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1 Departments of Nutrition, Food, and Exercise Sciences and 2 Psychology, the Program in Neuroscience, Florida State University, Tallahassee, Florida
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The primary purpose of the
study was to test the hypothesis that reduced leptin signaling is
necessary to elicit the cardiovascular and metabolic responses to
fasting. Lean (Fa/?; normal leptin receptor;
n = 7) and obese (fa/fa; mutated leptin
receptor; n = 8) Zucker rats were instrumented with
telemetry transmitters and housed in metabolic chambers at 23°C
(12:12-h light-dark cycle) for continuous (24 h) measurement of
metabolic and cardiovascular variables. Before fasting, mean arterial
pressure (MAP) was higher (MAP: obese = 103 ± 3; lean = 94 ± 1 mmHg), whereas oxygen consumption (
O2: obese = 16.5 ± 0.3;
lean = 18.6 ± 0.2 ml · min
1 · kg0.75)
was lower in obese Zucker rats compared with their lean
controls. Two days of fasting had no effect on MAP in either
lean or obese Zucker rats, whereas O2
(obese = 
3.1 ± 0.3; lean = 2.9 ± 0.1 ml · min1 · kg0.75)
and heart rate (HR: obese = 56 ± 4; lean = 42 ± 4 beats/min) were decreased markedly in both groups. Fasting
increased HR variability both in lean (+1.8 ± 0.4 ms) and obese
(+2.6 ± 0.3 ms) Zucker rats. After a 6-day period of ad libitum
refeeding, when all parameters had returned to near baseline levels,
the cardiovascular and metabolic responses to 2 days of
thermoneutrality (ambient temperature 29°C) were determined.
Thermoneutrality reduced O2 (obese = 2.4 ± 0.2; lean = 3.3 ± 0.2 ml · min1 · kg0.75), HR
(obese = 46 ± 5; lean = 55 ± 4 beats/min), and MAP
(obese = 13 ± 6; lean = 10 ± 1 mmHg)
similarly in lean and obese Zucker rats. The results indicate that the
cardiovascular and metabolic responses to fasting and thermoneutrality
are conserved in Zucker rats and suggest that intact leptin signaling
may not be requisite for the metabolic and cardiovascular responses to
reduced energy intake.
thermogenesis; obesity; caloric restriction; blood pressure; indirect calorimetry
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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CALORIC DEPRIVATION INVOKES a constellation of homeostatic, physiological responses including: increased appetite (57), reduced metabolic rate (49, 55), altered pituitary function (13, 54), reduced sympathetic nervous system activity to heart and brown adipose tissue (42, 59), decreased heart rate (HR), and blood pressure (55, 60), and increased sympathetic activity to white adipose tissue (33). The regulation of these divergent responses is likely to involve a complex array of neurohumoral pathways. Several lines of evidence suggest that decreased serum leptin levels and subsequent signaling within the hypothalamus are crucial mediators of the response to starvation (16, 17, 47). If reduced leptin signaling is a critical mechanism mediating the physiological responses to reduced caloric availability, then animals with disrupted leptin-signaling capabilities should display suppressed homeostatic responses to starvation.
The obese phenotype of the fatty Zucker rat is due to a point mutation (Gln269Pro) in the portion of the leptin receptor gene coding for the extracellular domain of all isoforms of the leptin receptor (10, 12, 38). The mutation leads to reduced receptor expression, reduced binding affinity for leptin, and defective leptin-mediated signal transduction (12). Thus the obese Zucker rat is markedly resistant to the physiological effects of leptin administration (3, 11, 14, 21, 23, 31, 48, 50). The leptin-resistant, obese Zucker rat exhibits many characteristics of animals exposed to caloric deprivation, including hyperphagia (19), reduced metabolic rate (27), hypothermia (36), reduced sympathetic activity (29, 41), and decreased HR (4). Therefore, we speculated that these animals would display minimal physiological responses to starvation. Thus the first purpose of this study was to test the hypothesis that the obese Zucker rat would display blunted cardiovascular and metabolic responses to 48 h of caloric deprivation.
