AJP - Regu AJP: Endocrinology and Metabolism
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Regul Integr Comp Physiol 279: R936-R943, 2000;
0363-6119/00 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (22)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Weber, R. V.
Right arrow Articles by Kral, J. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Weber, R. V.
Right arrow Articles by Kral, J. G.
Vol. 279, Issue 3, R936-R943, September 2000

Subcutaneous lipectomy causes a metabolic syndrome in hamsters

R. V. Weber1, M. C. Buckley1, S. K. Fried2, and J. G. Kral1

1 Department of Surgery, State University of New York, Health Science Center at Brooklyn, Brooklyn, New York 11203; and 2 Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey 08901


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS AND MATERIALS
RESULTS
DISCUSSION
REFERENCES

The insulin resistance syndrome X is related to excess intra-abdominal adipose tissue. With lipectomy of >50% of subcutaneous adipose tissue (SQAT) in nonhibernating, adult female Syrian hamsters on high-fat (HF; 50 calorie%) diet and measurements of oral glucose tolerance, oral [14C]oleic acid disposal, serum triglycerides, serum leptin, liver fat, perirenal (PR) adipose tissue cellularity, and body composition, we studied the role of SQAT. Sham-operated (S) animals on HF or low-fat (LF; 12.5 calorie%) diets served as controls. After 3 mo there was no visible regrowth of SQAT but HF diet led to similar levels of body weight and body fat in lipectomized and sham-operated animals. Lipectomized (L) animals had more intra-abdominal fat as a percentage of total body fat, higher insulinemic index, a strong trend toward increased liver fat content, and markedly elevated serum triglycerides compared with S-HF and S-LF. Liver and PR adipose tissue uptake of fatty acid were similar in L-HF and S-HF but reduced vs. S-LF, and were inversely correlated with liver fat content and insulin sums during the oral glucose tolerance test. In summary, lipectomy of SQAT led to compensatory fat accumulation implying regulation of total body fat mass. In conjunction with HF diet these lipectomized hamsters developed a metabolic syndrome with significant hypertriglyceridemia, relative increase in intra-abdominal fat, and insulin resistance. We propose that SQAT, via disposal and storage of excess ingested energy, acts as a metabolic sink and protects against the metabolic syndrome of obesity.

syndrome X; fatty liver; high-fat diet; insulin resistance; triglycerides; leptin


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS AND MATERIALS
RESULTS
DISCUSSION
REFERENCES

CONSIDERABLE EVIDENCE demonstrates the adverse health effects of a central distribution of adipose tissue with a preponderance of intra-abdominal or visceral accumulation of fat. The factors causing such distribution and the pathogenetic mechanisms are not known, but excess visceral fat is believed to have a key role in the etiology of the metabolic "syndrome X" of obesity (17).

This experiment investigates the role of subcutaneous adipose tissue (SQAT) in the metabolic syndrome of obesity by surgically creating a relative "deficiency" of SQAT. An analogy is proposed with various lipodystrophies, demonstrating metabolic abnormalities such as insulin resistance (45) and dyslipidemia (22, 34), considered to be "paradoxically" similar to abnormalities found in obesity or adipose tissue excess.

Earlier we noted that some of our patients undergoing extensive surgical reduction of SQAT postoperatively had increased serum insulin and triglyceride levels (21). Other patients in our experience who had had prior lipectomy subsequently developed severe or "morbid" obesity with non-insulin-dependent diabetes and dyslipidemia (19), implying a detrimental effect of removal of subcutaneous fat. Indeed, it actually has been suggested that thigh fat might be "protective" against lipoprotein abnormalities associated with cardiovascular disease (48), and one animal study demonstrates dysfunction of adipose tissue lipoprotein lipase as a determinant of hypertriglyceridemia (15).

Herein we extend our previous animal work using excision of adipose tissue, adipectomy (10, 18), to reduce the amount of SQAT in an animal model of dietary obesity to test the hypothesis that SQAT deficiency causes metabolic abnormalities. We also explored the impact of subcutaneous lipectomy on serum leptin, the adipose tissue-derived ob protein.


    METHODS AND MATERIALS
TOP
ABSTRACT
INTRODUCTION
METHODS AND MATERIALS
RESULTS
DISCUSSION
REFERENCES

Animals, Acclimatization, and Handling

Twenty-eight adult (125-135 g) female Syrian hamsters (Harlan Sprague Dawley) were housed in individual Plexiglas cages with cedar chip bedding. Room conditions were controlled for temperature (75oF), humidity (40%), and 16:8-h light-dark cycle. Animals were handled on a daily basis during daily gavage with tap water, as conditioning for future oral glucose tolerance tests (OGTT) and [14C]oleic acid uptake. Animals were weighed biweekly and were acclimatized to housing and handling for 2 wk preoperatively.

Diets

Animals had ad libitum access to tap water and isocaloric high-fat (HF) or low-fat (LF) control diets that met requirements for protein, minerals, and vitamins (Research Diets, New Brunswick, NJ). The HF diet contained 50 calorie% fat, 27.5% carbohydrate, and 22.5% protein. The LF diet contained 12.5 calorie% fat, 65% carbohydrate, and 22.5% protein. The fat sources were one-half each of soybean and hydrogenated coconut oils.

