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APPETITE, OBESITY, DIGESTION, AND METABOLISM
Department of Biology, Neurobiology and Behavior Program, Center for Behavioral Neuroscience, Georgia State University, Atlanta, Georgia
Submitted 16 February 2005 ; accepted in final form 24 March 2005
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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transplants; white fat; food intake; obesity; lipectomy
Lipectomy triggers a compensatory increase in the mass of the nonexcised WAT pads across a wide range of species and conditions that ultimately (8–16 wk depending on the species) results in the restoration of total body fat, as evidenced by equivalent carcass lipid contents between the lipectomized and sham lipectomized animals (for review, see Ref. 26). We recently (19) used combinations of lipectomy and WAT grafts to challenge the total body fat regulatory system in Siberian hamsters (Phodopus sungorus). Specifically, we removed epididymal WAT (EWAT) pads and replaced them subcutaneously at a different location (dorsum) within the same animals (i.e., autologous grafts), creating no initial change in total body fat levels. Surprisingly, autologous grafts in lipectomized hamsters triggered lipectomy-like compensation by the nonexcised fat pads (i.e., the animals responded as though the WAT was actually removed), which was exaggerated twofold compared with lipectomy without WAT replacement (19). It was observed that the animals showing the exaggeration of the lipectomy-induced increases in nonexcised WAT pad masses had autologous WAT grafts that directly contacted intact WAT on the dorsum [i.e., inguinal subcutaneous WAT (IWAT)], but this was not tested explicitly. This prompted speculation that this autologous graft-host WAT interaction underlies this exaggerated response to lipectomy.
As noted above, the effects of increased WAT mass on the hypothesized total body fat regulatory system can be tested by WAT additions to otherwise intact animals from donor animals. The addition of WAT to Siberian hamsters (19) or to laboratory mice (28) results in species-specific compensatory responses. Thus Siberian hamsters receiving additional WAT do not compensate for their elevated total body fat by reducing their native fat pad masses despite the normal macro- and microscopic appearance of the grafts 12 wk later (19). By contrast, laboratory mice respond to WAT additions by decreasing their native fat pad masses (28). Because WAT addition or removal-replacement in Siberian hamsters does not induce compensatory WAT responses consistent with total body fat regulation as does WAT subtraction, the present study was designed to answer the following questions. 1) Does the effect of autologous WAT transplantation vary depending on the location of graft placement? 2) Does the source of the donor graft, i.e., WAT pad [WAT vs. epididymal WAT (EWAT)], sibling vs. nonsibling, affect compensatory body fat responses? This was accomplished in experiment 1 by placing autologous EWAT grafts in direct contact with IWAT on the dorsum or not in contact with WAT on the ventrum and in experiment 2 by transplanting EWAT or IWAT from male sibling or male nonsibling donors to otherwise intact hamsters.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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All experimental procedures were approved by the Georgia State University Institutional Animal Care and Use Committee in accordance with the National Institutes of Health and United States Department of Agriculture guidelines. Adult male Siberian hamsters (3–4 mo old) were obtained from our breeding colony, the lineage of which has been described recently (3). Hamsters were housed in a long "summerlike" photoperiod (16:8-h light-dark cycle, lights on at 0200) and given PMI rodent diet no. 5001 and tap water ad libitum. In experiments 1 and 2 below, group-housed animals were singly housed for 2 wk before surgery. At that time, they were divided into groups matched for the percent change in body mass during the initial single housing period as well as for the absolute body mass after the 2 wk of single housing.
Experiment 1: Does the Effect of Autologous WAT Transplantation Vary Depending on the Location of Graft Placement?
It appeared previously that exaggerated body fat compensation occurred in lipectomized hamsters when the graft was in contact with IWAT, but this was not tested (19). To test whether the direct contact between the graft and intact WAT was necessary for this response, we transplanted WAT to a site in direct contact with IWAT on the dorsum or to a distal site without direct contact with other WAT on the ventrum.
