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High Fat Diets Elevate Adipose Tissue-Derived Tumor Necrosis Factor- Activity¹

University of Colorado Health Sciences Center, Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine (C.L.M., R.H.E., T.M.), Department of Pediatrics (M.J.P.), and Center for Human Nutrition (C.L.M., R.H.E., M.J.P.), Denver, Colorado 80262

Address all correspondence and requests for reprints to: Catherine Morin, University of Colorado Health Sciences Center, 4200 East 9th Avenue, C225, Denver, Colorado 80262. E-mail: Catherine.Morin{at}uchsc.edu

	Abstract

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Adipose tissue-derived tumor necrosis factor- (AT-TNF) has been associated with genetic models of insulin resistance and obesity. It is presently unknown if secreted AT-TNF protein is bioactive or whether it can be increased by environmentally induced obesity. In this study, male Wistar rats were fed either a low fat (LF; 12% of energy from corn oil) or a high fat (HF; 45% of energy from corn oil) diet for 5 weeks. From previous data, it is known that after 3 weeks, HF fed animals are obese and insulin resistant compared with the LF group. Hence, animals were killed at 1 week of HF feeding, during the acute response to the diet, and at 5 weeks, when differences in body fat are manifest. Weight gain was significantly increased by diet (P = 0.03) and time (P < 0.0001). AT-TNF bioactivity was measured on secreted protein collected from medium of minced, incubated epididymal (EPI), mesenteric (MES), and retroperitoneal (RETRO) fat pads. AT-TNF bioactivity was significantly increased by diet (P = 0.003) in the RETRO pad and tended to increase (P = 0.07) in EPI. AT-TNF activity was unaffected by diet or time in the MES pad. In the RETRO pad, TNF activity correlated negatively with RETRO fat cell number (r = -0.46, P = 0.002). Secreted AT-TNF protein did not correlate with AT-TNF activity but instead decreased in RETRO with time but not diet. In EPI, secreted AT-TNF protein decreased with the HF diet. Thus, these data suggest that high fat diets and obesity can influence AT-TNF bioactivity and secretion but in an apparent fat pad-specific manner.

	Introduction

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ADIPOSE TISSUE is a source of tumor necrosis factor- (AT-TNF) (1). Elevated levels of AT-TNF protein and messenger RNA (mRNA) in adipose tissue were originally observed in genetic rodent models of obesity and insulin resistance (1). More recently, AT-TNF has been measured in obese humans (2, 3). As expected, AT-TNF mRNA was decreased following weight reduction and the accompanying improvement in insulin action (2, 3). The effect of an environmentally induced obesity, such as that produced by a high fat diet, on AT-TNF has not been studied. Based on genetic models of obesity and insulin resistance in which AT-TNF is elevated, we hypothesized that AT-TNF activity, as well as protein and mRNA, would be increased by high fat feeding.

It is currently unknown if secreted AT-TNF protein is bioactive, and if this activity changes coordinately with AT-TNF mRNA and/or protein in adipose cells. Discordant regulation may be expected as previous studies in macrophages have shown that macrophage TNF mRNA, protein, bioactivity, and secretion are regulated in a disparate manner (4, 5). Due to sequences within the 3' untranslated region, TNF mRNA does not have to be translated (4). If translation occurs, the protein must then be transported to the membrane where it must be proteolytically cleaved to be secreted. The active TNF trimer can be inhibited by other proteins such as its shed receptor (6). Thus, TNF activity is a function of several parameters. In this study, we chose to incubate excised fat tissue taken from animals fed either a low-fat (LF) or a high fat diet (HF), and collect the medium containing the purported secreted AT-TNF. AT-TNF activity was then measured using a standard cytolytic bioassay that has historically been used in the immunology field (7). To further understand the regulation of AT-TNF, AT-TNF protein was measured from these same incubated samples along with tissue mRNA levels.

	Materials and Methods

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Animals
This study was part of a larger study that measured the enzymatic profile of muscle, liver, and heart in rats fed either a HF or LF diet. These results have been reported elsewhere (8). Male Wistar rats (Charles River Laboratories, Kingston, NY), approximately 150 g, were housed individually, with 12-h light, 12-h dark cycle and free access to food and water, as per the guidelines set by the American Association for the Accreditation of Laboratory Animal Care. All protocols were approved by the University of CO Health Sciences Center Animal Care Committee. All animals were weighed weekly and food intake was measured three times per week.