Groups

Animals were randomly assigned to one of three groups: lipectomy on an HF diet (L-HF, n = 9), sham lipectomy on an HF diet (S-HF, n = 9), or sham lipectomy on an LF diet (S-LF, n = 9).

Procedures

Surgical. After fasting for 16 h with free access to water, the animals were anesthetized intraperitoneally with 100 mg/kg ketamine plus 10 mg/kg xylazine. The abdomen was shaved and scrubbed with Betadine. A 3-cm transverse incision was made across the inguinal region. The superior cutaneous flap was dissected to the level of the costal arch; the inferior flap was dissected around the perineum on the inside of the thighs down to the knees. Both flaps were extended posterolaterally to the vertebral column ("belt lipectomy"). The subcutaneous fat pad was then sharply dissected from the fascia, excised, and weighed. There was no visible evidence of any brown adipose tissue in the surgical specimen. This procedure removes more than 50% of all subcutaneous dissectable adipose tissue in 130-g female hamsters corresponding to ~15-20% of all adipose tissue.

The incision was closed with interrupted 3-0 nylon sutures. Animals were returned to their cages after recovery from anesthesia. Sham procedures were identical to lipectomy with elevation of flaps but without fat-pad excision. All animals were followed daily for 2 wk to monitor postoperative wound healing and weight gain.

Fasting OGTTs. After 11 wk, 1 wk before death, all animals underwent an OGTT. After a 16-h fast with free access to water, 1.5 g/kg body wt of dextrose was mixed in 0.5 ml sterile water and given via gavage. Blood samples (0.5-0.75 ml) were taken from the retro-orbital sinus under CO2 sedation, at baseline, after 30 min, and after 120 min for serum glucose and serum insulin determination.

Nonfasting [14C]oleic acid uptake. All animals were gavaged with 0.9 ml sesame oil containing 1 µCi [14C]oleic acid (Dupont NEN Products, Boston, MA) 16 h before they were killed. This time interval was chosen based on the data of Li et al. (25) in rats demonstrating maximum uptake in adipose tissue after 16 h.

Death

At 12 wk, without fasting, at midday the animals were sedated with CO2, and 4-6 ml of blood were collected from the retro-orbital sinus into nonheparinized tubes for further serum analyses. The animals were then killed by exsanguination.

Carcasses were inspected for any regrowth at lipectomy sites. Subcutaneous (SQ), parametrial (PM), and perirenal (PR) fat pads were dissected, excised, weighed, and stored at -20oC until they were analyzed.

The liver was removed and weighed after discarding the gallbladder. Portions of liver were stored at -20oC for protein and lipid extractions and 14C analysis. One aliquot was stored in liquid nitrogen for determination of glutathione as a marker of lipid peroxidation (41). A small sample was fixed in Formalin for histological examination.

The gastrointestinal tract from esophagus to rectum was removed. The remaining carcass was homogenized in water, and aliquots were analyzed for lipid gravimetrically after lipid extraction using Dole's solution. Carcass dry weight was measured while fat-free dry weight and water content were calculated.

Chemical Analyses

Blood. Serum was stored at -20oC until spectrophotometric determination of alanine aminotranspeptidase, alkaline phosphatase, and triglycerides (Sigma, St. Louis, MO). A radioimmunoassay (RIA) kit was used for leptin determination. Samples collected during OGTT were measured for glucose levels using a Beckman Glucose Analyzer 2. Insulin was determined using 125I-RIA with rat insulin standard (IncStar, Stillwater, MN).

Liver. Liver protein determination was done spectrophotometrically from homogenized wet tissue samples (Sigma, modified Lowry method). Lipid extraction was performed according to Folch and measured gravimetrically. Liver glutathione, a sensitive marker of hepatocellular injury, was determined with the method described by Salazar et al. (41).

Histological hematoxylin and eosin stain of liver tissue was prepared according to the routines of the Department of Pathology. Specimens were examined by the pathologist without knowledge of the experimental groups, and graded on a semiquantitative scale for amount of lipid within hepatocytes.

Adipose tissue. Samples from the PR fat depot were placed in 0.9% NaCl. They were blotted and weighed and used for Folch extraction and osmium fixation for cell sizing and calculation of cell number (14). This depot was selected for fat cell sizing because it has been demonstrated consistently to be most sensitive to manipulations of body fat (e.g., Ref. 23). [14C]oleic acid counts in fat and liver tissues were determined before lipid extraction using a Packard Tricarb Liquid Scintillation Spectrometer.

Statistics

SPSS and Statview II, and Microsoft Excel 97 programs were used to calculate t-tests, ANOVAs, and Scheffé post hoc tests as appropriate. All results are presented as means ± SE. Pearson correlations were calculated for selected continuous variables.

The protocol was approved by the Institutional Animal Care and Use Committee in accordance with Association for Accreditation and Assessment of Laboratory Animal Care guidelines.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS AND MATERIALS
RESULTS
DISCUSSION
REFERENCES

General

HF diet resulted in equal body weights in the two HF groups, which were higher than in S-LF animals (Table 1; Fig. 1; P < 0.05). Close inspection of the lipectomy sites in the L-HF groups did not reveal any signs of adipose tissue regrowth.