In addition to energy deprivation, exposure to thermoneutral ambient
temperatures (Ta
29°C) also lowers oxygen consumption, HR, and blood pressure in rodents compared with levels observed at
typical laboratory conditions of Ta = 21-23°C
(22, unpublished results). These observations are
consistent with the idea that standard housing temperatures for rats
represent a form of mild cold stress requiring ongoing activation of
sympathetically mediated nonshivering thermogenesis that tonically
elevates HR and blood pressure. Obese Zucker rats exhibit reduced
capacity for nonshivering thermogenesis on exposure to cold stress
(7, 41). Given the reduced sympathetic outflow at rest and
the reduced capacity for nonshivering thermogenesis in obese Zucker
rats, the second purpose of this study was to examine the metabolic and
cardiovascular responses to removal of mild cold stress by exposure to
thermoneutrality. This additional protocol allowed for the comparison
of the cardiovascular responses to two distinct interventions that
reduce energy expenditure (caloric deprivation and thermoneutrality) in
lean and obese Zucker rats.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Male obese Zucker (fa/fa) rats (n = 8; 7-12 wk of age) and lean Zucker (Fa/?; n = 7) rats (12 wk of age; Harlan; Indianapolis, IN) were anesthetized (pentobarbital sodium, 50 mg/kg) and instrumented with a catheter in the descending aorta and coupled with a sensor and transmitter (TA11PA-C40; Data Sciences; St. Paul, MN) for telemetric monitoring of blood pressure. During recovery from surgery, rats were housed individually with ad libitum access to powdered rodent chow (Purina 5001; physiological energy value = 3.3 kcal/g) and deionized water in acclimation cages as described previously (55). During the initial phase of the experiment, rats were housed in an ambient temperature of 23 ± 0.1°C and maintained on a 12:12-h light-dark schedule.
Indirect calorimetry.
The apparatus and procedures used for environmental control and
indirect calorimetry have been described previously (40, 55). Oxygen consumption (O2) and
carbon dioxide production (CO2) were
determined every 2.5 min by open-circuit respirometry and stored on a
floppy disk. O2 was adjusted for mass
(ml · min1 · kg0.75).
Respiratory quotient [RQ
(CO2/O2)]
was calculated for the entire 12-h dark phase and for 10 h of the
light phase.
Telemetry monitoring. A telemetry receiver (RPC-1; Data Sciences) was positioned under the experimental cage within the metabolic chamber. Mean arterial blood pressure (MAP), HR, and the standard deviation of the interbeat interval (SDIBI) were calculated for each 30-s period of the day and stored on a floppy disk as described previously (55).
Locomotor activity monitoring. Some of the metabolic chambers were instrumented to record locomotor activity, which was measured in meters, accumulated in 30-s periods and stored with a 1-mm resolution as described previously (55). This resulted in n = 4 for activity measures both in the lean and in the obese groups.
Protocol. After the rats' recovery from surgery and acclimation to the housing conditions, 4 days of baseline cardiovascular, metabolic, and behavioral data were obtained at Ta = 23°C. Food and deionized water were available ad libitum. Food intake, water intake, and body weight were determined during a daily maintenance period that occurred 1-2 h before lights off at 10:00 AM. We then determined the cardiovascular, metabolic, and behavioral effects of food deprivation for 48 h. Food was removed at the maintenance period (just before lights off), and the deionized water was replaced with an electrolyte solution containing 78 meq/l NaCl and 15 meq/l KCl to provide sodium and potassium. After 48 h, food and deionized water were returned to the cages just before lights off to ensure that the rats would resume food consumption at a time consistent with normal circadian feeding behavior. In the refeeding period, food was available ad libitum for 6 days, during which recovery kinetics of all parameters was measured. We then examined the cardiovascular, metabolic, and behavioral responses to acute exposure to thermoneutrality. Ta within the environmental chambers was increased to 29 ± 0.1°C over a period of 20 min beginning 1 h before the onset of the dark phase. Cardiovascular and metabolic responses to Ta = 29°C were examined for 48 h, and the temperature in the chamber was returned to Ta = 23°C to verify that the responses to thermoneutrality were reversible.
