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Endocrinology, doi:10.1210/en.2003-1359
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Endocrinology Vol. 145, No. 5 2174-2185
Copyright © 2004 by The Endocrine Society

Interaction between Corticosterone and Insulin in Obesity: Regulation of Lard Intake and Fat Stores

Susanne E. la Fleur, Susan F. Akana, Sotara L. Manalo and Mary F. Dallman

Department of Physiology, University of California, San Francisco, San Francisco, California 94143-0444

Address all correspondence and requests for reprints to: Dr. Susanne E. la Fleur, Department of Physiology, University of California, San Francisco, 513 Parnassus Avenue, Box 0444, San Francisco, California 94143-0444. E-mail: susanne{at}itsa.ucsf.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Passive elevations in glucocorticoids result in increased insulin and abdominal obesity with peripheral wasting, as observed in Cushing’s syndrome, with little effect on chow intake. In the absence of insulin (streptozotocin-induced diabetes) diabetic rats markedly increase their chow intake in proportion to glucocorticoids. Given a choice of lard or chow, diabetic rats first eat lard, then reduce caloric intake to normal for 48 h before returning to hyperphagia on chow alone. We performed three experiments to determine the relationship of corticosterone and insulin to lard intake, chow intake, body weight, hormones, and fat depots. The results of these studies clarify the actions of both circulating glucocorticoids and insulin on caloric intake in adult male rats. Our experiments show that glucocorticoids provoke dose-related increases in total caloric intake that persist for days and weeks; the results also suggest that increasing insulin concentrations stimulated by glucocorticoids determine the amount of fat intake. Furthermore, we show that lard intake is associated with increasing insulin concentrations. Additionally, the results in adrenalectomized and adrenalectomized, streptozotocin-induced diabetic rats strongly suggest that it is a combination of corticosterone and insulin that increases abdominal fat depot weight. Independently of the hormonally manipulated rats, the results also show that intact rats voluntarily eat a considerable and stable proportion of their daily calories as lard when given a choice between lard and chow. These results suggest that some human obesities may result from elevated glucocorticoids and insulin increasing the proportional intake of high density calories.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
OBESITY IS A major and growing societal and medical problem. Although genetic factors contribute to the development of obesity, common environmental and lifestyle factors are also important (1, 2, 3). The consumption of dietary fat is an important environmental factor leading to obesity. Fat is easily overconsumed because it is palatable and leads to less satiety then carbohydrate and protein (4). Furthermore, average dietary fat intake correlates positively with the incidence of becoming obese (5, 6, 7, 8, 9, 10). Although body weight is tightly regulated, dietary fat alters negative feedback that normally regulates body weight, resulting in obesity (9, 11, 12). Thus, fat intake affects important processes that are involved in maintaining energy balance.

Insulin and corticosterone (B) are two of the many signals involved in regulating energy balance and intake. Insulin and B serve opposite roles in maintaining energy balance and energy storage (13, 14). Insulin is secreted in proportion to adiposity; it crosses the blood-brain barrier and reduces chow intake and body weight dose-dependently by acting on specific receptors in the hypothalamus (15, 16, 17, 18). Adrenalectomy (ADX) reduces chow intake, and B replacement normalizes it, but high B concentrations either do not stimulate chow intake or reduce it (19, 20, 21, 22, 23, 24). However, in the absence of insulin [streptozotocin (STZ)-induced diabetes] B increases chow intake dose-dependently (25), suggesting that insulin secretion, also stimulated dose-dependently by glucocorticoids, partially blocks chow intake stimulated by corticosteroids.

Insulin and B have complex interactions in the gain of body weight, as they do for food intake (25). Glucocorticoids inhibit energy storage, and insulin promotes energy storage (13, 14); the effects of these hormones usually occur in parallel at different caloric storage sites. However, they act synergistically in abdominal fat depots (26, 27, 28). This is particularly clear in patients with Cushing’s syndrome who are hypercortisolemic, hyperinsulinemic, and hyperglycemic with intraabdominal obesity and atrophy of the muscular extremities (29). Furthermore, increases in B concentrations decrease body weight similarly in both adrenalectomized (ADX) and diabetic-ADX rats, although diabetic-ADX rats have lower overall body weight (25).

We have shown previously that dietary fat changes caloric intake and hypothalamic peptides involved in the regulation of energy balance. In the absence of insulin, dietary fat reduces caloric intake and neuropeptide Y mRNA and peptide in the arcuate nucleus (30, 31). In the presence of insulin, dietary fat leads to increased caloric intake, body weight gain, and fat stores with high concentrations of leptin (10). Several of those obesogenic effects were observed after only 3 d of fat ingestion (30, 32). Although the role of B on caloric intake and body weight gain are evident when rats are fed a high carbohydrate diet (33), the role of B in obesity resulting from ingestion of dietary fat is not fully understood. ADX attenuates or prevents the development of obesity in the majority of genetic and experimental models of obesity (34, 35, 36, 37, 38), and glucocorticoid administration leads to obesity (39, 40, 41). The independent effects of B and insulin on caloric intake and adiposity in combination with fat consumption are unknown.