Sixty-five hamsters were divided into the following six groups: 1) bilateral EWAT lipectomy with sham dorsal transplant (EWATx + dorsal sham; n = 10), 2) bilateral EWAT lipectomy with sham ventral transplant (EWATx + ventral sham; n = 10), 3) bilateral EWAT lipectomy with implantation of this excised EWAT as dorsal subcutaneous transplants (EWATx + dorsal grafts; n = 12), 4) bilateral EWAT lipectomy with implantation of this excised EWAT as ventral subcutaneous transplants (EWATx + ventral grafts; n = 11), 5) sham lipectomy with sham dorsal transplant (sham EWATx + dorsal sham; n = 11), and 6) sham lipectomy with sham ventral transplant (sham EWATx + ventral sham; n = 11) (Fig. 1).
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10–20% of dissectible body fat (23). Briefly, fat pads were removed, with care taken to preserve the blood vessels supplying the testes. During sham surgery, the EWAT pads were exposed but were not removed. The peritoneum and abdominal muscles were sutured, and the skin was closed with wound clips. The masses of the excised pads were weighed before transplantation. For all transplants, the EWAT pads from each side were bisected and replaced as two subcutaneous transplants, ipsilateral to the side of removal. For dorsal transplantation, small bilateral dorsal incisions were made, the skin and fascia were loosened with blunt tissue forceps, and the transplants were placed under the skin after which the incision was closed with wound clips. For ventral transplantation, small bilateral incisions were made along the lower border of the ribcage, the skin and fascia were loosened rostrally, and the transplants were placed along the ribs under the skin. The incision was then closed with wound clips. Sham EWATx and sham transplantation consisted of exposing but not removing the pads, as well as all of the procedures for actual transplantation; however, no tissue was inserted under the skin (Fig. 1). Nitrofurozone powder was applied to all wounds to minimize infection. Food intake and body mass were measured weekly for 12 wk postsurgery to the nearest 0.1 g, the former corrected for pouching and spillage. At week 12, all animals were killed by pentobarbital sodium overdose and transplanted fat pads, and intact EWAT, IWAT, and retroperitoneal WAT (RWAT) were harvested and weighed.
Fat cell size and number.
EWAT, IWAT, and RWAT pads and all transplants were prepared for measurements of cellularity [fat cell number (FCN) and fat cell size (FCS)] from a subset of animals in each group reflecting the mean and standard error of the mean of the body mass change across the experiment for the entire group (n = 5–9 per group). Briefly, each pad was blotted dry and finely minced. A sample of each minced pad was further processed. For small tissues (RWAT, the residual EWAT from EWATx animals), aliquots of between 20 and 100 mg were used; for larger tissues, 250 mg of minced sample were used. Samples were fixed in osmium tetroxide according to the method of Hirsch and Gallian (17) for determination of FCN and FCS by a Coulter counter equipped with a channelizer (Beckman Coulter, Fullerton, CA), as previously described (3).
Experiment 2: Does the Source of the Donor Graft [i.e., WAT Pad (IWAT vs. EWAT), Sibling vs. Nonsibling] Affect Compensatory Body Fat Responses?
Eighty-eight hamsters were divided into the following seven groups: 1 and 2) WAT donors (siblings, n = 12; nonsiblings, n = 13), 3) sibling EWAT (sibling EWAT graft received; n = 12), 4) nonsibling EWAT (nonsibling EWAT graft received; n = 13), 5) sibling IWAT (sibling IWAT graft received; n = 12), 6) nonsibling IWAT (nonsibling IWAT graft received; n = 13), and 7) Sham (sham incision and transplantation). All transplants were placed dorsally and in contact with native IWAT.
EWAT and IWAT transplantation. The animals that gained the most mass during the period of single housing were used as donors of EWAT or IWAT. All surgeries were performed under pentobarbital sodium anesthesia (50 mg/kg ip). A fat donor and the two animals assigned to receive transplants from that donor were anesthetized at the same time to reduce the interval between fat removal and transplantation. Right and left side EWAT and IWAT pads were removed from the donor and weighed. Each pad was bisected, and the four smaller pieces of each WAT type were placed separately in cold (4°C) 0.15 M NaCl until transplantation into the appropriate recipient. Transplantation procedures were as in experiment 1 except that all transplants and sham procedures occurred dorsally. The incisions were closed with wound clips, and nitrofurozone powder was applied to minimize infection.