                              
View this table:
[in this window]
[in a new window]
  		Table 1.   Body weight, adipose tissue weights, and carcass lipid content in lipectomized or sham-operated female Syrian hamsters after 12 wk on HF or LF diets



View larger version (14K):
[in this window]
[in a new window]
  		Fig. 1.   Weights in lipectomized (L) and sham-operated (S) adult female hamsters on high-fat (HF) or control, low-fat (LF) diets followed for 12 wk.

Adipose Tissue Depots

Fat pad wet weights (SQ, PM, PR) were significantly greater in the HF groups than in S-LF group (P < 0.001; Table 1). The absolute weights of "visceral" or intra-abdominal depots (PR and PM) were not statistically different in lipectomized and S-HF groups but were greater than in the S-LF group. L-HF animals showed a strong trend to greater visceral fat vs. S-HF animals when expressed as %body weight (1.96 ± 0.08 vs. 1.75 ± 0.10%; P = 0.10) and %body fat (21.6 ± 2.9% vs. 15.8 ± 1.3%; P = 0.10). PR fat cell sizes were larger in the HF groups (P < 0.001), but there was no difference between L-HF and S-HF. There were no statistically significant differences in fat cell numbers in the PR depots between groups.

Carcass Analyses

The absolute amount of residual carcass lipid (after removal of major fat pads) was not statistically significantly different between the two HF groups [L-HF = 9.6 ± 1.2 g vs. S-HF = 7.9 ± 0.8 g; P = not significant (NS)], although expressed as %total body lipid, carcass lipid was 17% greater in the lipectomized group (62.7 ± 2.3 vs. 46.3 ± 2.9% in S-HF; P < 0.001), indicating increased fat deposition in the carcass after lipectomy. Both HF groups had greater carcass lipid content than the S-LF group. Total body lipid content (carcass lipid plus dissected depot lipid) in L-HF and S-HF hamsters was similar and higher than in S-LF hamsters.

Body composition was similar in the HF groups (L-HF: lipid = 10.5%, water = 68.8%, fat-free dry weight = 20.7%; S-HF: lipid = 11.8%, water = 68.4%, fat-free dry weight = 19.8%). The S-LF group had less lipid (8.0%; P < 0.001) and more water (72.3%; P < 0.001) than the two HF groups.

Liver analyses

Neither wet weight nor protein content per gram wet weight of liver tissue differed significantly between groups (Table 2). However, there was a 48% increase in chemically determined liver fat in the lipectomized group compared with the S-LF group (P = 0.07; Table 2), which was not evident on histological examination (data not shown). Differences in liver glutathione per gram protein between L-HF and S-HF groups did not reach statistical significance (Table 2). Serum alanine aminotranspeptidase and serum alkaline phosphatase also were not statistically significant (Table 3).

                              
View this table:
[in this window]
[in a new window]
  		Table 2.   Liver tissue in lipectomized or sham-operated female Syrian hamsters on HF or LF diets


                              
View this table:
[in this window]
[in a new window]
  		Table 3.   Blood chemistry and oral glucose tolerance tests in female Syrian hamsters

Glucose and Lipid Metabolism

When killed the S-HF animals had significantly higher baseline serum glucose than the other two groups (P < 0.05) and higher baseline serum insulin than S-LF (P < 0.01) and L-HF groups (P < 0.05; Table 3). However, the baseline insulinemic index (serum insulin /serum glucose) was higher in the L-HF group than in either sham-operated group (0.31 ± 0.01 vs. 0.29 ± 0.02 in S-HF and 0.27 ± 0.01 in S-LF; P < 0.05 by ANOVA). Both HF groups had elevated serum insulin sums during OGTT (P < 0.001) with the S-HF group being highest (P < 0.001 by ANOVA). There were no statistically significant differences in serum glucose sums between groups.

Serum triglycerides were markedly elevated in the L-HF group compared with the S-HF and S-LF groups (P < 0.02 by ANOVA).

[14C]oleic acid uptake in adipose tissue was significantly greater in the S-LF group than in either HF group with no difference between lipectomized and sham-operated animals (Table 4). In the S-LF animals uptake in the intra-abdominal depots (PM and PR) was greater than in SQAT [PM, 17.0 ± 2.8 counts/min (cpm) × 10-3/g; PR, 14.0 ± 2.3 cpm × 10-3/g; SQ, 8.4 ± 1.7 cpm × 10-3/g; P < 0.05 by ANOVA]. In the PR adipose tissue depot there was an inverse relationship between fat cell size and [14C]oleic acid uptake (r = -0.61; P < 0.001; Fig. 2). Furthermore, PR lipid uptake was inversely related to insulin sums during the OGTT (r = -0.48; P < 0.05). Liver uptake of [14C]oleic acid was also greater in the S-LF group than in both HF groups (P = 0.004; Table 4).

                              
View this table:
[in this window]
[in a new window]
  		Table 4.   [14C]oleate uptake in SQ, PM, and PR adipose tissue and liver in female Syrian hamsters



View larger version (17K):
[in this window]
[in a new window]
  		Fig. 2.   Relationship between fat cell weight and gavaged [14C]oleate uptake in perirenal adipose tissue. FCW, fat cell weight.