We designed three experiments to study the interactions of insulin and B on chow and lard intake, body weight gain, and adiposity in adult (60 d old) male rats; our previous studies studying only chow ingestion were performed in juvenile male rats (30–35 d old), and it was possible that this period of very rapid growth influenced the results (25). First, ADX rats replaced with different doses of B were presented with the choice of eating standard rat chow or lard ad libitum. We have shown previously that rats with this choice substitute 30–40% of total consumed calories with those from lard (30). In contrast to the high fat diet used in most studies, giving rats a choice of eating lard and/or chow allowed us to determine differential effects of B and insulin on caloric choice. Second, ADX rats made diabetic with STZ were presented with the same choice between lard and chow. These experiments permitted a test of the effects of B on food preference in the presence and absence of insulin. In the final experiment, groups of ADX rats replaced with high B were made diabetic and replaced with zero or one of two doses of insulin and presented with the choice between lard and chow. This experiment allowed us to test the hypothesis that in the presence of moderate insulin levels and high B, diabetic rats would increase lard and decrease chow consumption.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Male Sprague Dawley rats, weighing 280–320 g, from Bantin and Kingman Suppliers (Freemont, CA) were housed at University of California-San Francisco Lab Animal Resources Center in temperature-controlled (21–23 C) and light-controlled (12 h light; lights on at 0700 h) rooms in experiments 1 and 2. Experiment 3 was similar, but was conducted in a room with lower temperature (17–19 C). The rats were housed individually in hanging wire cages and given food (Purina chow 5008, Ralston Purina, St. Louis, MO) and water ad libitum until surgery, which occurred at least 5 d after the arrival of the rats from the supplier. All animal procedures were approved by the University of California-San Francisco institutional animal care and use committee.

Experiment 1
On d 0, rats were anesthetized with isoflurane, bilaterally ADX by the dorsal approach and implanted sc with 100-mg pellets containing 0% B (wax pellet; B0), 35% B/65% cholesterol (B35), or 100% B (B100). These percentages of B were designed to provide the rats with clamped plasma B concentrations in the normal basal daily range (B35; ~5 µg/dl) or daily peak levels (B100; >10 µg/dl). A fourth group of rats was sham-ADX. A fifth group was ADX, received a 35% B pellet, and received a STZ injection to deplete insulin (Sigma-Aldrich Corp., St. Louis, MO; 65 mg/kg in citrate buffer pH 4.2, sc). Postoperative care was provided with an injection of ketoprofen (10 mg/kg, sc; Abbott Laboratories, Inc., Chicago, IL). Rats were offered 0.5% saline from the time of ADX until the end of the experiment in their major drinking bottle to compensate for the loss of aldosterone. On d 7–14, half of the rats were provided in the morning with a cup of lard (Armour Inc., Omaha, NE; 9 cal/g) in addition to their normal Purina rodent chow (5008, Ralston Purina). At 1700 h on d 10 and at 0800 h on d 11, rats were taken from the home cage, and within 2 min a blood sample was collected from a cut made over the lateral tail vein. Samples of 300 µl were collected in EDTA-coated capillary tubes, kept on ice, and centrifuged in the cold. Aliquots of plasma were stored at –20 C until plasma concentrations of corticosterone were assayed. Body weight and food intake were recorded daily in the morning. All rats were killed on d 14 between 0900–1000 h by decapitation within 10 sec after they had been taken from their home cages. Hormonal concentrations in trunk blood were determined. Individual mesenteric, epididymal, sc (inguinal), and perirenal white adipose tissues were dissected, cleaned, and weighed.

Experiment 2
Thirty rats were ADX and replaced with B0, B35, or B100 as described above. All rats were given STZ (Sigma-Aldrich Corp.; 65 mg/kg in citrate buffer, pH 4.2, sc; ADX-STZ). An additional 10 rats were sham-ADX; five rats received STZ (sham-ADX-STZ), and five rats received only an injection with the citrate buffer (sham-ADX). Postoperative care was provided with an injection of ketoprofen (10 mg/kg, sc; Abbott Laboratories, Inc.). After 10 d of recovery, rats were provided with a cup of lard (Armour Inc.; 9 cal/g) in the morning in addition to their normal rodent chow (5008, Ralston Purina) for 48 h. Body weight and food intake were recorded daily in the morning. All rats were killed between 0900–1000 h on d 12 by decapitation within 10 sec after they had been taken from their home cages. Hormonal concentrations were determined in plasma from trunk blood.