Data analysis and statistics. Cardiovascular data and locomotor activity data were collected and stored in 30-s bins. Metabolic data were collected and stored in 2.5-min bins. Before further analysis, all data were averaged or cumulated into 10-min bins. The final 2 h of the light phase (during which daily chamber-maintenance procedures were performed) was excluded from analysis, resulting in 12-h averages for the dark phase and 10-h averages for the light phase. With the use of these values, baseline levels of variables were calculated as a 3-day average. Simple two-way ANOVA was used to determine whether there were significant circadian and group effects on baseline parameters before intervention. One-way ANOVA (within circadian phase, across days) was then performed to determine the effects of fasting, refeeding, and exposure to thermoneutrality on dependent variables. Finally, the effects of fasting, refeeding, and exposure to thermoneutrality were expressed as changes from baseline levels for between-group comparisons using ANOVA. Tukey's post hoc tests were used to determine significant differences between means. Significance levels of P < 0.05 were accepted.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Food/fluid intake and body weight.
During baseline, obese Zucker rats exhibited greater body weight, food
intake, and fluid intake compared with lean controls (Fig.
1, A-C). Baseline
sodium intake was also significantly greater (P < 0.05) in obese Zucker (5.9 ± 0.2 mmol/day) compared with lean
controls (4.0 ± 0.1 mmol/day). Two days of fasting
significantly reduced body weight both in lean (33 ± 1 g)
and in obese groups (47 ± 2 g). Fasting was associated
with marked reduction of fluid intake (electrolyte solution) in obese
Zucker rats but with only a slight decrease in lean Zucker animals
(Fig. 1B). Sodium intake during caloric deprivation was
lower in the obese Zucker rats (0.6 ± 0.1 mmol/day) than the lean
controls (1.7 ± 0.3 mmol/day). On the first day of refeeding,
lean (baseline intake = 77 ± 1 kcal; refeeding intake = 97 ± 4 kcal; P < 0.05), but not obese, (baseline
caloric intake = 114 ± 4 kcal; refeeding intake = 108 ± 3 kcal) rats displayed a significantly increased caloric
intake. In addition, both groups drank significantly more water during the first day of refeeding.
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10 ± 3 kcal) and in obese
(21 ± 3 kcal) animals, with no effect on body weight or water
intake (Fig. 1, A-C). One day of normalization of
Ta to 23°C restored food intake to levels not
significantly different from baseline conditions.
Blood pressure and HR.
MAP was elevated at baseline in obese Zucker rats (dark: 106 ± 3 mmHg; light: 103 ± 3 mmHg) compared with lean Zucker controls (dark: 99 ± 1 mmHg; light: 94 ± 1 mmHg) (Fig.
2A). Fasting significantly reduced dark-phase MAP in lean Zucker rats but had no effect on light-phase MAP in lean Zucker rats and had no effect on MAP in obese
Zuckers (Fig. 2, A-C). After transient elevations
in MAP during the initial refeeding period, MAP returned to baseline levels both in lean and in obese animals. Exposure to thermoneutrality (Ta = 29°C) produced reductions in MAP of 7-12
mmHg in lean and obese Zucker rats (Fig. 2C). These
reductions in MAP were statistically significant with the exception of
the decrease in MAP observed during the dark phase in obese Zucker rats
(Fig. 2C). Restoration of Ta to standard
conditions (23°C) normalized MAP within 24 h (Fig. 2,
A and B).