There were inverse relationships between liver uptake and insulin sums (r = -0.39; P < 0.05; Fig. 3) and liver fat (r = -0.40; P < 0.05), with a trend toward a positive correlation between insulin sums and liver fat content (r = 0.34; P = 0.075). However, there were no statistically significant relationships between serum insulin and serum triglycerides nor between liver fat and serum triglycerides.


View larger version (18K):
[in this window]
[in a new window]
  		Fig. 3.   Insulin sum during oral glucose tolerance tests and [14C]oleate uptake in liver tissue.

Leptin Analysis

Mean serum leptin values were similar in all three groups of hamsters (Table 3). There were statistically significant positive correlations between serum leptin values and dissectable adipose tissue depot weights with similar slopes in each group (L-HF, r = 0.75; S-HF, r = 0.85; S-LF, r = 0.81; P < 0.05). Serum leptin did not correlate with body weight, total lipid, or serum insulin.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS AND MATERIALS
RESULTS
DISCUSSION
REFERENCES

HF diet in these adult female hamsters was associated with relative hyperinsulinemia, increased body fat and body weight, larger PR fat cell size, and increased weights of dissectable adipose tissue depots compared with sham-operated hamsters on a control, LF diet (S-LF). Lipectomy in conjunction with the HF diet resulted in compensatory deposition of lipid in the carcass and remaining fat depots leading to similar levels of body fat and body weight as in the sham-operated group (S-HF), thus clearly demonstrating regulation of body fat in hamsters as previously determined by Hamilton and Wade (12) in adult female Syrian hamsters having more extensive lipectomy. Furthermore, in the present study lipectomy was associated with significant hypertriglyceridemia, a 40% increase in liver fat content, a relative increase in intra-abdominal adipose tissue, and an elevated basal insulinemic index, components of the metabolic, insulin resistance syndrome X of obesity described in people (1, 11, 17).

There are three potential sites of peripheral insulin resistance in this model: 1) adipose tissue, 2) liver, and 3) muscle. We studied in vivo oleic acid uptake to detect differences in fatty acid uptake into tissues and as a marker of insulin resistance. In the absence of tissue studies of insulin action, however, we are unable to determine the extent or relative contributions of the various tissues to overall insulin resistance. Both of our HF-fed groups exhibited decreased uptake of oral oleic acid compared with the group on control diet in all dissected white adipose tissue, implying insulin resistance. On the control diet oleic acid uptake was greater in the metabolically more active intra-abdominal depots than in subcutaneous fat, in agreement with findings by Li et al. (25) in intact fed rats.

The substantial increase in serum triglycerides in the lipectomized hamsters implies a quantitative role for SQAT as a "metabolic sink" for dietary fat. The lack of triglyceride elevation in the sham-operated hamsters on an HF diet is consistent with the findings of others of an "absence of changes in circulating triglyceride levels" during fat feeding (39). Similar elevations of triglycerides as those in the lipectomized animals have been described during seasonal obesity in female Syrian hamsters (4), in lipectomized female ground squirrels (9), and in lipectomized male rats with dexamethasone-induced insulin resistance (31). A recent study of lipectomy of inguinal and interscapular adipose tissue in female obese and lean Zucker rats on a LF diet demonstrated great variability in serum insulin and glucose levels as well as serum triglycerides in both groups at different times postoperatively (26). Unfortunately, there were no sham-operated controls, and the sampling circumstances were not described. Furthermore, the interscapular depot of rats and other rodents contains substantial amounts of brown adipose tissue (which were not described in the paper), further contributing to difficulties in interpreting their data.

We did not measure adipose tissue lipoprotein lipase (LPL) levels in our animals and cannot determine whether quantitative or qualitative (15) changes in LPL could account for impaired clearance of circulating lipids. However, female ground squirrels undergoing extensive visceral and subcutaneous lipectomy exhibited elevated plasma triglyceride levels in the face of markedly elevated SQAT LPL activity (9). On the other hand, Mauer and Bartness (28), in a study of long-day-housed male Siberian hamsters with lipectomy of the epididymal white adipose tissue depot (a relatively small depot), did not detect any changes in SQAT LPL.

The reduction of a significant amount of SQAT in these hamsters on an HF diet was associated with a trend toward increased fatty infiltration of the liver. There was a reduction in the uptake of oleic acid by the liver, which might reflect hepatic insulin resistance similar to that found in adipose tissue. Earlier we showed that elevated plasma insulin levels and serum free fatty acids are correlated with liver fat and triglyceride synthesis (20), and we demonstrated recently that insulin resistance is associated with fatty infiltration of the liver and increased intra-abdominal fat in humans (1, 11) without being able to determine the mechanism(s). One mechanism of insulin resistance is thought to be mediated by free fatty acids delivered to liver tissue via the portal vein, interfering with insulin binding and degradation (13, 47) contributing to the Randle effect (35).

A different mechanism of hepatic insulin resistance with decreased hepatic insulin clearance (6) might be due to toxic effects of lipid peroxidation in the fatty liver (5), reflected in the slight elevation of serum alanine aminotranspeptidase in the lipectomized animals. However, in the absence of elevations of serum alkaline phosphatase or decreases in liver glutathione levels we are unable to conclusively determine the validity of this proposed mechanism. Nevertheless, in our lipectomy model with reduced SQAT acting as a metabolic sink and with a relative increase in intra-abdominal fat, it is likely that the fatty infiltration of the liver is a cause rather than a consequence of insulin resistance.