Experiment 3
After adaptation days, as in experiments 1 and 2, 12 rats were sham-ADX and injected with citrate buffer (sham-ADX); 36 rats were ADX and replaced with B100 pellets and insulin pellets, followed by injection of 65 mg/kg STZ sc (ADX-B100-STZ). The diabetic rats were divided into three groups of 12 animals and were replaced with 0, 1, or 2 U/d insulin on d 0 using sc implanted pellets of bovine insulin (Linplant, Toronto, Canada) (42). These implants slowly release insulin for up to 40 d. On d 7 of the experiment, all groups were further subdivided into rats maintained on chow and rats allowed access to lard, as in experiments 1 and 2. These rats were killed on d 14 of the experiment, similarly to those in experiment 1. In this experiment, possibly because the rat room was colder, there was an overall mortality of 25% (compared with ~10% mortality in experiments 1 and 2) that was spread fairly equally across the ADX-B100-STZ groups. Rats with failure to thrive were removed from the experiment and humanely killed.

Plasma measurements
Plasma glucose concentrations were measured using the glucose oxidase assay on a plate reader (Sigma-Aldrich Corp.). All plasma concentrations of hormones were determined by RIA. Plasma B kits were from ICN Biochemicals, Inc. (Costa Mesa, CA). The leptin, insulin, and adiponectin kits were obtained from Linco Research, Inc. (St. Charles, MO) and used at quarter volumes.

Statistical analyses
Data were first analyzed by two-way ANOVA. A significant (P <= 0.05) global effect of ANOVA was followed by one-way ANOVA and post hoc tests of individual group differences (Fisher’s protected least significant difference). Simple linear regression analyses were performed to determine the possible relationship between some variables. A t test was used to test the null hypothesis that slopes did not significantly differ from zero (P <= 0.05). When two regression analyses were performed to determine the possible relationship between variables with and without lard, and the null hypothesis of the separate slopes could be rejected, t tests were performed to test whether the slopes and/or the elevations were significantly different (P <= 0.05).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
ADX with or without B, with or without lard
In the ADX B35 and B100 rats, pellets provided plasma B ranging from 3–6 µg/dl and 14–18 µg/dl, respectively. These concentrations are comparable to the average daily values (B35) and peak values (B100) of the diurnal rhythm (43). There was no effect of 7 d of lard consumption on B concentrations (Fig. 1AGo). We also measured B concentrations in tail nick samples taken after 3 d of lard access (d 10–11). For the ADX rats, plasma B concentrations in the morning and evening were not different (data not shown). As expected, sham-ADX rats showed significantly higher plasma B concentrations in the evening than in the morning, but there were no effects of lard (after 3 d; morning: chow, 0.3 ± 0.3; chow plus lard, 0.6 ± 0.3; evening: chow, 26.3 ± 2.5; chow plus lard, 29 ± 3.4). Figure 1BGo shows the cumulative caloric intake over the 7-d period of lard access, starting 1 wk after ADX. There were no significant differences in total caloric intake between the groups when rats were eating chow. All ADX and sham-ADX rats substituted part of their caloric intake with lard; all but the ADX-B0 rats increased total caloric intake (Fig. 1BGo). Seven days of lard consumption increased abdominal and sc fat stores and plasma concentrations of leptin and adiponectin in sham-ADX rats (Fig. 1Go, C–F). In ADX rats, abdominal fat stores (aWAT; mesenteric, epididymal, and perirenal depots) increased with B concentrations, with the largest stores found in ADX-B100 rats consuming lard (Fig. 1CGo). Subcutaneous fat stores (sWAT) increased significantly with lard in ADX-B100 (Fig. 1DGo). Interestingly, ADX-B35 rats ate similar amounts of lard as sham-ADX rats (94 ± 17 and 114 ± 12 cal/100 g body weight, respectively; Fig. 1BGo), but did not increase fat stores or plasma concentrations of leptin or adiponectin (Fig. 1Go, E and F). Furthermore, insulin concentrations were significantly higher in ADX-B100 rats; lard increased insulin concentrations in this group further (Fig. 1GGo). ADX-B100 rats gained weight more slowly when consuming only chow, but weight gain was restored with eating lard plus chow (Fig. 1HGo).