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24 ± 3 beats/min; obese: 43 ± 2 beats/min,
P < 0.05) and the second (lean: 42 ± 4 beats/min; obese: 56 ± 4 beats/min, P < 0.05)
days of fasting (Fig. 2F). Refeeding promptly increased HR
toward control levels, although HR tended to remain below baseline
levels for the first several days of the refeeding period (Fig. 2,
D-E). Increasing Ta to thermoneutrality promptly
reduced HR both in lean and in obese Zucker rats. The response was
generally similar, although the lean Zucker rats displayed a greater
bradycardia during the dark phase of the second day of exposure to
thermoneutrality (Fig. 2F; lean: 60 ± 6 beats/min; obese: 40 ± 5 beats/min, P < 0.05). Decreasing
Ta back to 23°C promptly restored HR toward baseline
levels (Fig. 2, D and E).
Baseline HR variability, as quantified by the SDIBI, was significantly
lower in obese Zucker rats (Fig. 2G) during both the light
(lean: 5.7 ± 0.4 ms; obese: 4.7 ± 0.3 ms, P < 0.05) and the dark (lean: 6.2 ± 0.4 ms; obese: 4.6 ± 0.2 ms, P < 0.05) phases. Fasting significantly increased
HR variability in both lean and obese Zucker rats, with the magnitude
of this increase being greater during the dark phase of the second
fasting day in the obese Zucker rats compared with lean controls (Fig.
2, H and I). Refeeding rapidly normalized HR
variability in both strains. In contrast to fasting, the marked
bradycardia associated with exposure to thermoneutrality was not
accompanied by altered HR variability in either lean or obese Zucker
rats (Fig. 2, H and I).
O2 and locomotor activity.
Baseline O2, normalized for body mass,
was significantly reduced in the obese Zucker rats compared with lean
controls in the dark phase (lean: 18.6 ± 0.2; obese: 16.5 ± 0.3 ml · min1 · kg0.75,
P < 0.05) but not the light phase (Fig.
3A). Fasting produced similar
reductions in O2 in lean and
obese Zucker rats (Fig. 3, B and C). Refeeding
restored O2 toward baseline levels over the course of a few days. Exposure to thermoneutrality resulted in
rapid and sustained reductions in
O2 in both lean and obese rats (Fig. 3, A-C), although the magnitude of the decrease
was greater in lean compared with obese rats in both the light (lean: 3.3 ± 0.2; obese: 2.4 ± 0.3 ml · min1 · kg0.75,
P < 0.05) and the dark phase (lean: 3.4 ± 0.2;
obese: 2.2 ± 0.4 ml · min1 · kg0.75,
P < 0.05). One day of return to standard
Ta = 23°C increased O2 toward baseline levels.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We hypothesized that obese Zucker rats would exhibit diminished
cardiovascular and metabolic responses to caloric deprivation. Instead,
fasting reduced O2 and HR, while
increasing HR variability, both in lean and in obese Zucker rats. There
was no evidence of either a reduced magnitude of response or a delay in
the activation of the homeostatic cardiovascular and metabolic
responses to reduced caloric intake in obese Zucker rats.
Interestingly, the fasting-induced decrease in HR and
O2 was not accompanied by lower MAP in
the obese Zucker rats but was associated with a modest decrease in dark-phase MAP in the lean Zucker rats. Nonetheless, it is clear that
obese Zucker rats, which display a starvationlike phenotype in the ad
libitum-fed condition due to dysfunctional leptin signaling, exhibit a
vigorous homeostatic response to caloric deprivation. Thus our findings
suggest that reductions in circulating leptin and central nervous
system leptin signaling are not requisite for the metabolic and
cardiovascular responses to caloric deprivation.
Increasing Ta from standard conditions of mild cold
(23°C) to thermoneutrality (29°C) elicited concurrent reductions in
O2, HR, and MAP both in lean and in
obese Zucker rats. The responses are similar to those we have recently
observed in spontaneously hypertensive rats (SHR) and Sprague-Dawley
rats (unpublished results) and suggest that the decreased requirement
for thermogenesis at thermoneutrality is accompanied by systemic
cardiovascular adaptations including reductions in HR and MAP.