It has been speculated recently that leptin may contribute to hepatic steatosis via effects on insulin secretion (16). In the present experiment using an HF diet known to decrease leptin, we found no differences between leptin levels among the groups in the face of increased fatty infiltration and varying levels of plasma insulin. Our finding in conjunction with findings of fatty liver in the leptin-deficient models described below (30, 43) lead us to believe that increased leptin likely does not contribute to fatty liver in this context, although decreased levels might be of pathogenetic importance.

Lipectomy did not cause any change in serum leptin levels compared with the sham-operated controls on HF diets (S-HF). This is not surprising in the face of similar levels of total body lipid and the leptin-lowering effects of the HF diet. We are unable, however, to explain the lack of a difference in serum leptin level in the S-LF group, with 37% less body lipid, particularly in view of the robust correlations between serum leptin and dissectable adipose tissue depot weights in all groups.

The third peripheral site of insulin resistance may be muscle tissue. Deposition of lipid within or between muscle fibers in these lipectomized hamsters on an HF diet would be consistent with the findings of Perseghin et al. (33) in people. Insulin resistance is well documented in skeletal muscle tissue of rats fed an HF diet (46). Although not measured, we have no reason to expect significant differences in physical activity, which hypothetically also could contribute to differences in insulin action between the groups.

The metabolic manifestations of surgical reduction of SQAT in our study are similar to those described in lipodystrophy (22, 34, 45) characterized by an absence of subcutaneous but presence of visceral adipose tissue. Another "natural model" for reduced SQAT mass might be fetal undernutrition, inhibiting the development and growth of adipose tissue. Fetal undernutrition has been described recently as a risk factor for subsequent development of components of the metabolic syndrome X (2, 36). Interestingly, in utero exposure to famine during the fetal period when adipose tissue normally develops, resulted in significantly higher obesity rates in young men (38). Recent follow-up studies of women and men at 50 yr of age have demonstrated an abdominal distribution of adipose tissue in the women (37), which might explain a higher prevalence of metabolic abnormalities later in life.

Based on the present experiments and our earlier clinical observations, we believe that surgical reduction of SQAT can be used as an experimental model for studying the importance of this adipose tissue depot in the pathogenesis of the metabolic syndrome of obesity. Earlier studies of antiserum with cytotoxic effects to rat adipocyte plasma membranes in vivo affected both visceral and SQAT cell numbers with a predominant effect on the internal depots (8). In a follow-up study these authors noted "grossly affected liver morphology" but no effects of the antiserum on lipid or glucose metabolism (32). Wright and Hausman (51) demonstrated cytotoxicity of monoclonal antibodies in rats in vivo, with greater effects on inguinal than PR depot weights. They did not address metabolic effects of the intervention.

Initial studies on various transgenic mice with knock-out of white adipose tissue led to lethal phenotypes characterized by enlarged, fatty livers and metabolic disturbances (40, 50). More recent studies on transgenic mice with alterations of transcription factors successfully created phenotypes with absence of white fat (30, 43). The metabolic consequences in those experiments, expressed after life-long or delayed exposure to generalized adipose tissue deficiency were similar to our findings after the more acute intervention of surgically reducing SQAT in adult animals. The conclusions of those authors are similar to ours, postulating a role for adipose tissue deficiency in the pathogenesis of diabetes and hyperlipidemia. Interestingly a recent sophisticated study of hepatic insulin resistance in male rats with lipectomy of epididymal and PR depots (3) is complementary to ours. Although their study neither reduced SQAT nor visceral depots draining into the portal vein (omental and mesenteric) they found a significant increase in hepatic insulin sensitivity in their lipectomized rats as well as altered gene expression in SQAT. Although performed in different species, with different sex and different designs with respect to diet and duration, taken together these two studies seem to imply the importance of optimal amounts of subcutaneous vs. visceral adipose tissue, as has been proposed in clinical studies (27, 44).

In conclusion, the present results confirm earlier findings by others and by us of regulation of body fat and imply that a lack of SQAT may have detrimental consequences. These findings in hamsters are in line with preliminary data from severely obese patients with extensive subcutaneous lipectomy (19). Further studies will be necessary to determine whether there is a critical relative or absolute amount of subcutaneous fat necessary to "protect" against the metabolic abnormalities of the insulin resistance syndrome X. Such studies might require greater numbers of animals and longer periods of observation.

Perspectives

With the recognition of the seriousness of the world-wide epidemic of obesity and its significant comorbidities, all interest has focused on detrimental aspects of excess adipose tissue without considering the possibility of necessary functions of the tissue beyond simple storage of substrate. Separate from concerns over health consequences of obesity, the prevailing cosmetic ideals have driven the wide-spread performance of suction-assisted lipectomy among the overweight and obese and even among normal weight individuals exclusively targeting SQAT (27). This study demonstrates that lipectomy, by reducing the number of subcutaneous adipocytes, causes lipid deposition in visceral adipose tissue and the liver with metabolic consequences similar to the insulin resistance syndrome X.