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  		FIG. 1. Effect of increasing B concentrations and 7 d of lard ingestion in ADX rats with different doses of circulating B (B0, B35, and B100) and in sham-ADX rats on plasma B concentrations in the morning (panel A), cumulative caloric intake (calories per 100 g body weight) measured over 7 d (panel B; for the lard-eating rats: , calories from lard; {blacksquare}, calories from chow), abdominal fat (panel C), plasma leptin concentrations (panel D), sc fat stores (panel E), plasma adiponectin concentrations (panel F), plasma insulin concentrations (panel G), and body weight gain (panel H) over the 7 d that lard plus chow or chow was available. , Rats that were offered only chow; {blacksquare}, rats that were offered chow and lard. Body weights of the groups on the day of ADX surgery: ADX-B0, 281 ± 2 g; B35, 283 ± 5 g; B100, 281 ± 3 g; and sham-ADX, 279 ± 5 g. All data were measured by two-way ANOVA, and when significant, post hoc analyses were performed (Fisher’s protected least significant difference test). Groups with different letters (a, b, c, and d in the chow group; A, B, C, and D in the chow+lard group) differ significantly (P <= 0.05). L, Significant effect of lard in that group of rats. Data are the mean ± SEM (n = 4–7/group; see Table 3Go for results of overall two-way ANOVA analyses that were performed for all groups and treatments).

 
Figure 2Go shows individual data from ADX rats. Abdominal fat stores correlated positively with plasma B concentrations in ADX rats eating chow or chow plus lard (Fig. 2AGo; chow: r2 = 0.61; P < 0.001; chow plus lard: r2 = 0.68; P < 0.0001). The slope of the regression line was significantly steeper in ADX rats eating chow plus lard than in those eating chow only (0.074 ± 0.016 vs. 0.133 ± 0.022, by t test, P < 0.001). Leptin and adiponectin correlated positively with aWAT in all ADX rats, and again an increase in the slope occurred when rats ate lard [leptin, 3.43 ± 0.78 vs. 4.8 ± 0.64 (P < 0.001; adiponectin, 1.43 ± 0.51 vs. 1.78 ± 0.29 (P < 0.001); Fig. 2Go, B and C]. Subcutaneous fat stores in ADX rats correlated with plasma B concentrations only when ADX rats ate chow plus lard (r2 = 0.47; P < 0.01; Fig. 2DGo). Leptin and adiponectin correlated positively with sWAT in ADX rats only when lard was consumed (leptin: r2 = 0.63; P < 0.0001; adiponectin: r2 = 0.48; P = 0.001; Fig. 2Go, E and F).



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  		FIG. 2. ADX plus B replacement in ADX rats with chow ({bullet}) or with chow plus lard for 7 d ({circ}). Panel A, B increases aWAT more in rats with access to lard. Panels B and C, Access to lard augments hormone secretion at higher doses of B, see text for details. Panel D, B increases sWAT dose-dependently only when lard is available. Panels E and F, sWAT correlates positively with plasma concentrations of leptin and adiponectin in ADX rats with access to lard.

 
Figure 3Go shows the linear relationship of 7 d of lard intake to the ratio of plasma concentrations of B/insulin. The higher the hormone ratio, the greater the lard intake (r2 = 0.41; P < 0.01). We next tested whether circulating insulin concentrations affected the effect of B on lard intake.



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  		FIG. 3. Correlation of the hormone ratio (plasma B/plasma insulin) on 7-d lard intake (calories per 100 g body weight). {circ}, Individual data from ADX rats receiving different doses of circulating B that had access to lard in addition to chow. r2 = 0.41; P < 0.005.

 
ADX-STZ with or without B, with or without lard
In the second experiment we used sham-ADX, sham-ADX-STZ, and ADX-STZ rats without (chow) or with access to lard for 48 h (chow plus 48-h lard); ADX-STZ groups were given no B replacement (ADX-STZ B0), average B replacement (ADX-STZ B35), or stress level B (ADX-STZ B100). Plasma B concentrations in ADX-STZ B35 and ADX-STZ B100 rats were successfully clamped at approximately 4–5 and 20 µg/dl, respectively, and concentrations in ADX-STZ B0 rats were undetectable [Table 1Go, effect of group: F(2,22) = 221; P < 0.0001]. In ADX-STZ rats, increasing circulating B concentrations decreased body weight gain dose-dependently (r2 = 0.52; P < 0.001); the catabolic effects of B were pronounced at the high steroid dose (Fig. 4Go, {circ}).


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  		TABLE 1. Body weight before surgery, caloric intake after 24 h of lard access and plasma concentrations of glucose, B, insulin, leptin, and adiponectin in rats in experiment 2

 


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  		FIG. 4. ADX and B replacement in rats without ({circ}) and with ({bullet}) diabetes when only chow was provided. B inhibits the gain in body weight over 5 d in both ADX and ADX-STZ rats. The presence of insulin in ADX rats augments body weight gain. There is no interaction between the two hormones (see text for statistical analyses).

