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1 Department of Foods and Nutrition, University of Georgia, Athens 30602; and 3 Department of Biology, Georgia State University and 2 Center for Behavioral Neuroscience, Atlanta, Georgia 30303
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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One hypothesis for the regulation of total body fat suggests that leptin is a lipostatic feedback signal that acts at brain sites involved in regulation of energy balance. The importance of leptin in recovery from partial surgical lipectomy was tested by performing bilateral epididymal lipectomy or sham surgery on wild-type and leptin-deficient ob/ob mice. Eight weeks later, nonexcised pads of lipectomized mice were increased but total carcass fat was lower than in sham-operated ob/ob mice. In experiment 2, ob/ob mice, wild-type mice, and two db/db mutants, C57BL/6J dbLepr/dbLepr (BL/6J) mice possessing short-form and circulating leptin receptors and C57BL/6J db3J/db3J (BL/3J) mice expressing only circulating receptors, were lipectomized or sham operated. Sixteen weeks later, body mass and carcass lipid were not different between sham and lipectomized ob/ob mice, wild-type mice, or BL/6J db/db mice, whereas there was incomplete (decreased carcass fat) but suggestive recovery (increased retroperitoneal fat mass and cell number) in lipectomized BL/3J db/db mice. These data indicate that leptin is not required for the regulation of total body fat.
ob/ob mice; db/db mice; total body fat; cell size distribution
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE NOTION THAT TOTAL BODY FAT is regulated has a long history in regulatory biology. Various feedback systems have been hypothesized to account for observations that lipid energy stores are regulated at levels appropriate for the internal and external environment of an animal. As early as 1953, Kennedy (23) proposed the "lipostatic hypothesis," suggesting that long-term energy balance is achieved by controlling lipid energy stores. Evidence often cited in support of a hypothetical total body fat regulatory system involves experimental modification of adiposity by fasting or overfeeding to decrease and increase body fat, respectively (31, 38, 39). These studies, however, may be confounded by responses associated with the energetic challenge, such as stress, changes in feeding behavior, and changes in activity of the autonomic nervous system, each of which has the potential to affect energy balance independently. Thus it is difficult to determine whether the metabolic and behavioral changes occur as a direct consequence of under- or overfeeding or are secondary to a change in body fat mass. One experimental challenge of the regulatory system that is more selective is surgical partial lipectomy (referred to hereafter as lipectomy). As we noted in a review of the literature recently (34), lipectomy immediately decreases total body fat, and because recovery from the surgery is rapid, changes in metabolism and behavior can be directly attributed to changes in adiposity. The literature on recovery of total body fat after lipectomy overwhelmingly supports an apparent regulation of adiposity levels in a variety of species, including laboratory rats and mice, Syrian and Siberian hamsters, and ground squirrels (for review, see Ref. 34).
The mechanism by which total body fat levels are recovered after lipectomy is unknown. One obvious possibility is that leptin, a peptide hormone produced primarily, but not exclusively, by white fat (for review, see Ref. 1), serves as a feedback signal of the size of body lipid stores. Circulating leptin levels tend to reflect total body fat in human and nonhuman animals (10). Thus a decrease in circulating concentrations of leptin could potentially inform the brain of a loss of body fat and trigger compensatory responses such as increasing food intake and decreasing energy expenditure (9, 16). The importance of leptin as a signal of energy deficit is discussed elsewhere (2), but in the experiments described here we tested the hypothesis that leptin is part of a feedback system that regulates total body fat levels (7, 32).
The specific purpose of the present experiment was to test whether leptin plays a critical role in the recovery of total body fat in mice that have experienced lipectomy-induced lipid deficits. This was accomplished by performing lipectomy in mice that exhibit genetically induced alterations in the production of leptin or of some of its receptor subtypes. The first experiment used ob/ob mice, which do not secrete leptin (41), and their wild-type counterparts. The second experiment included ob/ob and wild-type mice and mice with two different leptin receptor mutations: C57BL/6J dbLepr/dbLepr (BL/6J) and C57BL/6J db3J/db3J (BL/3J) mice. BL/6J db/db mice possess a point mutation resulting in a shortening of the intracellular domain of the long-form leptin receptor (Ob-Rb) (29) but retain all of the membrane-bound short-form receptors (Ob-Ra, Ob-Rc, Ob-Rd) and the circulating receptor (Ob-Re). The mutation in BL/3J db/db mice prevents expression of both long- and short-form membrane-bound leptin receptors, but the mice express a truncated form of the circulating receptor (28). Both of these db/db mutations result in a phenotype of hyperphagia, obesity, and diabetes with the diabetes being more severe in BL/3J than BL/6J db/db mice (30).