The results also have implications for the controversy over the etiology and earliest events of syndrome X. Candidates range from genes, fetal stress, undernutrition, and dietary excess (mainly lipid and simple carbohydrates) to sedentary lifestyle and include hypothalamic neuroendocrine activity, pancreatic beta -cell responsiveness, and neoglucogenetic enzyme abnormalities. Most of these factors influence adipogenesis, either through inhibition (e.g., via undernutrition) or stimulation (e.g., via fatty diet or sedentariness) of fat cell growth causing adipose tissue deficiency or adipocyte hypertrophy. Syndrome X is prevalent in people born in areas with perinatal and infant undernutrition when they are exposed to "Western" diets and lifestyles (29). Their decreased numbers of fat cells in SQAT, developmentally the earliest fat compartment, places them at risk for lipid deposition in tissues poorly equipped to handle excess lipid [e.g., pancreas (23), liver, artery, skeletal muscle, or heart (52)].

Further support for this metabolic sink hypothesis can be found in clinical lipodystrophy, a naturally occurring state of adipose tissue deficiency. All lipodystrophies associated with components of syndrome X described to date involve dystrophy exclusively of subcutaneous fat. In this context, mutations affecting lamin have just been discovered in people with partial lipodystrophy (42), in turn contributing to the development of type II diabetes (7).

The broad general implication of this study of lipectomized hamsters is recognition of the fact that SQAT may protect against lipotoxicity in nonadipose tissue and thus be of primary pathogenetic importance for avoiding the development of metabolic abnormalities. It raises concerns over long-term adverse effects of large-volume lipectomy.


    ACKNOWLEDGEMENTS

We gratefully acknowledge Dr. Daniel P. Penha for histopathological analyses of liver tissue, M. Nicholson (Amgen, Thousand Oaks, CA) for leptin determination analyses, and Diane Zarb for preparing the manuscript. We also appreciate the thoughtful efforts of the expert reviewers of this manuscript.


    FOOTNOTES

This research was funded by the Department of Surgery, State University of New York Health Science Center at Brooklyn.

Address for reprint requests and other correspondence: J. G. Kral, Dept. of Surgery, Box 40, SUNY Downstate Medical Center, 450 Clarkson Ave., Brooklyn, New York 11203.

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Received 8 December 1999; accepted in final form 31 March 2000.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS AND MATERIALS
RESULTS
DISCUSSION
REFERENCES

1.   Banerji, MA, Buckley MC, Chaiken RL, Gordon D, Lebovitz HE, and Kral JG. Liver fat, serum triglycerides and visceral adipose tissue in insulin-sensitive and insulin-resistant black men with NIDDM. Int J Obes 19: 846-850, 1995.

2.   Barker, DJP Fetal origins of coronary heart disease. BMJ 311: 171-174, 1995[Free Full Text].

3.   Barzilai, N, She L, Liu BQ, Vuguin P, Cohen P, Wang J, and Rossetti L. Surgical removal of visceral fat reverses hepatic insulin resistance. Diabetes 48: 94-98, 1999[Abstract].

4.   Cincotta, AH, MacEachern TA, and Meier AH. Bromocriptine redirects metabolism and prevents seasonal onset of obese hyperinsulinemic state in Syrian hamsters. Am J Physiol Endocrinol Metab 264: E285-E293, 1993[Abstract/Free Full Text].

5.   Comporti, M. Lipid peroxidation and cellular damage in toxic liver injury. Lab Invest 53: 599-623, 1985[ISI][Medline].

6.   Faber, OK, Christensen K, Kehlet H, Madsbad S, and Binder C. Decreased insulin removal contributes to hyperinsulinemia in obesity. J Clin Endocrinol Metab 53: 618-621, 1981[Abstract].

7.   Flier, JS. Pushing the envelope on lipodystrophy. Nat Genet 24: 103-104, 2000[ISI][Medline].

8.   Flint, DJ, Coggrave H, Futter CE, Gardner MJ, and Clarke TJ. Stimulatory and cytotoxic effects of an antiserum to adipocyte plasma membranes on adipose tissue metabolism in vitro and in vivo. Int J Obes 10: 69-77, 1986[ISI][Medline].

9.   Forger, NG, Dark J, Stern JS, Wade GN, and Zucker I. Lipectomy influences white adipose tissue lipoprotein lipase activity and plasma triglyceride levels in ground squirrels. Metabolism 37: 782-786, 1988[ISI][Medline].

10.   Fried, SK, Born M, Vasselli JR, Haraczkiewicz E, and Kral JG. Effects of total subcutaneous lipectomy (LPX) in female rats fed a high fat diet (Abstract). Fed Proc 45: 350, 1986.

11.   Goto, T, Onuma T, Takebe K, and Kral JG. The influence of fatty liver on insulin clearance and insulin resistance in nondiabetic Japanese subjects. Int J Obes 19: 841-845, 1995.

12.   Hamilton, JM, and Wade GN. Lipectomy does not impair fattening induced by short photoperiods or high fat diets in female Syrian hamsters. Physiol Behav 43: 85-92, 1988[Medline].

13.   Hennes, MMI, Shrago E, and Kissebah AH. Receptor and postreceptor effects of free fatty acids on hepatocyte insulin dynamics. Int J Obes 14: 831-841, 1990[ISI][Medline].

14.   Hirsch, J, and Gallian E. Methods for the determination of adipose cell size in man and animals. J Lipid Res 9: 110-119, 1968[Abstract].