 
Five days after ADX or sham surgery and injection of STZ, ADX-STZ B35, ADX-STZ B100, and sham-ADX-STZ rats were hyperphagic. The ADX-STZ B100 rats consumed more then the ADX-STZ B35, sham-ADX-STZ and B0 rats (Table 1Go; P < 0.0001). ADX-STZ B0 rats ate similar amounts of calories as sham-ADX rats (Table 1Go, chow; P = 0.60). During the first 24 h of lard access, sham-ADX-STZ and ADX-STZ rats maintained total caloric intake similar to that on the preceding day, but they substituted part of the total calories with calories from lard. During the subsequent 24 h, sham-ADX-STZ rats decreased caloric intake significantly (Table 1Go, chow plus lard). The ADX-STZ rats all decreased caloric intake by a similar percentage, so that the ADX-STZ B35 rats ate similar amounts of calories as the sham-ADX-STZ rats eating lard, but more than the ADX-STZ B0 rats and less than the ADX-STZ B100 rats [effect of group: F(2,12) = 7; P < 0.01].

STZ decreased plasma insulin and increased plasma glucose concentrations in all ADX-STZ rats compared with sham-ADX rats (Table 1Go), although, as reported previously (25), ADX-STZ-B0 rats had higher plasma insulin concentrations than rats in the other ADX-STZ groups [effect of group: F(2,22) = 9; P < 0.002; B0 vs. B35 and B100, P < 0.02]. STZ decreased leptin concentrations in all ADX rats. Neither different doses of B nor 48-h lard intake affected leptin concentrations in ADX-STZ rats (Table 1Go). Plasma adiponectin concentrations were not affected by STZ or 48-h lard intake (Table 1Go).

Combination of both experiments
As the sham-ADX groups in both experiments had similar caloric intakes, body weight gains, and hormone measures (Table 2Go), we compared caloric intake from chow or lard and plasma insulin concentrations at different plasma B concentrations in Fig. 5Go. The left panel shows ADX, and the right panel shows ADX-STZ rats. Cumulative calories from chow or lard intake over only the first 48 h of lard exposure in experiment 1 are presented to enable comparisons with experiment 2 in which ADX-STZ rats had access to lard for only 48 h. Chow intake in ADX rats was similar at all B doses [Fig. 5AGo, {bullet}; chow: F(2,13) = 2.59; P = 0.113]. When allowed to consume lard, ADX rats consumed less chow [effect of lard: F(2,16) = 33; P < 0.0001], and there was no change in chow intake with different B concentrations [Fig. 5AGo, {circ}; chow plus lard: F(2,16) = 0.77; P = 0.478]. However, there was a significant increase in lard intake with increasing circulating B concentrations [Fig. 5BGo; F(2,16) = 9.279; P < 0.005]. Insulin concentrations increased with circulating B concentrations in both chow and chow plus lard ADX rats [Fig. 5CGo; chow ({bullet}): F(2,13) = 9; P < 0.005; chow plus lard ({circ}): F(2,16) = 23; P < 0.0001]. There was an interaction effect of lard vs. B dose in ADX rats [F(2,29) = 3.3; P = 0.05], and at the highest B dose, insulin concentrations were significantly higher in the lard plus chow group than in the chow group (P < 0.04).


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  		TABLE 2. Caloric intake, body weight (gain), and hormone concentrations in sham-vehicle-treated rats in experiments 1–3

 


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  		FIG. 5. Comparison of B and STZ on chow and lard intake and insulin concentrations (combined experiments 1 and 2). Effects of ADX with different B concentrations in ADX and ADX-STZ rats with ({circ}; chow plus lard) and without ({bullet}; chow) access to lard for 48 h. A, Increasing B does not change chow intake (calories per 100 g BW over 48 h) in ADX rats with or without lard. With access to lard, chow intake is significantly decreased at all B concentrations. B, Increasing circulating B increases lard significantly in ADX rats. C, Increasing B increases insulin secretion in all ADX rats (with and without access to lard). Lard augments insulin secretion at the higher B concentration. D, Increasing B increases chow intake in ADX-STZ rats with and without the access to lard. With access to lard, chow intake in ADX-STZ rats is significantly decreased at all B concentrations. E, Increasing B does not change lard intake when insulin is absent. F, Increasing B decreases insulin concentrations in ADX-STZ rats. See text for details on statistical analyses. Data are the mean ± SEM (n = 4–7/group).