The magnitude of the bradycardia was similar to that produced by
caloric deprivation (~50 beats/min). In contrast to fasting, this
bradycardia was accompanied by significantly lower MAP both in lean and
in obese animals but was not associated with increased HR variability.
This suggests that different autonomic and cardiovascular mechanisms
are involved in the responses to fasting and exposure to
thermoneutrality. Together, the findings reveal that both lean and
obese Zucker rats display concurrent cardiovascular and metabolic
responses to reduced energy expenditure produced by exposure to thermoneutrality.
Cardiovascular and metabolic responses to fasting and thermoneutrality. Whereas the major focus of our study was not obesity-induced hypertension, our work confirms other reports indicating that obese Zucker rats have elevated blood pressure and lower resting HR compared with their lean counterparts (4, 28, 61). In this model of obesity, the mechanism for the elevated MAP appears to be enhanced angiotensin II responsiveness and not augmented sympathetic outflow (4, 61). In contrast, the obese diabetic Zucker rat exhibits hypertension that is accompanied by greater sympathetic support of blood pressure (8).
We are not aware of any previous reports of the effects of fasting or thermoneutrality on cardiovascular function in lean and obese Zucker rats, although pair feeding did not reduce blood pressure in female obese Zucker rats (28). Whereas we hypothesized that obese Zucker rats would display attenuated cardiovascular responses to fasting, we observed greater fasting-induced bradycardia during the light phase in the obese Zucker rats. The mechanisms producing this bradycardia are not completely understood but are likely to be due to a combination of increased vagal tone and reduced sympathetic tone. As in prior studies with other rat strains (55), we observed that fasting-induced bradycardia in lean and obese Zucker rats is accompanied by increased HR variability. We have also recently observed that chronic beta-1-receptor blockade has no effect on this measure of HR variability (unpublished observations). Thus we suggest that fasting-induced increases in HR variability are indicative of increased vagal tone that contributes to fasting-induced bradycardia. In the current study, it is interesting to note that the obese Zucker rats display lower HR variability at baseline. This observation is somewhat consistent with reduced baroreflex control of HR that has been reported in obese Zucker rats (5). At this time, we have no information concerning the role of altered arterial baroreflex function on the modulation of the cardiovascular responses to caloric deprivation. Caloric deprivation produced a modest (6-7 mmHg) reduction in dark-phase MAP in lean rats with no effect on MAP in obese Zucker rats or during the light- phase in lean rats. We have recently observed a similar pattern of modest, dark-phase specific reductions in MAP in Sprague-Dawley rats (unpublished observations) but have previously observed much more significant fasting-induced reductions in MAP in SHR (55). There are a number of mechanisms that might explain the variable fasting effects on MAP between obese and lean Zucker rats. Given that the obese Zucker rats exhibited greater bradycardia, it is unlikely that the explanation is directly related to a failure to invoke homeostatic responses to fasting. One possibility is that compensatory responses to reduced sodium and fluid intake may be involved. During fasting, lean rats consumed normal levels of an electrolyte solution, whereas obese Zucker rats had dramatic reductions in fluid intake (Fig. 1). It is possible that reduced fluid and sodium intake in obese Zucker rats during fasting activated the renin-angiotensin-aldosterone system that served to defend arterial pressure to a greater extent in obese than in the lean Zuckers. We have no direct support for this hypothesis, but it is consistent with the trend for MAP to be elevated during the first few days of refeeding in obese but not lean rats. Importantly, the significant decrease in blood pressure observed on exposure to thermoneutrality demonstrates that MAP can respond to reduced energy expenditure both in lean and in obese Zucker rats. Increasing Ta from standard conditions of mild cold (23°C) to thermoneutrality (29°C) produced similar reductions in HR compared with fasting yet reduced MAP by 7-12 mmHg in lean and obese rats. Two points concerning the bradycardia produced by thermoneutrality should be noted. First, the magnitude of the bradycardia during the dark phase was greater in lean than obese Zucker rats. We noted that obese Zucker rats exhibited an intriguing increase in locomotor activity when Ta was increased to 29°C. This raises the question of the selection of 29°C as thermoneutral temperature for both lean and obese Zucker rats, which differ in body and fat mass. Both lean and obese Zucker rats exhibit a maximum of rapid eye movement sleep at 29°C (32), which may be a more precise estimate of thermoneutrality than resting metabolic rate (53). Thus, whereas we acknowledge that the selection of 29°C as thermoneutrality for both lean and obese rats may be a limitation of the current study, it is clear that exposure to this Ta reduces food intake, HR, andO2 in both strains of rats compared with
23°C. The observations are consistent with the possibility that
29°C is within or near the zone of thermoneutrality both for lean and
for obese Zucker rats.
