. Dogan for reading the manuscript and providing important feedback, and Dr. S. Kick and D. Mutchler for editing the manuscript.
| |
FOOTNOTES |
|---|
The study was supported in part by National Institute of Neurological Disorders and Stroke Grant R01-NS-41233.
Address for reprint requests and other correspondence: A. A. Romanovsky, Trauma Research, St. Joseph's Hospital and Medical Center, 350 West Thomas Rd., Phoenix, AZ 85013 (E-mail: aromano{at}chw.edu).
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. Section 1734 solely to indicate this fact.
10.1152/ajpregu.00376.2001
Received 2 June 2001; accepted in final form 11 October 2001.
| |
REFERENCES |
|---|
|
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
1.
Al-Barazanji, KA,
Buckingham RE,
Arch JR,
Haynes A,
Mossakowska DL,
Holmes SD,
McHale MT,
Wang XM,
and
Gloger IS.
Effect of intracerebroventricular infusion of leptin in obese Zucker rats.
Obes Res
5:
387-394,
1997[Web of Science][Medline].
2.
Bing, C,
Pickavance L,
Wang Q,
Frankish H,
Trayhurn P,
and
Williams G.
Role of hypothalamic neuropeptide Y neurons in the defective thermogenic response to acute cold exposure in fatty Zucker rats.
Neuroscience
80:
277-284,
1997[Web of Science][Medline].
3.
Busbridge, NJ,
Carnie JA,
Dascombe MJ,
Johnston JA,
and
Rothwell NJ.
Adrenalectomy reverses the impaired pyrogenic responses to interleukin-1 in obese Zucker rats.
Int J Obes
14:
809-814,
1990[Web of Science][Medline].
4.
Chua, SC,
White DW,
Wu-Peng XS,
Liu SM,
Okada N,
Kershaw EE,
Chung WK,
Power-Kehoe L,
Chua M,
Tartaglia LA,
and
Liebel RL.
Phenotype of fatty due to Gln269Pro mutation in the leptin receptor (Lepr).
Diabetes
45:
1141-1143,
1996[Abstract].
5.
Conn, CA,
Borer KT,
and
Kluger MJ.
Body temperature rhythm and response to pyrogen in exercising and sedentary hamsters.
Med Sci Sports Exerc
22:
636-642,
1990[Web of Science][Medline].
6.
Crouse, JA,
Elliott GE,
Burgess TL,
Chui L,
Bennett L,
Moore J,
Nicolson M,
and
Pacifici RE.
Altered cell surface expression and signaling of leptin receptor containing the fatty mutation.
J Biol Chem
273:
18365-18373,
1998
7.
Dallongeville, J,
Fruchart JC,
and
Auwerx J.
Leptin, a pleiotropic hormone: physiology, pharmacology, and strategies for discovery of leptin modulators.
J Med Chem
41:
5337-5352,
1998[Web of Science][Medline].
8.
Dascombe, MJ,
Hardwick A,
Lefeuvre RA,
and
Rothwell NJ.
Impaired effects of interleukin-1 on fever and thermogenesis in genetically obese rats.
Int J Obes
13:
367-373,
1989[Web of Science][Medline].
9.
Elmquist, JK,
Maratos-Flier E,
Saper CB,
and
Flier JS.
Unraveling the central nervous system pathways underlying responses to leptin.
Nat Neurosci
1:
445-450,
1998[Web of Science][Medline].
10.
Faggioni, R,
Fantuzzi G,
Fuller J,
Dinarello CA,
Feingold KR,
and
Grunfeld C.
IL-1 mediates leptin induction during inflammation.
Am J Physiol Regulatory Integrative Comp Physiol
274:
R204-R208,
1998
11.
Feng, JD,
Price M,
Cohen J,
and
Satinoff E.
Prostaglandin fevers in rats: regulated change in body temperature or change in regulated body temperature?
Am J Physiol Regulatory Integrative Comp Physiol
257:
R695-R699,
1989
12.
Foster, DO.
Quantitative contribution of brown adipose tissue thermogenesis to overall metabolism.
Can J Biochem Cell Biol
62:
618-622,
1984[Web of Science][Medline].
13.
Fox, AS,
and
Olster DH.
Effect of intracerebroventricular leptin administration of feeding and sexual behaviors in lean and obese female Zucker rats.
Horm Behav
4:
377-387,
2000.
14.
Glaum, SR,
Hara M,
Bindokas VP,
Lee CC,
Polonsky KS,
Bell GI,
and
Miller RJ.