It should be noted that, before the discovery of leptin, it was reported that body fat was restored after lipectomy in older ob/ob that had reached a static, elevated level of adiposity (8). This test of body fat compensation in leptin-deficient mice, however, was far from thorough because it is unclear exactly which fat pads were removed for the lipectomy, and at the end of the experiment, total carcass lipid was measured but the weights of the nonexcised fat depots were not reported. The experiments described below test the response to lipectomy not only in leptin-deficient ob/ob mice but also in db/db mice that are deficient in different isoforms of the leptin receptor.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Experiment 1: lipectomy of ob/ob and wild-type mice. The objective of this experiment was to determine whether ob/ob mice, which do not secrete functional leptin, regulate total body fat content after surgical removal of their epididymal fat depots. All experimental procedures were approved by the Institutional Animal Care and Use Committee of the University of Georgia and were conducted in conformity with the "Guiding Principles for Research Involving Animals and Humans" of the American Physiological Society (3).
Thirty male C57BL/6J ob/ob mice and 30 male wild-type mice, aged 28 days, were obtained from Jackson Laboratories (Bar Harbor, ME). They were housed two or three mice per cage in a temperature- and humidity-controlled room with free access to chow and water. The mice were weighed at 30, 32, 34, and 35 days of age. On day 35, mice within each genotype were divided into three weight-matched groups. One group was killed for determination of baseline body composition. Both epididymal fat pads were removed from a second group of mice (lipectomized), and the third group was a sham-operated control. The mice were anesthetized with isoflurane, a small incision was made in the skin of the abdomen, and a second incision was made in the peritoneal wall. The epididymal pads and testes were pulled out of the cavity, and both epididymal fat pads were removed, taking care to leave the spermatic artery to the testes intact. The testes were returned to cavity, and the incisions were sutured. Sham surgery was the same as the lipectomy except that the epididymal pad was left intact and placed back inside the peritoneal cavity. The mice were weighed daily for 5 days after surgery and then twice per week. Small samples of blood were collected from the lipectomized and sham-operated mice by tail bleeding 1 and 5 wk postoperatively. The lipectomized and sham-operated mice were killed 8 wk after surgery, when they were 13 wk old. This was equivalent to the time after surgery that animals were killed in the previously reported lipectomy study with ob/ob mice (8). Trunk blood was collected, and inguinal, epididymal, retroperitoneal, perirenal, and mesenteric fat depots and the testes were dissected, weighed, and returned to the carcass. Serum leptin concentrations were determined by radioimmunoassay (Mouse Leptin RIA Kit; Linco Research). A small piece (~50 mg) of retroperitoneal fat was fixed in osmium tetroxide for determination of fat cell size and distribution by Coulter counter as described previously (18). This fat depot was chosen as it had been reported to significantly increase in size after removal of inguinal and epididymal fat in chow-fed rats (14) and because it contains less connective tissue than inguinal fat and fewer blood vessels than perirenal or mesenteric fat. The gastrointestinal tract was cleaned and returned to the carcass, which was analyzed for body composition as described previously (21). In brief, the carcass was autoclaved for 25 min at 120°C and homogenized with an equal weight of water. Lipid content of triplicate aliquots of homogenate was determined by chloroform-methanol extraction. Water content was determined on triplicate aliquots dried to constant weight, ash was determined by holding the same samples at 500°C for 8 h, and protein was calculated by difference. Statistically significant differences in body weight of lipectomized and sham-operated mice within each genotype were determined by repeated-measures ANOVA, using presurgical body weight as a covariate, and post hoc Student's t-test. Differences in other end-point measures were determined by unpaired Student's t-test for samples with equal variance or by one-way ANOVA and Duncan's multiple range test (Statistica; StatSoft, Tulsa, OK).Experiment 2: lipectomy of wild-type, ob/ob, and db/db mice. The results of the previous experiment showed that there was a trend for most fat depots to increase in ob/ob mice that had been lipectomized, but there was a significant deficit in total body fat content compared with sham-operated controls. The objective of this study was to test whether extending the duration of the study allowed for a more accurate compensation for lipectomy in ob/ob mice and, if leptin was essential for recovery of fat, whether the compensation was mediated by long- or short-form leptin receptors. Mice were lipectomized at 5 wk of age and killed 16 wk after surgery, a time period that exceeded that required to demonstrate accurate compensation for lipectomy in rats (4, 26) and ground squirrels (11).