15.   Julius, U, Leonardt W, Noack D, Schulze J, Nikulcheva NG, Jaross W, and Hanefeld M. Pathogenetic role of adipose tissue lipase deficit for development of hypertriglyceridaemia. Exp Clin Endocrinol 94: 187-193, 1989[ISI][Medline].

16.   Kaplan, LM. Leptin, obesity, and liver disease. Gastroenterology 115: 997-1001, 1998[ISI][Medline].

17.   Kissebah, AH, and Krakower GR. Regional adiposity and morbidity. Physiol Rev 74: 761-811, 1994[Free Full Text].

18.   Kral, JG. Surgical reduction of adipose tissue in the male Sprague-Dawley rat. Am J Physiol 231: 1090-1096, 1976.

19.   Kral, JG. Surgical treatment of regional adiposity. Acta Med Scand Suppl 723: 225-231, 1988[Medline].

20.   Kral, JG, Lundholm K, Sjöström L, Björntorp P, and Schersten T. Hepatic lipid metabolism in severe human obesity. Metabolism 26: 1025-1031, 1977[ISI][Medline].

21.   Kral, JG, and Sjöström LV. Surgical reduction of adipose tissue hypercellularity. Recent Adv Obes Res 1: 327-330, 1975.

22.   Lawrence, RD. Lipodystrophy and hepatomegaly with diabetes, lipaemia and other metabolic disturbances. Lancet 1: 724-741, 1946.

23.   Lee, Y, Hirose H, Ohneda M, Johnson JH, McGarry JD, and Unger RH. beta -Cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte beta -cell relationships. Proc Natl Acad Sci USA 91: 10878-10882, 1994[Abstract/Free Full Text].

24.   Lemonnier, D. Effect of age, sex, and on the cellularity of the adipose tissue in mice and rats rendered obese by a high-fat diet. J Clin Invest 51: 2907-2915, 1972.

25.   Li, M, Yang S, and Björntorp P. Metabolism of different adipose tissues in vivo in the rat. Obesity Res 1: 459-468, 1993[Medline].

26.   Liszka, TG, Dellon AL, Im M, Angel MF, and Plotnick L. Effect of lipectomy on growth and development of hyperinsulinemia and hyperlipidemia in the Zucker rat. Plast Reconstr Surg 102: 1122-1127, 1998[ISI][Medline].

27.   Matarasso, A, Kim RW, and Kral JG. The impact of liposuction on body fat. Plast Reconstr Surg 102: 1686-1689, 1998[ISI][Medline].

28.   Mauer, MM, and Bartness TJ. A role for testosterone in the maintenance of seasonally appropriate body mass but not in lipectomy-induced body fat compensation in Siberian hamsters. Obesity Res 3: 31-41, 1995[ISI][Medline].

29.   Mi, J, Law C, Zhang KL, Osmond C, Stein C, and Barker D. Effects of infant birthweight and maternal body mass index in pregnancy of components of the insulin resistance syndrome in China. Ann Intern Med 132: 253-260, 2000[Abstract/Free Full Text].

30.   Moitra, J, Mason MM, Olive M, Krylov D, Gavrilova O, Marcus-Samuels B, Feigenbaum L, Lee E, Toshifumi A, Eckhaus M, Reitman ML, and Vinson C. Life without white fat: a transgenic mouse. Genes Dev 12: 3168-3181, 1998[Abstract/Free Full Text].

31.   Palacios, E, Piñon-López MJ, Racotta IS, and Racotta R. Effect of lipectomy and long-term dexamethasone on visceral fat and metabolic variables in rats. Metabolism 44: 1631-1638, 1995[ISI][Medline].

32.   Panton, D, Futter C, Kestin S, and Flint D. Increased growth and protein deposition in rats treated with antibodies to adipocytes. Am J Physiol Endocrinol Metab 258: E985-E989, 1990[Abstract/Free Full Text].

33.   Perseghin, G, Scifo P, de Cobelli F, Pagliato E, Battezzati A, Arcelloni C, Vanzulli A, Testolin G, Pozza G, del Maschio A, and Luzi L. Intramyocellular triglyceride content is a determinant of in vivo insulin resistance in humans. Diabetes 48: 1600-1606, 1999[Abstract].

34.   Powell, EE, Searle J, and Mortimer R. Steatohepatitis associated with limb lipodystrophy. Gastroenterology 97: 1022-1024, 1989[ISI][Medline].

35.   Randle, PJ, Hales CN, Garland PB, and Newsholme EA. The glucose fatty acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1: 785-789, 1963[ISI][Medline].

36.   Ravelli, ACJ, van der Meulen JHP, Michels RPJ, Osmond C, Barker DJP, Hales CN, and Bleker OP. Glucose tolerance in adults after prenatal exposure to famine. Lancet 351: 173-177, 1998[ISI][Medline].

37.   Ravelli, ACJ, van der Meulen JHP, Osmond C, Barker DJP, and Bleker OP. Obesity at the age of 50 y in men and women exposed to famine prenatally. Am J Clin Nutr 70: 811-816, 1999[Abstract/Free Full Text].

38.   Ravelli, GP, Stein ZA, and Susser MW. Obesity in young men after famine exposure in utero and early infancy. N Engl J Med 295: 349-353, 1976[Abstract].