Leptin, the obese gene product, rapidly modulates synaptic transmission in the hypothalamus.
Mol Pharmacol
50:
230-235,
1996[Abstract].
15.
Grunfeld, C,
Zhao C,
Fuller J,
Pollack A,
Moser A,
Friedman J,
and
Feingold KR.
Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters.
J Clin Invest
97:
2152-2157,
1996[Web of Science][Medline].
16.
Ivanov, AI,
Kulchitsky VA,
and
Romanovsky AA.
Role of cholecystokinin A receptor (CCK Ar) in fever.
Soc Neurosci Abstr
26:
1740,
2000.
17.
Janik, JE,
Curti BD,
Considine RV,
Rager HC,
Powers GC,
Alvord WG,
Smith J,
Gause BL,
and
Kopp WC.
Interleukin 1 increases serum leptin concentrations in humans.
J Clin Endocrinol Metab
82:
3084-3086,
1997
18.
Kent, S,
Price M,
and
Satinoff E.
Fever alters characteristics of sleep in rats.
Physiol Behav
44:
709-715,
1988[Medline].
19.
Kluger, MJ,
O'Reilly B,
Shore TR,
and
Vander AJ.
Further evidence that stress hyperthermia is a fever.
Physiol Behav
39:
736-766,
1987.
20.
LeMay, LG,
Vander AJ,
and
Kluger MJ.
The effect of psychological stress on plasma interleukin-6 activity in rats.
Physiol Behav
47:
957-961,
1990[Medline].
21.
Loffreda, S,
Yang SQ,
Lin HZ,
Karp CL,
Brengman ML,
Wang DJ,
Klein AS,
Bulkley GB,
Bao C,
Noble PW,
Lane MD,
and
Diehl AM.
Leptin regulates proinflammatory immune responses.
FASEB J
12:
57-65,
1998
22.
Lord, GM,
Matarese G,
Howard JK,
Baker RJ,
Bloom SR,
and
Lechler RI.
Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression.
Nature
394:
897-901,
1998[Medline].
23.
Luheshi, GN,
Gardener JD,
Rushforth DA,
Loudon AS,
and
Rothwell NJ.
Leptin actions on food intake and body temperature are mediated by IL-1.
Proc Natl Acad Sci USA
96:
7047-7052,
1999
24.
Malkinson, TJ,
Cooper KE,
and
Veale WL.
Physiological changes during thermoregulation and fever in urethane-anesthetized rats.
Am J Physiol Regulatory Integrative Comp Physiol
255:
R73-R81,
1988
25.
Megirian, D,
Dmochowski J,
and
Farkas GA.
Mechanism controlling sleep organization of the obese Zucker rats.
J Appl Physiol
84:
253-256,
1998
26.
Phillips, MS,
Liu Q,
Hammond HA,
Dugan V,
Hey PJ,
Caskey CT,
and
Hess JF.
Leptin receptor missense mutation in the fatty Zucker rat.
Nat Genet
13:
18-19,
1996[Web of Science][Medline].
27.
Plata-Salamán, C,
Peloso E,
and
Satinoff E.
Cytokine-induced fever in obese (fa/fa) and lean (Fa/Fa) Zucker rats.
Am J Physiol Regulatory Integrative Comp Physiol
275:
R1353-R1357,
1998
28.
Romanovsky, AA,
Ivanov AI,
and
Shimansky YP.
How to determine whether a given environment is thermoneutral for a given animal.
Soc Neurosci Abstr
27:
2506,
2001.
29.
Romanovsky, AA,
Simons CT,
and
Kulchitsky VA.
"Biphasic" fever often consists of more than two phases.
Am J Physiol Regulatory Integrative Comp Physiol
275:
R323-R331,
1998
30.
Rosenthal, M,
Roth J,
Störr J,
and
Zeisberger E.
Fever response in lean (Fa/
) and obese (fa/fa) Zucker rats and its lack to repeated injections of LPS.
Physiol Behav
59:
787-793,
1996[Medline].
31.
Sarraf, P,
Friderich RC,
Turner EM,
Ma G,
Jaskowiak NT,
Rivet D,
Flier JS,
Lowell BB,
Fraker DL,
and
Alexander HR.
Multiple cytokines and acute inflammation raise mouse leptin level: potential role in the inflammatory anorexia.
J Exp Med
185:
171-175,
1997
32.