The experimental design was essentially the same as for experiment 1. Thirty male ob/ob mice, 28 days of age, were purchased from Jackson Laboratories. Although these mice were the same age, according to the supplier, as those used in experiment 1, the wild-type and ob/ob mice in this experiment were significantly smaller than those used in experiment 1. Despite the differences in the size of the animals, the proportion of total body fat that was removed as epididymal fat was similar for the two experiments. Thirty male wild-type C57BL/6J mice, 30 male BL/3J db/db mice, and 26 male BL/6J db/db mice were obtained from breeding colonies maintained at the University of Georgia. These colonies were developed from founder BL/6J and BL/3J heterozygote mice that were generously provided by Dr. G. Truett, University of Tennessee, and Dr. S. Chua, Rockefeller University, respectively. The mice were included in the experiment at 28 days of age and housed as described above. Body weights were recorded at 30, 32, 34, and 35 days of age. On day 35, the mice within each genotype were divided into three weight-matched groups: baseline, lipectomy, and sham operated. There were 10 mice per group except the baseline BL/6J group, which included only 6 mice. Lipectomy and sham surgeries were performed and body weights were recorded as described above; tail-blood samples were collected 3 days and 9 wk after surgery. The mice were killed 16 wk postoperatively, at 21 wk of age. Fat pads and testes were weighed, a piece of retroperitoneal fat was fixed for determination of cell-size distribution, and carcass composition was measured. Statistical analyses were performed within genotype as described for experiment 1.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Experiment 1.
Surgery caused a small, transient weight loss in both ob/ob
and wild-type mice, with a greater weight loss in the lipectomized than
sham-operated mice (see Fig. 1).
Epididymal fat represented ~18% of total body fat at the time of
surgery (Table 1), and the body weights
of wild-type lipectomized and sham-operated mice were significantly
different for the first 3 days after surgery but were not different
from day 4 to the end of the experiment [lipectomy, not
significant (NS); time, P < 0.0001; interaction, P < 0.0001]. In contrast, the weights of lipectomized
and sham-operated ob/ob mice were significantly different on
all but the last day of the experiment (lipectomy, P < 0.0001; time, P < 0.0001; interaction, P < 0.0001). Serum leptin concentrations of wild-type
lipectomized mice were significantly lower than those of the
sham-operated mice 1 wk after surgery but were not different 5 or 8 wk
after surgery (see Fig. 2). Leptin was
not measured in ob/ob mice because they do not express a
functional protein. At the end of the experiment the epididymal fat had
not regenerated in either wild-type or ob/ob mice. In
sham-operated wild-type mice, epididymal fat represented 20% of total
carcass fat, similar to the start of the experiment, but in
ob/ob mice, epididymal fat represented only 9% of total carcass fat (Table 1). There were no significant differences in the weights of remaining fat pads (Fig.
3) or in carcass fat content (Table 1) of
sham-operated and lipectomized wild-type mice, but the lipectomized
animals had more lean tissue (protein plus water). Lipectomized
ob/ob mice had significantly more lean tissue and less
carcass fat than their sham-operated controls at the end of the
experiment (Table 1). The mesenteric fat depot in lipectomized
ob/ob mice was significantly larger than in sham-operated controls; there was a trend for retroperitoneal and perirenal fat to be
increased, but the differences did not reach significance (P < 0.08). There were no significant differences in
the total number of fat cells in the retroperitoneal depots of
lipectomized and sham-operated wild-type mice, but there was a
significant increase in retroperitoneal fat cell number in lipectomized
ob/ob mice compared with sham-operated controls (Table 1).