Food intake and body mass were measured weekly for 12 wk postsurgery to the nearest 0.1 g, the former corrected for pouching and spillage. At week 12, all animals were anesthetized with isofluorane (Pittman-Moore, Mundelein, IL) and bled from the retro-orbital sinus using Natelson tubes (250 µl) between 0800 and 1100 during test day. Blood was stored overnight at 4°C, and serum was separated by centrifugation at 1,000 g for 20 min and stored at –20°C until assayed for serum leptin (see below). After the blood sample was obtained, subgroups of animals were killed as described below, matched for the mean percent change in body mass from surgery to week 10. Animals from each treatment were killed with an overdose of pentobarbital sodium, and the transplanted fat pads, as well as the native EWAT, IWAT, and RWAT, were dissected and weighed. Testes mass (an integrated measure of reproductive status) was determined after harvesting.
Leptin radioimmunoassay.
Serum leptin concentrations were determined in a single assay using a commercial kit according to manufacturer specifications (multispecies kit, Linco Research, St. Charles, MO). This assay kit has been previously validated for use with Siberian hamsters (8). In addition, we checked for parallelism using a serial dilution of pooled serum from sham-treated animals compared with the standard curve provided by the manufacturer. All samples were detectible in the range of the assay (1.85–49.83 ng/ml).
Statistical Analysis
Experiment 1. Initial and terminal tissue and body masses, cumulative food intake, the percent change in body and graft masses, and FCN for grafts and intact WAT were analyzed by two-factor, univariate ANOVA (general linear model, version 11.5; SPSS, Chicago, IL), with the factors "surgery" (EWATx, EWATx + graft, sham) and "location" (dorsal, ventral), followed by post hoc testing using Duncan's new multiple range tests when appropriate. If the interaction of "location x surgery" was significant, then separate one-way ANOVAs for each location were done next, followed by Duncan's new multiple range post hoc tests to determine differences among surgery types on each location. Because there were suggestive but not statistically significant differences in IWAT mass between the two sham-operated control groups (P = 0.064, data not shown) and because IWAT mass was used in the calculation of total dissected WAT (combined mass of dissected IWAT, EWAT, RWAT, and grafts), IWAT mass and total dissected WAT (with and without grafts included) in EWATx + dorsal sham, EWATx + dorsal grafts, EWATx + ventral sham, and EWATx + ventral grafts animals were expressed and analyzed as percentages of the mean masses of their appropriate sham-operated control group. Paired t-tests were used to compare the initial vs. the final graft masses. Weekly body mass and food intake were analyzed by two-factor ANOVA for repeated measures with the ANOVA design of surgery x location x time (for body mass from surgery to week 12, 3 x 2 x 13; for food intake week 1 to week 12, 3 x 2 x 12). The proportion of WAT cells that were between 30 and 240 µm diameter were analyzed in 10-µm increments by two-factor ANOVA for repeated measures with the ANOVA design of surgery x location x cell size (3 x 2 x 21). For all repeated-measure ANOVAs, if the main effects of week or cell size were significant, post hoc two-factor ANOVA was done next, followed by Duncan's new multiple range tests to determine differences between treatments for each week or size range. If the interaction of "location x surgery" was significant for the two-factor ANOVA, separate post hoc one-way ANOVAs were done next, followed by Duncan's new multiple range tests to determine differences between treatments for each location.
Experiment 2. For all tests, data were analyzed separately for animals receiving EWAT vs. IWAT grafts because EWAT and IWAT transplants differ in size (Table 1). Initial and terminal tissue and body masses, cumulative food intake, percent change in body and tissue masses, and circulating leptin concentrations were analyzed by one-way ANOVA, with the factor being "donor type" (none, sibling, nonsibling). Paired t-tests were used to compare the initial vs. the final graft masses. Weekly body mass and food intake were analyzed with one-way ANOVA for repeated measures with the ANOVA "donor type" x "time" (for body mass, 3 x 13; for food intake, 3 x 12), with post hoc testing using one-way ANOVA to determine differences between treatments for each week. Two-tailed Pearson's product moments were used to determine covariation among variables.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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EWAT lipectomy deficits, graft mass, and graft cellularity.