Seeley, RJ,
van Dijk G,
Campfield LA,
Smith FJ,
Burn P,
Nelligan JA,
Bell SM,
Backin DG,
Woods SC,
and
Schwartz MW.
Intraventricular OB protein (leptin) reduces food intake and body weight of lean rats but not obese Zucker rats.
Horm Metab Res
28:
664-668,
1996[Web of Science][Medline].
33.
Seydoux, J,
Benzi RH,
Shibata M,
and
Girardier L.
Underlying mechanisms of atrophic state of brown adipose tissue in obese Zucker rats.
Am J Physiol Regulatory Integrative Comp Physiol
259:
R61-R69,
1990
34.
Székely, M,
and
Szelényi Z.
Endotoxin fever in the rat.
Acta Physiol Hung
53:
265-277,
1979.
35.
Szelényi, Z,
Barthó L,
Székely M,
and
Romanovsky AA.
Cholecystokinin-octapeptide (CCK-8) injected into a cerebral ventricle induces a fever-like thermoregulatory response mediated by type B CCK-receptor in the rat.
Brain Res
638:
69-77,
1994[Web of Science][Medline].
36.
Szelényi, Z,
and
Székely M.
Comparison of the effector mechanisms during endotoxin fever in the adult rabbit.
Acta Physiol Hung
54:
33-41,
1979.
37.
Szelényi, Z,
Székely M,
and
Romanovskii AA, (Romanovsky AA)
The central thermoregulatory action of cholecystokinin-8 and prostaglandin E1.
Fiziol Zh
78:
94-101,
1992 (in Russian).
38.
The Commission for Thermal Physiology of the International Union of Physiological Sciences (I.U.P.S. Thermal Commission).
Glossary of terms for thermal physiology: third edition.
Jpn J Physiol
51:
i-xxxvi,
2001.
39.
Trayhurn, P,
Thurlby PL,
and
James WP.
A defective response to cold in the obese (ob/ob) mouse and the obese Zucker (fa/fa) rat (Abstract).
Proc Nutr Soc
35:
133A,
1976[Medline].
40.
Wang, T,
Hartzell DL,
Flatt WP,
Martin RJ,
and
Baile CA.
Responses of lean and obese Zucker rats to centrally administered leptin.
Physiol Behav
65:
333-341,
1998[Medline].
41.
Yamashita, T,
Murakami T,
Iida M,
Kuwajima M,
and
Shima K.
Leptin receptor of Zucker fatty rat performs reduced signal transduction.
Diabetes
46:
1077-1080,
1997[Abstract].
42.
Yang, Y,
and
Gordon CJ.
Ambient temperature limits and stability of temperature regulation in telemetered male and female rats.
J Therm Biol
21:
353-363,
1996.
This article has been cited by other articles:
|
|
 |
|
  W. Inoue, G. Somay, S. Poole, and G. N. Luheshi Immune-to-brain signaling and central prostaglandin E2 synthesis in fasted rats with altered lipopolysaccharide-induced fever Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2008; 295(1): R133 - R143. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Romanovsky Do fever and anapyrexia exist? Analysis of set point-based definitions Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2004; 287(4): R992 - R995. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Romanovsky Anorexia: the toll for lipopolysaccharide recognition Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2004; 287(2): R274 - R275. [Full Text] [PDF]
|
|
|
|
|
|
A. A. Romanovsky, N. Sugimoto, C. T. Simons, and W. S. Hunter The organum vasculosum laminae terminalis in immune-to-brain febrigenic signaling: a reappraisal of lesion experiments Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2003; 285(2): R420 - R428. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Romanovsky and S. R. Petersen The spleen: another mystery about its function Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2003; 284(6): R1378 - R1379. [Full Text] [PDF]
|
|
|
|
|
|
H. Scholz Fever Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2003; 284(4): R913 - R915. [Full Text] [PDF]
|
|
|
|
 |
|
 A. I Ivanov, V. A Kulchitsky, and A. A Romanovsky Role for the cholecystokinin-A receptor in fever: a study of a mutant rat strain and a pharmacological analysis J. Physiol., March 15, 2003; 547(3): 941 - 949. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. F. DiBona Thermoregulation Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2003; 284(2): R277 - R279. [Full Text] [PDF]
|
|
|
|
 |
|
 A. A. Romanovsky, A. I. Ivanov, and Y. P. Shimansky Molecular Biology of Thermoregulation: Selected Contribution: Ambient temperature for experiments in rats: a new method for determining the zone of thermal neutrality J Appl Physiol, June 1, 2002; 92(6): 2667 - 2679. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