The second key point concerning the bradycardia associated with
thermoneutrality is that unlike fasting, the reduction in HR is not
associated with an increase in HR variability. We suspect this pattern
of response reflects a reduction in cardiac sympathetic activity with
no increase in vagal tone. Experiments are currently underway to test
this hypothesis. Nonetheless, the results of this study are consistent
with our recent findings from SHR and Sprague-Dawley rats indicating
that thermogenic mechanisms related to the regulation of body
temperature have important effects on cardiovascular function
(9). We speculate that the reduction in MAP due to
thermoneutrality reflects some combination of a generalized reduction
in thermogenic sympathetic outflow, reduced metabolic vasodilation in
peripheral tissues, reduced cardiac output, and perhaps altered blood
flow distribution.
Evidence that leptin is a key starvation signal.
Results of studies performing exogenous leptin administration during
fasting support the concept that reduced circulating leptin, and thus
reduced central nervous system leptin signaling, is a critical mediator
of the homeostatic responses to reduced energy availability. Leptin
administration by twice daily intraperitoneal injections during fasting
attenuated (but did not prevent) the reductions in thyroxine,
luteinizing hormone, and testosterone levels, as well as the increase
in corticosterone, that accompanied 48 h of fasting in mice
(2). More recently, the same group reported that
physiological peripheral leptin replacement using osmotic pumps
prevented fasting-induced reductions in thyroxine and testosterone but
not fasting-induced increases in corticosterone (1).
Furthermore, leptin replacement prevented fasting-induced increases in
neuropeptide Y (NPY) mRNA and decreases in cocaine- and
amphetamine-related transcript and proopiomelanocortin (POMC) mRNA
(1). The finding is consistent with others
indicating that exogenous leptin administration blunts the hypothalamic
gene-expression responses to starvation (46) and the
development of starvation-induced anestrous (58). These
studies provide convincing evidence that leptin plays a critical role
in many aspects of the homeostatic adaptive response to reduced caloric
availability. Indeed, we have recently completed studies that indicate
that continuous central leptin infusion during fasting virtually
abolishes the reduction in HR and O2
that accompanies 48 h fasting in Sprague-Dawley rats
(37). Thus there is compelling evidence that leptin
replacement prevents the hypothalamic, neuorendocrine, metabolic, and
cardiovascular responses to fasting. The logical conclusion from these
studies is that reduced leptin signaling represents a requisite signal for activation of homeostatic responses to starvation.
Evidence of homeostatic responses to starvation independent of
leptin.