 
In ADX-STZ rats, circulating B concentrations correlated strongly with chow intake, with and without lard [Fig. 5DGo; chow ({bullet}): F(2,10) = 41; P < 0.0001; chow plus lard ({circ}): F(2,12) = 16; P < 0.001]. Calories from chow were higher in the ADX-STZ chow groups than in the ADX-STZ lard plus chow groups [effect of treatment: F(1,22) = 93.5; P < 0.0001]. However, lard intake was similar at all B concentrations (Fig. 5EGo). Plasma insulin concentrations were significantly higher in the ADX-STZ B0 rats (Fig. 5FGo; effect of group: F(2,22) = 9; P < 0.005).

Effect of B on body weight with and without insulin in ADX rats eating only chow
Figure 4Go shows body weight gain over 5 d in ADX-STZ and in ADX rats on chow alone (before the introduction of lard) with different doses of steady state B. The presurgery body weight was similar in both groups, and the sham-ADX groups in both experiments were similar in body weight, food intake, and hormone measures (Tables 2Go and 3Go, and Fig. 1Go). We show here the body weight gain between d 2–7 after ADX surgery, B replacement, and injection of STZ or vehicle. Increasing B decreased body weight gain dose-dependently in both groups; the catabolic effects were profound at the high B dose (Fig. 4Go; linear regression: ADX: r2 = 0.42; P < 0.0001; ADX-STZ: r2 = 0.52; P < 0.001). The slopes were not significantly different, but there was a trend for a significant effect of elevation; ADX-STZ rats gained less body weight than ADX rats (by t test, P = 0.08).


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  		TABLE 3. Two-way ANOVA for data of experiments 1 and 3 shown in Figs. 1Go and 6Go, respectively

 
Together, the results of the first two experiments suggested strongly that although B stimulates caloric intake, insulin is responsible for the intake of high density lard, and that lard, in turn, reduces chow ingestion.

ADX high B with or without insulin, with or without lard
In the final experiment we tested the effects of insulin replacement in ADX-B100-STZ rats on preferences for chow or lard, and the effects of these on body weight gain and fat stores. The design of this experiment was parallel to that of experiment 1, in that the comparison of calories ingested as chow and lard were determined over a 7-d period, rather than just during 48 h as in experiment 2. Importantly, we found that insulin treatment did increase lard intake and reduce chow intake as percentages of total caloric intake (Fig. 6AGo). Although there were no effects of insulin in ADX-STZ rats on body weight gain (Table 4Go), there were effects of added insulin on caloric intake and of insulin and lard ingestion on fat stores (Fig. 6DGo). Plasma B and glucose did not differ among the ADX-B100-STZ groups treated with insulin, but were increased compared with those in sham-ADX rats (Table 4Go). Plasma insulin concentrations differed as a function of the replacement dose of insulin provided (Fig. 6BGo). Plasma leptin concentrations increased with lard ingestion in sham-ADX rats and in ADX-B100-STZ rats with 2 U insulin replacement (Fig. 6CGo). Body weight increased with lard ingestion in sham-ADX rats, but not in the ADX-B100-STZ insulin-treated groups (Table 4Go). As anticipated, all fat stores increased in sham-ADX rats fed lard (Fig. 6DGo). Lard also increased aWAT significantly in ADX-B100-STZ rats receiving 2 U insulin replacement (Fig. 6DGo), but the effect of lard on sWAT tended to be significant (not shown).



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  		FIG. 6. Insulin replacement in ADX-B100-STZ rats increases lard ingestion and total fat depot weight over 7 d. Panel A, Lard ingestion increased and chow ingestion decreased in insulin-treated rats, although total caloric intake was not markedly affected. For the lard-eating rats (on the right): , calories from lard; {blacksquare}, calories from chow. Panel B, Plasma insulin concentrations increased with increasing insulin treatment. Panel C, Leptin increased with lard ingestion in sham-ADX rats, but did not change significantly in diabetic rats with either insulin infusion or lard ingestion. Panel D, Total fat depot weight was increased by lard ingestion in sham-ADX and ADX-B100- STZ plus 2 U insulin groups. Two units per day increased summed fat depot weight compared with 0 U insulin (by Fisher’s protected least significant difference test). , Rats that were offered only chow; {blacksquare}, rats that were offered chow and lard. Groups with different letters (a, b, c, and d in the chow group; A, B, C, and D in the chow plus lard group) differ significantly (P <= 0.05). L, Significant effect of lard in that group of rats. Data are the mean ± SEM (n = 4–7/group). See Table 3Go for results of overall two-way ANOVA analyses.

 

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  		TABLE 4. Plasma concentrations of B and glucose and body weight (gain) in rats in experiment 3

 
A strong correlation between steady state plasma insulin in the presence of fixed high B and percentage of calories ingested as lard is shown in Fig. 7AGo. A similarly strong correlation between steady state insulin and aWAT or sWAT is shown in Fig. 7Go, B and C.