After 1 week of quarantine, rats were provided a semipurified diet ad libitum (LF; Research Diets, New Brunswick, NJ) (Table 1) with 12% of calories from fat (corn oil), 20% from protein (casein), and 68% from carbohydrate (maltodextrins and cornstarch). After a 2-week baseline period, 45 rats were placed on a high fat diet (HF; Research Diets) in which 45% of the calories were derived from corn oil and fed ad libitum (Table 1). Fourteen rats continued on the LF diet ad libitum. From previous data, it is known that HF fed animals are obese and insulin resistant by week 3. Thus, rats were killed at 1 week of HF feeding, during the acute response to the diet, and at 5 weeks when differences in body fat are evident. The HF group contained more rats to accommodate the variability displayed by this group in weight gain, circulating hormones, and AT-TNF activity.

TNF bioassay
Under sterile conditions, adipose tissue was minced and incubated in DMEM containing 0.5% low endotoxin-fatty acid free albumin (Sigma, St. Louis, MO) for 1 h. Medium was collected and frozen at -70 C for later analysis.

TNF activity was measured in a bioassay which uses WEHI cells, a murine fibroblastic cell line that is very sensitive to TNF (7). In this paper AT-TNF activity was defined as the TNF bioactivity measured with this method. Samples containing AT-TNF were aliquoted into a 96-well plate in triplicate, in serial dilution, with the WEHI cells. After 48 h, the number of live cells was quantified using Alamar blue (Alamar Biosciences, Inc., Sacramento, CA), a dye that is reduced by live cells only. Cytotoxicity curves for each sample were then generated based on the percent survival of cells and the log of sample dilution. TNF activity is expressed as fg/ml relative to that of the recombinant TNF standard curve (R&D Systems, Minneapolis, MN). AT-TNF containing samples incubated with a TNF antibody (R&D Systems) showed no reduction in live cells confirming that AT-TNF was the only cytotoxic protein secreted from these adipose tissue samples (Fig. 1). The assay typically had a 2% interassay coefficient of variation.

View larger version (19K): [in this window] [in a new window]   Figure 1. Neutralization of AT-TNF activity by TNF antibody.

RNA-PCR
To further understand the relationship between TNF protein and TNF mRNA, mRNA was isolated from week 5 fat tissue only because this time point represented less of a transition state and more of a chronic effect of diet. Briefly, homogenized tissue was incubated in a guanidine-containing solution, Trizol (Gibco BRL, Gaithersburg, MD). The RNA was then purified using centrifugation and ethanol precipitation. After DNase 1 treatment, RNA was quantified and frozen in 10 µg aliquots. Primers were obtained from Clonetech (Palo Alto, CA) or were synthesized from Gibco BRL. The following primers were used:

TNF: 5'-TACTGAACTTCGGGGTGATTGGTCC-3'

5'-CAGCCTTGTCCCTTGAAGAGAACC-3'

B₂-microglobulin: 5'-CTCCCCAAATTCAAGTGTACTCTCG-3'

5'-GAGTGACGTGTTTAACTCTGCAAGC-3'

RNA and oligo (deoxythymidine) primers (all PCR reagents were purchased from Gibco BRL) were mixed and heated to 65 C for 10 min. Reverse transcription was performed in 50 mM KCL, 10 mM Tris-HCl, pH 8.3, 1 mM deoxynucleotide triphosphates, 5 mM MgCl₂, 1 U/µl RNase inhibitor, and 300 U RT in a 20 µl reaction. For every RNA sample, a no-RT control was run to assure no DNA contamination. All no-RT reactions were negative, indicating that all PCR products were of RNA origin. B₂-microglobulin was measured as a control for RNA loading and RT activity. From each RT reaction, 9 µl were added to two separate PCR reactions (25 pmol of each primer, 1.5 mM MgCl₂, 2 mM deoxynucleotide triphosphates, and 4 U Taq polymerase in 50 µl total). The first PCR reaction containing the TNF primers was amplified for 40 cycles (94 C, 30 sec; 60 C, 30 sec; 72 C, 1 min; Perkin-Elmer Corp., Norwalk, CT, 9600), as this number of cycles had previously been determined to be in the exponential range of PCR amplification (unpublished observations). The second PCR reaction, containing the B2 microglobulin primers, was amplified 25 cycles to keep within the exponential amplification range. There was no significant effect of diet on B2 microglobulin mRNA levels (LF = 8.7 ± 2.8, HF = 11.9 ± 0.6 arbitrary units). PCR products were run on a 4% gel (NuSieve, FMC, Rockland, ME), and the bands were then quantified by densitometer.