We interpret the observations of fasting-induced reductions in HR and
O2 along with increased HR variability
in obese Zucker rats as strong evidence that reductions in central
leptin signaling are not requisite for recruitment of homeostatic
mechanisms to starvation. Indeed, it is clear that various responses to
starvation occur in ob/ob mice, db/db mice, and Zucker rats. For
example, long-term energy restriction reduces metabolic rate in obese
Zucker rats (27, 52). Furthermore, the ob/ob mouse
exhibits an appropriate reduction in body temperature in response to
fasting (20). Thus there is some prior physiological
evidence indicating that animals genetically lacking leptin signaling
respond appropriately to reduced energy availability. In addition,
hypothalamic NPY and agouti-related protein (AGRP) mRNA are further
increased, and POMC mRNA is further decreased by fasting in the db/db
mouse (34, 35). Thus hypothalamic neuropeptide systems
regulated by leptin can be activated by other mechanisms during fasting
in mice devoid of leptin signaling. In obese Zucker rats, there are
conflicting reports showing that fasting either increases
(43) or does not increase hypothalamic NPY mRNA
(25). In addition, 24 h of fasting the ob/ob mouse
increases both melanin-concentrating hormone mRNA and NPY mRNA
(39). It should be noted that others have failed to demonstrate fasting-induced increases in AGRP mRNA in ob/ob or db/db
mice (15, 56). Together, these findings provide a body of
evidence that physiological and hypothalamic responses to starvation
are engaged in the absence of a reduction in tonic leptin signaling. We
suggest that there are redundant mechanisms capable of engaging
homeostatic hypothalamic pathways in the absence of leptin signaling.
O2,
and RQ while increasing HR variability both in lean and in obese Zucker rats. Acute exposure to thermoneutrality reduced HR, MAP, and O2 with no effect on RQ or HR
variability. The magnitude and timing of these responses were, for the
most part, indistinguishable between obese and lean Zucker rats. We
conclude that intact leptin signaling is not requisite for the
cardiovascular and metabolic responses to caloric deprivation or thermoneutrality.
Perspectives
The role of leptin signaling in the regulation of thermogenesis has yet to be clarified. Reduced food availability rapidly engages multiple energy-conservation mechanisms in many species. Whereas it is well known that circulating leptin levels are generally proportional to adipose tissue mass, it is also clear that reduced caloric intake is associated with a rapid suppression of circulating leptin levels before reductions in fat mass. The observations that animals devoid of leptin signaling display several aspects of a "starvation" phenotype, in concert with a number of studies indicating that exogenous leptin administration attenuates or prevents many adaptive responses to fasting, provide a compelling case for the concept that a primary evolutionary role for leptin is energy conservation. Yet, it is clear that this concept requires additional examination. Our findings add to a body of evidence indicating that animals devoid of leptin signaling display vigorous physiological responses to reduced caloric availability. It is our view that animals devoid of leptin signaling will provide an excellent model for the identification of the mechanisms allowing appropriate physiological responses to negative energy balance in the absence of leptin. Careful studies will then be required to dissect the relative importance of leptin-dependent and -independent pathways in the control of the homeostatic responses to reduced caloric availability.| |
ACKNOWLEDGEMENTS |
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We acknowledge the technical assistance of Akiko Nakamura and Danielle Strickland. The Florida State Univ. (FSU) Neuroscience Program's Technical Support Group provided expertise in instrumentation (Ross Henderson, Paul Hendricks, Ron Thompson) and computer programming (Don Donaldson).
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FOOTNOTES |
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This work was supported by National Institutes of Health (NIH) Grant HL-56732 and a Program Enhancement Grant from the FSU Research Foundation. T. D. Williams was supported by an NIH Joint Neuroscience Predoctoral Training Grant and is a predoctoral fellow of the American Heart Association, Florida/Puerto Rico Affiliate.
Address for reprint requests and other correspondence: J. M. Overton, Dept. of Nutrition, Food and Exercise Sciences and Program in Neuroscience, 236 Biomedical Research Facility, Florida State Univ., Tallahassee, FL 32306-4340 (E-mail: moverton{at}mailer.fsu.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.
Received 28 August 2000; accepted in final form 6 December 2000.
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TOP
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METHODS
RESULTS
DISCUSSION
REFERENCES
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MAP, difference in MAP from baseline average;
C: 