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  		FIG. 7. Insulin concentrations are tightly related to lard intake and to total fat depot weight in ADX-B100 rats treated with STZ with or without insulin. A, As insulin increases, so does lard intake [F(1,12) = 104; P < 0.0001, r2 = 0.90]. As insulin increases, so does aWAT depot weight [B; F(1,12) = 21.1; P = 0.0008; r2 = 0.66] and sWAT depot weight [C; F(1,12) = 13.5; P = 0.0037; r2 = 0.55].

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The results of these studies clarify the actions of both circulating glucocorticoids and insulin on caloric intake in adult male rats. From experiments 1 and 2, it is apparent that glucocorticoids provoke dose-related increases in total caloric intake that persist for days and weeks; the results also suggest that increasing insulin concentrations stimulated by glucocorticoids determine the amount of fat intake. The results of experiment 3 show that lard intake is associated with increasing insulin concentrations. Additionally, the results in ADX and ADX-STZ rats strongly suggest that it is a combination of B and insulin that increases abdominal fat depot weight. Independently of the hormonally manipulated rats, the results also show that intact rats voluntarily eat a considerable and stable proportion of their daily calories as lard when given a choice between lard and chow. This dietary choice causes abdominal obesity and increased body weight gain, an effect commonly observed in wealthy societies in which high energy foods are both readily available and inexpensive.

Characteristics of B and insulin replacements
Replacement of ADX rats with sc implanted B pellets provides constant plasma concentrations of B, which do not exhibit the circadian fluctuations that usually occur in this hormone. Nonetheless, target tissues throughout the body are provided with equivalent concentrations of B that they would normally experience after the adrenal origin of B secretion, and we have shown previously that, with the exception of regulation of ACTH secretion, replacement of ADX rats with clamped B that is equivalent to the daily mean B concentrations (~5 µg/dl) restores other variables to normal (44).

In contrast, replacement of STZ rats with sc pellets of insulin provides constant plasma concentrations of insulin, unlike intact rats in which the pancreas is continually responsive to neural and metabolic inputs. Importantly, sc replacement does not provide the liver, a major insulin target tissue, with the high concentrations of insulin that it normally experiences when endogenous secretion from the pancreas occurs.

This difference in the efficacy of hormonal replacements is clear when plasma glucose concentrations in ADX-B100-STZ with or without insulin groups from experiment 3 are considered. The high B replacement clearly drove hepatic gluconeogenesis, resulting in very high plasma glucose concentrations. However, there was no opposing effect of increasing insulin doses on plasma glucose despite the fact that at the higher dose, circulating insulin concentrations did not differ from those in intact rats with normal glucose. Thus we can rule out insulin-mediated effects on glucose as the cause of any of the results. Although the actions of B may have been exerted at any of its target sites, it is likely that the action of insulin on liver was negligible. Therefore, the effects of insulin were probably mediated by its actions on targets that are not directly perfused by blood from the portal vein.

Roles of glucocorticoids and insulin on caloric intake
There is a B dose-related increase in caloric intake in both the presence and absence of insulin. This, together with other data, suggests that the role of glucocorticoids on feeding may be to increase the level of drive. That is, increasing concentrations of circulating glucocorticoids increase the incentive salience of calories (45). This interpretation of the role of glucocorticoids on caloric intake is consistent with other motivational effects of glucocorticoids. Wheel-running behavior, favored by intact rats, is nearly nonexistent in ADX rats and increases in a dose-related fashion with B replacement (46); similarly, the amount of drug self-administration depends on circulating glucocorticoids (47, 48). Furthermore, we have shown previously that ADX rats treated with increasing concentrations of B (and thus insulin) increase both saccharin (nonnutritive) and sucrose (nutritive) ingestion in a dose-related fashion (49, 50), although access to neither palatable drink increased chow intake in ADX, B-treated rats. ADX rats eating chow have only a slight increase in chow intake that plateaus after plasma B concentrations are elevated to normal (this study and Refs. 13 and 51). Similarly, ADX wild-type and corticotropin-releasing factor-deficient mutant mice have food intake and insulin restored to normal by B replacement (52). Thus, it seems possible that insulin may quite specifically reduce B-mediated signals to chow intake.