The mass of EWAT removed by lipectomy did not differ among lipectomized groups nor did the mass of EWAT grafts replaced as autologous dorsal vs. ventral grafts (Table 1). The mass of all grafts was significantly decreased by 35% at week 12 (P < 0.05; Table 1), and both the absolute and percent decreases in mass were the same regardless of their placement (dorsally or ventrally; Table 1). The total FCN in the dorsal and ventral graphs was also similar (Fig. 2A). There were, however, differences in the FCS distributions between the grafts. Thus there were significantly more smaller adipocytes for the ventral grafts (30–40 µm diameter) and significantly more larger adipocytes for the dorsal grafts (60–100 µm diameter) (P < 0.05; Fig. 2, B and C).
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100% compared with their sham-operated counterparts. By contrast, IWAT and RWAT masses from EWATx + ventral graft hamsters were not different from their lipectomized and sham-operated controls (Fig. 4A). EWAT mass was significantly reduced by EWATx, indicating little or no regrowth of this pad (Fig. 4A). Total dissected WAT mass was significantly increased in the EWATx + dorsal grafted animals compared with lipectomized and sham-operated controls (P < 0.05; Fig. 4B). This effect was suggestive but not statistically significant (P = 0.06, Fig. 4B), even when the graft mass was excluded, indicating that the effect on total dissected WAT was not due to the graft mass alone. Total dissected WAT including or excluding graft mass was not different in animals with ventral grafts or their lipectomized and sham-operated controls (Fig. 4B).
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Although placement site of the EWAT graft did not affect the distribution of FCS for RWAT adipocytes, when both graft locations were considered together, EWATx + graft consistently and significantly shifted the FCS distribution toward larger adipocytes compared with the EWATx + sham animals, beginning with 90- to 100-µm and 100- to 230-µm-diameter adipocytes (P < 0.05; Fig. 6) except for 170- to 190-µm and 200- to 210-µm adipocytes (Fig. 6C).
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Initial and final transplant mass.
Because we transplanted the entire fat pads removed from the donors to the recipients and because EWAT mass is approximately one-half the mass of IWAT, EWAT grafts were smaller than IWAT grafts at the beginning and end of the study (P < 0.05; Table 1). For both EWAT and IWAT transplants, the initial and final graft masses did not differ between groups receiving transplants from a sibling vs. a nonsibling. Both types of WAT pads, whether from siblings or nonsiblings, significantly decreased in mass by 25–50% across the 12-wk experiment (P < 0.05; Table 1). Overall, the larger the size of the initial graft, the greater the final decrease in graft mass (R = 0.356, P = 0.05).
Weekly food intake and body mass. In general, food intake was not different across the experiments among the EWAT or IWAT groups except for decreased food intake, which was likely attributable to surgery-associated effects at week 1 by sibling EWAT recipients vs. nonsibling EWAT animals, by both groups compared with their sham-operated controls, and by the nonsibling IWAT hamsters compared with their Sham counterparts (P < 0.05; data not shown). These were transient decreases in food intake because cumulative food intakes were not different among the groups (data not shown).
Weekly body mass did not differ significantly among EWAT and IWAT groups, and cumulative body mass did not gain (data not shown).
WAT mass.
IWAT mass of EWAT grafted animals was significantly greater (55%) than that from sham-treated controls (P < 0.05; Fig. 7A) regardless of whether the donor was a sibling. By contrast, RWAT mass was only significantly greater (55%) than controls for sibling EWAT grafted hamsters (P < 0.05; Fig. 7A). EWAT mass was not significantly different among EWAT graft groups (Fig. 7A). Total dissected WAT was significantly greater in both groups that received EWAT grafts than in the sham-operated animals (P < 0.05; Fig. 7A), and this was not solely due to the graft mass because these significant differences persisted after the graft masses were subtracted from the total dissected WAT (P < 0.05; Fig. 7A).