This was due to a nonsignificant increase in the number of cells within each size range measured (treatment, P < 0.09; size,
P < 0.0001; interaction, P < 0.08;
Fig. 4).
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Experiment 2.
All genotypes of lipectomized and sham-operated mice lost a small
amount of weight due to surgery that was recovered within 1 wk. The
proportion of total body fat that was removed as epididymal fat was the
same for all genotypes (Table 2), but the
effect of lipectomy on body weight varied by genotype (see Fig.
5). There was no significant difference
in the weights of lipectomized and sham-operated wild-type mice except
for the first day after surgery (lipectomy, NS; time, P < 0.001; interaction, NS). Lipectomized ob/ob mice weighed
less than their sham-operated controls for 6 wk after surgery
(lipectomy, NS; time, P < 0.0001; interaction, P < 0.01). Lipectomized BL/6J db/db mice
weighed less than their controls for 2 wk after surgery (lipectomy, NS;
time, P < 0.0001; interaction, NS), whereas
lipectomized BL/3J db/db mice weighed less than their
controls throughout the experiment (lipectomy, P < 0.0005; time, P < 0.0001; interaction, NS). At the end
of the experiment there were no significant differences in body fat content of sham-operated and lipectomized mice in any genotype except
the BL/3J db/db mice in which body fat content was lower in
the lipectomized mice (see Table 3).
Epididymal fat did not regenerate in any of the mice (Fig.
6) Although epididymal fat represented
the same proportion of total body fat in the different mice at the
start of the experiment, it represented <10% of total carcass fat in
all of the obese sham-operated mice at the end of the experiment
compared with 20% in wild-type sham-operated mice (Table 2). All other
pads except the inguinal fat tended to increase with lipectomy in all
of the genotypes. This difference reached significance for the
retroperitoneal depot in all of the obese mice and was also significant
for the perirenal and mesenteric fat in the ob/ob mice (Fig.
6). Fat cell number was increased in the retroperitoneal pads of the
lipectomized mice compared with their sham-operated control, but this
difference only reached significance for the BL/3J db/db
mice (see Fig. 7). Fat cell size distribution was not significantly different between sham-operated and
lipectomized ob/ob or BL/6J db/db mice (Fig. 7).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The results of the present study generally suggest that disruption of the leptin signaling system, due either to a lack of leptin synthesis (ob/ob) or to a truncated long-form leptin receptor (Ob-Rb; BL/6J db/db), does not prevent the recovery of lipectomy-induced lipid deficits. This extends and confirms the earlier (pre-leptin discovery) findings of Chlouverakis and Hojnicki (8), in which abdominal fat was removed and total carcass lipid was restored in ob/ob mice. To our surprise, BL/3J db/db mice, expressing the circulating leptin receptor (Ob-Re) but not the long- or short-form receptors (Ob-Ra, Ob-Rc, Ob-Rd), did not fully compensate for the surgically induced lipid loss during the 16 wk after surgery. These mice, however, did respond to lipectomy by significantly increasing retroperitoneal fat pad mass and retroperitoneal fat cell number, which may indicate that total fat mass would have reached that of sham-operated BL/3J db/db if the experiment had been continued for a longer period of time.