Cell sizing and number
Fat cell size was determined by measuring the diameter of 50 collagenase-treated cells (10) under a microscope. Fat cell number (FCN) was determined using the following calculations: number of cells/g = average cell size (pl) x (0.95 ng lipid/1 pl) x g/10⁹ ng. This is then multiplied by the number of grams of tissue to get FCN. We have previously found this method to correlate well (r>0.9 in all three fat pads) with FCN determinations based on lipid content (unpublished data). Nevertheless, lipid content was measured in all the fat samples and used to recalculate FCN and TNF activity/10⁶ cells. This method of calculation produced different absolute numbers but did not change the results or interpretation. Due to the variation this measurement introduced, we have chosen to present the data based on the method using the equations listed above.

Data analysis
Data were analyzed by two-way ANOVA. When significant differences (P < 0.05) were found among groups, pairwise multiple comparisons were made following the Student-Newman-Keuls method (SigmaStat, Jandel, San Rafael, CA). Data are expressed as means ± SEM.

	Results

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Energy intake
Energy intake averaged 101 ± 5 kcal/day during the 2-week baseline period, and there were no significant differences between groups (data not shown). Rats who remained on the LF diet did not significantly alter their intake over the subsequent 5-week interval. Energy intake in HF fed rats was significantly increased compared with LF rats (Table 2).

Fasting plasma values
Fasting plasma insulin was significantly increased by diet (P = 0.03) and time (P = 0.02) (Table 2). No significant differences by diet or time were observed in fasting plasma glucose (data not shown). Plasma triglycerides were significantly decreased by the HF diet (P = 0.005) (Table 2).

TNF activity
The response of AT-TNF activity to the HF diet differed among the individual fat pads. In RETRO, AT-TNF activity was significantly elevated by diet (P = 0.003). Increased AT-TNF activity was observed at both week 1 (235 ± 29 vs. 402 ± 44 fg/10⁶ cells in LF vs. HF) and at week 5 of HF feeding (115 ± 14 vs. 330 ± 55 fg/10⁶ cells in LF vs. HF) (Fig. 2A). In contrast, a diet effect was not observed in either EPI (P = 0.07) or MES (P = 0.9). It should be noted that Peyer’s patches, immune cells that line the intestine, could be contributing to the TNF activity measured in MES. However, MES TNF activity/10⁶ cells is similar to values noted for both EPI and RETRO TNF activity.

View larger version (14K): [in this window] [in a new window]   Figure 2. AT-TNF activity in (A) RETRO: diet, P = 0.003; week, P = 0.12; D x W: P = 0.70. (B) EPI: diet, P = 0.07; week: P = 0.76; D x W: P = 0.35. (C) MES: diet, P = 0.90; week, P = 0.40; D x W: P = 0.63. (At all time points, n = 5–6/LF and 15–21 in HF).

AT-TNF activity was not correlated with fasting plasma insulin. There was a significant, negative correlation between AT-TNF activity and cell number in RETRO only (r = -0.46, P = 0.002). AT-TNF activity correlated with cell size in MES at week 1 only (r = 0.43, P = 0.05) and at week 5 in RETRO (r = 0.59, P = 0.003).

AT-TNF mRNA
To determine the relationship between AT-TNF activity and AT-TNF mRNA, RNA was purified from the week 5 adipose tissue samples. RETRO-TNF mRNA tended to increase with the HF diet (LF = 0.2, HF = 1.5 arbitrary units x 10^-4; P = 0.09). EPI-TNF mRNA increased with HF feeding (Table 4). However, under RT-PCR conditions necessary for semiquantitation, EPI-TNF was generally undetectable in the LF animals (n = 4). It could be detected if the number of cycles was increased but then the conditions were no longer in the exponential phase of amplification for the other RNA samples. MES-TNF mRNA showed no significant differences between groups. Although TNF mRNA responded in similar directions as TNF activity, only in the RETRO fat pad was the relationship significant (r = 0.55, P = 0.05).

	Discussion

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High fat feeding for 5 weeks resulted in increased energy intake, weight gain, and fat mass in all three fat pads. In response to the HF diet, plasma triglycerides were decreased and fasting plasma insulin, an estimate of whole body insulin action, was increased. The data suggest that insulin resistance is elevated by both the age of the animal and by the HF diet. AT-TNF activity did not relate to body weight, weight gain, or fasting plasma insulin. It is possible that the considerable variance (up to 90% in some cases) shown in AT-TNF bioactivity obscured any potential relationships. However, this variance was of biological origin as the interassay CV was only 2%. This magnitude of biological variance was not seen in any other variable measured in this study. Although some studies have shown a relationship between TNF mRNA and fasting plasma insulin (2), neither AT-TNF mRNA nor protein correlated with fasting plasma insulin in this study. It is possible that a more robust measure of insulin resistance or some specific aspect of insulin regulated glucose metabolism may be related to AT-TNF activity. However, we have recently found that AT-TNF activity was not correlated with either endogenous glucose appearance or glucose infusion rate and was only weakly correlated with glucose disappearance (r = -0.38, P = 0.056) during hyperinsulinemic, euglycemic clamps in rats fed either LF, HF, or high sucrose diets (11a).