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Circulating leptin concentrations and correlations with WAT mass. Mean serum leptin concentrations ranged from 11.75 to 15.36 ng/ml (range 3.45–38.60 ng/ml) and did not differ among treatments for either EWAT or IWAT grafts (Fig. 8A). Serum leptin was significantly positively correlated with body mass at week 12 and with IWAT mass or with RWAT mass (R = 0.452, 0.494, and 0.452, respectively, P < 0.05; Fig. 8, B and C, RWAT data not shown).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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The mechanism through which autologously transplanted EWAT triggers these exaggerated compensatory increases in nonexcised WAT mass after lipectomy (present study and Ref. 19) is unknown. The exaggerated growth of nonexcised WAT seems consistent with the notion that the presence of the grafts goes unrecognized by the central nervous system. One way that the brain may receive information as to the presence or size of WAT pads may be via the sensory innervation of WAT (11, 27, 30), and the grafted WAT may not get reinnervated by the sensory nerves. Indeed, we have failed to see calcitonin gene-related peptide immunoreactivity, indicative of sensory nerves (12, 30), in autologous grafted pads (Lacy and Bartness, unpublished results). It also could be that the failure to respond to autologously transplanted WAT may be due to the absence of a circulating signal (e.g., leptin) conveying the presence or size of WAT to the central nervous system. An intact leptin signaling system, however, is not necessary for the lipectomy-induced compensatory responses of nonexcised WAT pads because ob/ob and db/db mice show normal compensatory WAT responses to lipectomy (5, 14).
In the present experiment, if the autologous grafts were transplanted so as to have direct contact with the intact WAT (IWAT) in lipectomized hamsters, then the nonexcised WAT pads increased their growth beyond that of lipectomy alone. By contrast, their ventrally transplanted graft counterparts that had no direct contact with intact WAT did not do so. One possible underlying mechanism for this effect could involve a circulating factor because not only was there an increase in the mass of WAT that was in contact with the graft (IWAT) but there was an increase in the mass of the distally located WAT that was not in contact with the graft (RWAT). It is not clear, however, whether this hypothesized contact-induced WAT growth factor originates from the graft, from the intact pad, or from both; speculation as to possible candidates is difficult because this is a hitherto undiscovered phenomenon in any species. Alternatively, a circulating factor may not be involved, despite the response of the distal RWAT pad. That is, a locally produced (paracrine) factor from the graft and/or intact IWAT could trigger the exaggerated responses of WAT in contact with the graft, as well as those distal and not in contact with the graft, via changes in the sympathetic drive to these WAT pads. Thus the signal generated from the WAT-graft contact could reach the brain via the sensory innervation of the intact WAT (11, 30), that, in turn, could decrease activity of the centrally located sympathetic outflow circuits to WAT (1). Decreased sympathetic drive to the WAT would result in decreased lipid mobilization (i.e., increased lipid accumulation) (2, 4, 7) and/or increased adipocyte proliferation (3, 6, 30, 32). Indeed, our recent work (29) suggests that lipectomy triggers a decrease in the sympathetic drive to WAT, as measured by norepinephrine turnover. This decrease in sympathetic drive would, in turn, promote decreases in basal lipolysis, thereby enhancing lipid accumulation and/or increasing fat cell proliferation in the nonexcised WAT pads. These hypothesized decreases in the sympathetic drive to, and responses of, nonexcised WAT pads in lipectomized hamsters bearing autologous grafts remain to be tested.
Although the intact pad in contact with the graft (IWAT) had increased FCN and the fat pad distal to and not in contact with the graft (RWAT) had increased FCS, this does not necessarily mean that proliferation and lipid accumulation, respectively, were the only or even primary responses of these depots. That is, it has been hypothesized (10) and tested and confirmed by us in a number of animal models (15) that adipocytes first fill to capacity and then, through as yet unidentified mechanisms, trigger a proliferative response. Thus the accumulation of lipid may have occurred for both pads, but the lipid filling in IWAT resulted in a more rapid achievement of maximum FCS that, in turn, triggered the likely proliferative response. By contrast, the maximum FCS may not have been achieved by RWAT at the time of death and thus no proliferative response occurred.