The simple notion that leptin informs the brain of peripheral lipid stores as part of a hypothesized total body fat regulatory system is challenged by the present results, as well as by data from other models. The removal of epididymal fat depots was sufficient to cause a temporary, but significant, decrease in circulating leptin concentrations of wild-type mice in experiment 1. This observation was not repeated in experiment 2, possibly because leptin was suppressed in all animals due to the stress of surgery 3 days after lipectomy, whereas leptin was measured 1 wk after surgery in experiment 1. Despite this indirect manipulation of leptin in lipectomized animals, the results from these studies demonstrate that leptin is not essential for the regulation of total body fat mass. Similarly, studies with genetically obese Zucker and Koletsky rats, each of which are obese due to distinct recessive mutations of the leptin receptor (22, 36), show that a fully functional leptin system is not required for regulation of body weight or energy balance (13, 20). In humans, the typical correlation between body fat levels and circulating leptin levels (12) is not found in postmenopausal (27) or lactating (6) women. Additionally, little brown bats, which increase body fat levels before hibernation, show elevations of circulating leptin concentrations and in vitro white fat leptin secretion well before body fat is increased (24). Thus there is precedent that disruption of the leptin system does not prevent the regulation of total body fat mass. This study and the earlier study with ob/ob mice (8) show not only that leptin is not required for the regulation of body fat but that genetically obese mice are regulating their fat at an elevated level. If leptin was integral to the regulation of body fat mass, then the adiposity of ob/ob and db/db mice would not be regulated but would be determined indirectly by the balance between energy intake and expenditure. This would result in large individual and daily variability in fat mass, which was not seen in this experiment, and there would be no drive to compensate for the removal of fat depots, which was observed in this experiment.
The inability of the db/db BL/3J mice to completely restore
total body fat levels within the 16 wk after lipectomy in
experiment 2 was unexpected, as it was anticipated that they
would respond in exactly the same manner as ob/ob mice. The
most conservative view is that these animals take longer to compensate
for the surgically induced lipid deficit than the other mouse genotypes
tested here (i.e., >16 wk) and longer than needed for restoration of
total body fat by lipectomized Siberian hamsters (12 wk; Ref.
33), ground squirrels (16 wk; Ref. 11),
Syrian hamsters (12-13 wk; Ref. 17), or laboratory
rats (13 wk; Ref. 26). Although the BL/3J db/db
mice seemed to be progressing toward a recovery, the recovery appeared
to be stalled, possibly by a lack of lipid filling of the fat cells.
The retroperitoneal pad was increased in size in all lipectomized mice
compared with their respective controls, but it was the only fat depot
in the BL/3J db/db mice that was significantly larger in
lipectomized than sham-operated mice, and it was the only fat depot on
which fat cell size distribution was determined. The increased mass of
the pad appeared to be due to hyperplasia in BL/3J db/db
mice as there was a significantly increased number of cells in all size
ranges up to 140 µm, with the biggest increase in cell number
apparent in cells that were 
60 µm in diameter (see Fig. 7). The
lipectomized BL/3J db/db mice had twice as many cells as
ob/ob or BL/6J db/db mice in the size ranges up
to 100 µm, whereas the difference in cell number between the obese
genotypes was less exaggerated, or not apparent, for the larger cell
diameters. The cellularity of other fat depots was not determined, so
it is not clear whether the hyperplasia was a retroperitoneal-specific
response in BL/3J db/db mice. The weights of perirenal and
mesenteric depots also tended to be higher in lipectomized than
sham-operated BL/3J db/db mice; therefore it is likely that
there was also an increase in the number of cells present in these
depots. The increase in the number of small fat cells may result either
from a promotion of adipocyte proliferation without an accompanying
mechanism to permit lipid filling of the cells or from an inhibition of
lipid filling that results in a drive to produce more small cells as a
site for lipid storage.
One interpretation of these data is that the presence of short-form leptin receptors inhibits cell proliferation but facilitates lipid filling of adipocytes. If this were true, then a significant hyperplasia should also be present in ob/ob mice, which have short-form receptors but no ligand. An alternative explanation is that the leptin in BL/3J db/db mice is cross-reacting with a non-leptin receptor and that activation of this receptor is responsible for the failure to compensate for lipectomy and for the high rate of adipocyte proliferation. The BL/3J db/db mice express high concentrations of a truncated form of the soluble leptin receptor (28), and it has not been determined whether it has normal binding affinity for leptin. If there is an abnormally high concentration of free leptin in BL/3J db/db mice, then there is the potential for leptin to inhibit adipocyte filling by cross-reacting with receptors for other members of the family of class I cytokines. The metabolic function of circulating and short-form leptin receptors has not been thoroughly investigated or elucidated. Others have suggested that the short-form receptors act as transport proteins, facilitating passage of leptin into the brain (15). Recently we have shown that BL/6J db/db mice, which do not express the long-form leptin receptor, are metabolically responsive to leptin administered peripherally (19), suggesting that short-form receptors have a function beyond that of a transport protein. It does not appear, however, that the failure of BL/3J db/db mice to accurately compensate for lipectomy as quickly as the other genotypes of mice in experiment 2 is due to either a decreased energy intake or an increased thermogenesis compared with BL/6J db/db mice, because food intakes and rectal temperatures are not different between genotypes (Harris, unpublished observations).