The proposal that AT-TNF plays a role in peripheral insulin resistance was originally noted in studies where obese rats were infused with TNF-receptor-immunoglobulins (12). Because TNF is made in several other cell types including keratinocytes and muscle (13, 14), it is not possible to distinguish the role of AT-TNF from TNF secreted from these cells in this experiment. It is possible that the TNF-receptor-immunoglobulin was inhibiting TNF that was secreted from a cell other than the adipocyte. There are two other studies using TNF antibody infusions that have demonstrated no change in lipid parameters such as LPL acitivity (15) or in insulin sensitivity (16). Thus, it is not altogether clear how AT-TNF effects metabolism in vivo. It should be emphasized that this study measured TNF parameters during the development of obesity and insulin resistance, and in this setting, the role of AT-TNF appears to be minor.

In vitro studies have shown that exogenous TNF, when applied to 3T3-L1 cells, an adipogenic cell line, decreased glucose uptake (17). Additionally, TNF in tissue culture causes dedifferentiation of adipocytes (18, 19), and apoptosis (20). This clearly is not occurring in environmental or genetic obesity. It is possible that the levels of TNF used in tissue culture are not seen in vivo due to the secretion of soluble inhibitors. Alternatively, TNF activity or its effects may be modified in adipose tissue by other cells such as preadipocytes, the endothelium, or perhaps by catecholamines, as has been suggested by Lang (21). Thus, the obvious differences between in vivo and in vitro TNF metabolism remain to be elucidated.

AT-TNF protein levels decreased with diet in EPI and with time in RETRO. Increases in AT-TNF activity did not correlate with changes in AT-TNF protein, nor did differences in protein correlate with changes in mRNA levels. Discordance between mRNA and protein levels suggest that AT-TNF is regulated posttranscriptionally and/or at the secretion step. In the present study, protein levels were measured in the medium of minced, incubated adipose tissue. Therefore, changes in AT-TNF protein could be due to alterations in synthesis and/or secretion. Discordance between protein and activity suggest that inhibitors of AT-TNF activity exist in vivo. This postulate is consistent with the regulation of macrophage-derived TNF (5). One possible inhibitor of TNF activity is its shed receptor (6). Indeed, an increase in soluble TNF receptors has been documented in obese humans (22). Increased TNF protein in obesity has been observed in other studies, but their results are not comparable to this study due to differences in the study groups or in data expression (1, 2). The relationship of AT-TNF activity with respect to AT-TNF protein clearly requires further study.

Secreted protein levels did not parallel changes in AT-TNF mRNA. The small sample size in the RNA data, and hence lack of power, could be one explanation for the absence of significant relationships. However, regulation at either the translation or secretion steps could obscure any linear relationships among mRNA, protein, and activity levels. The regulation of steady-state AT-TNF mRNA is not well understood. Previous studies have shown that diet restriction decreased AT-TNF mRNA in obese, nondiabetic humans (3) but had little effect in obese, diabetic mice (23). In fact, severely obese individuals appear to be characterized by decreased TNF mRNA (3). Nevertheless, this data strongly suggests that changes in AT-TNF mRNA may not always be an accurate reflection of AT-TNF activity.

In summary, this study has shown that high fat feeding can increase AT-TNF activity, in a fat tissue specific manner, through posttranscriptional mechanisms. It should be emphasized that previous studies involving AT-TNF have been in models where insulin resistance and obesity were well established and not in the developmental stage. It is possible that feeding animals longer than 5 weeks would result in more obvious relationships between AT-TNF and obesity and/or insulin resistance.

	Acknowledgments

 
We would like to extend our gratitude to Isabel R. Schlaepfer, David Pennington, and Carrie Ganong for their assistance. We would also like to thank Dr. John Moorhead for generously providing the WEHI cells and the related methodology.

	Footnotes

 
¹ This work was supported by National Institutes of Aging Grant KO1-AG00645 (to C.M.) and the National Institutes of Health Grant DK-47416 (to M.P.) and the the Energy Balance Core and the Cellular and Molecular Core of the Colorado Clinical Nutrition Research Unit (P30 Grant DK-48520).

Received April 3, 1997.

	References

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Morin, C. L. Articles by Pagliassotti, M. J. Search for Related Content PubMed PubMed Citation Articles by Morin, C. L. Articles by Pagliassotti, M. J.