39.   Robins, SJ, Fasulo JM, Patton GM, Schaefer EJ, Smith DE, and Ordovas JM. Gender differences in the development of hyperlipemia and atherosclerosis in hybrid hamsters. Metabolism 44: 1326-1331, 1995[ISI][Medline].

40.   Ross, SR, Graves RA, and Spiegelman BM. Targeted expression of a toxin gene to adipose tissue: transgenic mice resistant to obesity. Genes Dev 7: 1318-1324, 1993[Abstract/Free Full Text].

41.   Salazar, DE, Sorge CL, Jordan SW, and Corcoran GB. Obesity decreases hepatic glutathione concentrations and markedly potentiates allyl alcohol-induced periportal necrosis in the overfed rat. Int J Obes 18: 25-33, 1994.

42.   Shackleton, S, Lloyd DJ, Jackson SNJ, Evans R, Niermeijer MF, Singh BM, Schmidt H, Brabant G, Kumar S, Durrington PN, Gregory S, O'Rahilly S, and Trembath RC. LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. Nat Genet 24: 153-156, 2000[ISI][Medline].

43.   Shimomura, I, Hammer RE, Richardson JA, Ikemoto S, Bashmakov Y, Goldstein JL, and Brown MS. Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev 12: 3182-3194, 1998[Abstract/Free Full Text].

44.   Sjöström, CD, Lissner L, and Sjöström L. Relationships between changes in body composition in cardiovascular risk factors. Obesity Res 5: 519-530, 1997[ISI][Medline].

45.   Smith, U, diGirolamo M, Blohmé G, Kral JG, and Tisell LE. Possible systemic metabolic effects of regional adiposity in a patient with Werner's syndrome. Int J Obes 4: 153-163, 1980[ISI][Medline].

46.   Susini, C, and Lavau M. In vitro and in vivo responsiveness of muscle and adipose tissue in rats rendered obese by a high-fat diet. Diabetes 27: 114-120, 1978[ISI][Medline].

47.   Svedberg, J, Björntorp Smith U, and Lönnroth P. Free fatty acid inhibition of insulin binding, degradation and action in isolated rat hepatocytes. Diabetes 39: 570-574, 1990[Abstract].

48.   Terry, RB, Stefanick ML, Haskell WL, and Wood PD. Contributions of regional adipose tissue depots to plasma lipoprotein concentrations in overweight men and women: possible protective effects of thigh fat. Metabolism 40: 733-740, 1991[ISI][Medline].

49.   Unger, RH, Zhou YT, and Orci L. Regulation of fatty acid homeostasis in cells: novel role of leptin. Proc Natl Acad Sci USA 96: 2327-2332, 1999[Abstract/Free Full Text].

50.   Wang, ND, Finegold MJ, Bradley A, Ou CN, Abdelsayed SV, Wilde MD, Taylor LR, Wilson DR, and Darlington GJ. Impaired energy homeostasis in C/EBP alpha knockout mice. Science 269: 1108-1112, 1995[Abstract/Free Full Text].

51.   Wright, JT, and Hausman GJ. Monoclonal antibody-mediated cytotoxicity of adipocytes. Obesity Res 3: 265-272, 1995[ISI][Medline].

52.   Zhou, YT, Grayburn P, Karim A, Shimabukuro M, Higa M, Baetens D, Orci L, and Unger RH. Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci USA 97: 1784-1789, 2000[Abstract/Free Full Text].

Am J Physiol Regul Integr Comp Physiol 279(3):R936-R943
0363-6119/00 $5.00 Copyright © 2000 the American Physiological Society


This article has been cited by other articles:


Home page
 Am. J. Clin. Nutr.Home page
E. W Demerath, D. Reed, N. Rogers, S. S Sun, M. Lee, A. C Choh, W. Couch, S. A Czerwinski, W C. Chumlea, R. M Siervogel, et al.
Visceral adiposity and its anatomical distribution as predictors of the metabolic syndrome and cardiometabolic risk factor levels
Am. J. Clinical Nutrition, November 1, 2008; 88(5): 1263 - 1271.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
H. Shi, A. D. Strader, S. C. Woods, and R. J. Seeley
The effect of fat removal on glucose tolerance is depot specific in male and female mice
Am J Physiol Endocrinol Metab, October 1, 2007; 293(4): E1012 - E1020.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
T. Tchkonia, M. Lenburg, T. Thomou, N. Giorgadze, G. Frampton, T. Pirtskhalava, A. Cartwright, M. Cartwright, J. Flanagan, I. Karagiannides, et al.
Identification of depot-specific human fat cell progenitors through distinct expression profiles and developmental gene patterns
Am J Physiol Endocrinol Metab, January 1, 2007; 292(1): E298 - E307.
[Abstract] [Full Text] [PDF]

Home page
 Int J EpidemiolHome page
M. Snijder, R. van Dam, M Visser, and J. Seidell
What aspects of body fat are particularly hazardous and how do we measure them?
Int. J. Epidemiol., February 1, 2006; 35(1): 83 - 92.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (22)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Weber, R. V.
Right arrow Articles by Kral, J. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Weber, R. V.
Right arrow Articles by Kral, J. G.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online