If leptin is not necessary for total body fat regulation, then the mechanisms responsible for the compensatory responses to lipectomy still need to be identified. One possible regulatory system involves sensory innervation of white adipose tissue. Although the existence and roles of the sympathetic nervous system innervation of white adipose tissue are now acknowledged and somewhat understood (for review, see Ref. 5), the existence and role of the sensory innervation of white adipose tissue are less well recognized (for review, see Ref. 5). It has been speculated that one possible function of the sensory nerves is to inform the central nervous system of the size of individual fat pads (34), although the means by which this might be accomplished is unknown at present. Another possible role of the sensory innervation that would aid in the regulation of total body fat is through a negative-feedback loop adjusting the level of sympathetically driven lipolysis to modify the size of lipid stores (34). Although speculative at this point, an analogous feedback system exists in which sensory nerves modulate the sympathetic drive on mesenteric arteries (37). If sensory nerves are involved in the feedback regulation of fat mass, this would provide a means of detecting the loss of lipid from a specific site, rather than a circulating factor providing nonlocalized information on a decrease in total fat mass.
One study with Djungarian hamsters suggests that the depot from which lipid is lost has a specific effect on the physiology of an animal. Removal of parametrial fat from pregnant hamsters had no adverse effect on the dam or the litter but decreased the probability of the mother investing in a subsequent litter (35). This suggests a vital function for gonadal fat in determining maternal investment in offspring (35) and that some lipid depots might be monitored more closely than others, especially those intimately involved with the reproductive organs, such as parametrial and epididymal white adipose tissue. If epididymal fat is monitored, and compensated for, more carefully than other fat depots, then it is possible that we would find different responses to lipectomy if a fat depot other than epididymal fat was removed. It was interesting to note that, in this experiment, the epididymal fat represented the same proportion of body fat in all of the different genotypes of mice when they were 35 days old, but that it represented <10% of body fat in obese mice compared with 20% in wild-type mice when they were 21 wk old at the end of experiment 2. Obese male ob/ob mice are fertile when they are young but infertile as they become older and more obese (25). If the relative size of epididymal and parametrial fat depots is determined by the reproductive state of an animal, this would imply that there is fat depot-specific relationship between reproductive organs and gonadal fat that has yet to be explored.
Regardless of how the compensation for the lipectomy-induced lipid deficit was accomplished in ob/ob, wild-type, and BL/6J db/db mice, it is clear that leptin and its receptor subtypes are not necessary for the compensatory increases in the nonexcised fat pad masses to occur. Although the value of lipectomy has been questioned (40), the partial lipectomy model has several noteworthy features. First, physiology is altered as a consequence of the fat removal rather than altered physiology being used to produce a lipid deficit, as is the case with food deprivation/restriction. Second, partial lipectomy allows one to test the function of specific lipid depots, an important issue because body fat is not a unitary organ. Collectively, the results of the present study indicate that the apparent regulation of total body fat mass is possible without a fully functioning leptin system and that mice lacking leptin, or the long-form leptin receptor, compensate for surgically induced lipid deficits by some other means. The usefulness of the lipectomy model as a tool to test the regulation of total body fat was demonstrated, but further studies are needed to test the importance of white fat sensory and sympathetic innervation and of site-specific depletion of fat mass in determining the response to lipectomy.
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ACKNOWLEDGEMENTS |
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We thank J. Hausman for technical assistance.
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FOOTNOTES |
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This research was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant RO1-DK-53903 to R. B. S. Harris.
Address for reprint requests and other correspondence: R. B. S. Harris, Dept. of Foods and Nutrition, Univ. of Georgia, Dawson Hall, Athens, GA 30602 (E-mail: harrisrb{at}arches.uga.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.00339.2002
Received 10 June 2002; accepted in final form 10 July 2002.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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