The compensatory increase in mass of the nonexcised WAT pads after EWATx without replacement in experiment 1 was somewhat less than that seen in our previous studies with similarly treated hamsters (20, 21, 23–25). Specifically, the IWAT mass of EWATx hamsters was nonstatistically significantly increased (30%) with considerable variability across animals, whereas previously the compensatory increase of IWAT was 40–50% with less variability across animals (20, 21, 23–25). One reason for this muted compensatory response to lipectomy in the present study may be differences in surgical procedures between this work and our previous studies. That is, less EWAT mass was removed in experiment 1 of the present study compared with our previous studies (20, 21, 23–25) because of a more aggressive tendency to remove all EWAT in the earlier work, whereas a more conservative approach was taken by the surgeon here. Regardless of the differences between the previous studies and the present study, this compensatory response to lipectomy was clearly exaggerated in animals with dorsal grafts and was statistically significantly greater than EWATx alone.
Transplantation of EWAT but not IWAT in nonlipectomized hamsters (i.e., fat additions) significantly increased native IWAT mass regardless of the relatedness of the donor and also increased RWAT mass when the donor was a sibling, with a suggestive but not statistically significant increased mass with nonsibling donors. The individual increased WAT masses resulted in significantly increased total dissected WAT mass, even when graft mass was taken into account, an effect seen previously by us (19) in our study of EWAT transplants between siblings. Thus we extended the results here to show that, regardless of the relatedness of the donor (brother or nonbrother), the response to EWAT addition is an increase in body fat. This is in sharp contrast to our recent study with laboratory mice (28) in which WAT additions (EWAT grafts) triggered decreases in native fat pad masses, ultimately resulting in no change in total body fat. The response by these mice is the predicted result if total body fat is regulated and if the added WAT is incorporated into the sensing of total body fat. One possible difference between these two studies is the species (Siberian hamsters vs. laboratory mice). Both species, however, respond similarly to fat subtractions (lipectomy) (14, 20, 21, 23–25), making such an explanation plausible only if fat additions promote species-specific effects.
As noted above, EWAT but not IWAT graft additions to nonlipectomized hamsters increased native WAT pad growth (IWAT and RWAT, but not EWAT). The underlying mechanism for this fat pad-specific ability of EWAT to increase WAT growth in all but its native counterpart pad as well as the inability of IWAT to significantly affect any WAT pad (although there was a suggestive, but nonsignificant similar pattern of increases) is unknown. Unfortunately, we did not measure the cellularity responses of the grafts or of the native pads in experiment 2, making it more difficult to speculate as to the possible mechanisms underlying this phenomenon on the basis of known factors that stimulate adipocyte hypertrophy or hyperplasia. The ability of the EWAT grafts to trigger increases in some but not all pads should facilitate subsequent investigations of factors that stimulate adipocyte proliferation and/or lipid accumulation, allowing for within-animal comparisons among the native WAT pads.
Collectively, the present data show a remarkable stimulation of body fat by either the addition of body fat to lipectomized or nonlipectomized hamsters. A common feature of these increases in adiposity is the contact of the grafted WAT pad with native/intact WAT pads. The mechanism underlying this interesting phenomenon is unknown at present, but the finding appears to have important implications for understanding the growth of WAT. Specifically, although several factors, both circulating and paracrine, have been suggested as stimulators of FCN and/or proliferation (for review, see Ref. 16), the hypercellularity associated with obesity is poorly understood at best, despite it being a hallmark of this disease. WAT grafts, therefore, afford a useful and relatively simple in vivo means of stimulating WAT growth including increases in FCN and/or proliferation with the goal of isolating underlying circulating or paracrine factors involved in this process. Finally, the ability of WAT grafts to stimulate WAT growth of pads with which it makes contact as well as distant pads with which it has no contact has implications for the use of WAT in reconstructive and cosmetic surgery in humans (for review see, Ref. 9). That is, if humans respond to WAT grafts in a manner similar to Siberian hamsters, then a potentially adverse consequence of such a surgery might be increases in adiposity, perhaps in visceral fat, where health risks could increase as a consequence.
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GRANTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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ACKNOWLEDGMENTS |
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Present address for E. L. Lacy: Yerkes National Primate Research Center, Emory Univ., Atlanta, GA 30322.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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