In contrast to the action of glucocorticoids on the motivation to ingest calories, insulin appears to specifically increase lard intake at the expense of chow intake. The dose-related effect of B on fat ingestion that we observed in ADX rats that could secrete insulin is similar to that found in a previous study (51). Given the results of other experiments using nonnutritive saccharin (50), we speculate that insulin primarily enhances the palatability as well as increases the postingestive effects of the calories. However, elevated concentrations of insulin into the third ventricle inhibit carbohydrate intake in ad libitum-fed rats that had normal circulating plasma insulin concentrations. In contrast, our studies on the effects of insulin were from no hormone to the normal range. It may be that, like many hormones, insulin exerts a {cap}-shaped dose response in its central effects. We suspect that insulin concentrations in this low range did not exceed the saturable insulin transport into brain (53). In exploring the role of dietary fat on the effect of central insulin infusions, Chavez et al. (54) showed that insulin decreased food intake and body weight in rats fed low fat diets (7–22% fat calories), but that insulin did not affect these when dietary fat was high (39–54% of the total). Moreover, when rats were allowed to select a macronutrient diet, normal rats in that study opted for 38–40% of their calories as fat (54), similar to the choice of lard in sham-ADX rats in these studies. However, under conditions of macronutrient choice, intraventricular insulin decreased fat choice (53). Further studies are necessary to determine whether insulin increases palatability.

Roles of glucocorticoids and insulin in metabolism
B reduces and insulin augments body weight gain, as shown in experiments 1 and 2. Briefly, the overall action of B on metabolism is to release the energy stored in large molecules of protein and fat, yielding small molecules that can be used by the liver for gluconeogenesis. As gluconeogenesis is increased through the action of B on hepatic gluconeogenetic enzymes (55), large molecule storage is depleted. Thus, at high B concentrations there is a decrease in body weight gain because of the mobilization of muscle and peripheral fat stores, even when rats are eating ad libitum. Insulin acts to increase peripheral glucose uptake and storage in protein and fat molecules, thus accounting for the differential decreases in body weight gain shown in Fig. 4Go.

Fat depots are major storage sites for calories ingested in excess of those used. In most depots, glucocorticoids act to enable mobilization of fat, and insulin acts to enable fat synthesis, an antagonistic interaction, although both hormones stimulate lipoprotein lipase in adipose tissue (56, 57, 58). The most labile (and dangerous) (59) fat storage site is the intraabdominal depot (57, 60). This fat depot can release its calories directly to the liver for ketogenesis under conditions of need.

After the removal of food from rats, intraabdominal fat stores are the first to decline in weight (61). However, abdominal fat, under ad libitum feeding conditions, can also accrue fat stores under the combined influences of glucocorticoids and insulin. In this site, probably because of the relative complements of insulin and glucocorticoid receptors, there is a synergistic effect of insulin and glucocorticoids that may induce the proliferation of stromal (preadipocyte) cells to fat cells in times of plenty (57, 62).

B preferentially increases mesenteric fat depots in ADX rats, even in the absence of insulin. Insulin and lard intake further increase mesenteric fat (aWAT) depots in ADX rats replaced with high B. However, in the absence of insulin, B was less effective on aWAT depot weight. Moreover, in the ADX-B100-STZ groups, increasing insulin concentrations did not increase mesenteric WAT mass, although total aWAT weight was increased at the higher dose of insulin. These results suggest that the increased stores induced by insulin in labile mesenteric WAT were recruited in diabetic rats for supplying triglycerides to liver in the insulin-replaced ADX-B100-STZ rats. The effect seems to be independent of insulin-induced fat synthesis in aWAT.

Intact rats with or without lard
In all experiments sham-ADX rats were studied in parallel to the manipulated groups. These rats ate more calories when provided with the choice of lard in experiments 1 and 3 and became obese. Clearly, the option of lard as well as chow was attractive to these rats. Given the option of lard or chow, the intact rats chose to consistently supplement their diets with approximately 40–50% of total daily calories as lard and increased their total caloric intake above normal. The consequence of this was increased fat stores. This also occurs in people and is associated with long-term pathophysiological outcomes (see introduction).

Although lard ingestion had no effect on the circadian extremes in plasma B, it did tend to increase plasma insulin measured a few hours after lights on and the last meal of the night. It seems possible that had insulin been measured during the meal times, we would have found consistently significant elevations in rats eating lard. In the intact rats, the increased insulin concentrations would be expected to reduce hypothalamic neuropeptide Y concentrations and enhance the palatability of lard. This idea should be tested. If the two insulin-mediated mechanisms are not precisely coupled, one might expect an altered set-point for body weight that could occur in either direction.

Finally, under chronic stress, adult male rats secrete more B and reduce chow intake and body weight gain. If provided with approximately 1 M sucrose to drink, rats subjected to cold substitute calories from sucrose for chow, provided there is a sufficient elevation in B (33). In a subsequent experiment using repeated restraint, rats given a choice of lard, sucrose, or chow increased the proportions of both sucrose and lard intake, again at the expense of calories ingested from chow (Pecoraro, N., F. Reyes, and M. F. Dallman, unpublished results). Thus, with chronic stress and high B, together with some insulin, there is sustained avidity for high density calories. Under conditions of both chronic and acute stress, there is some evidence that people also increase their intake of high density food (63, 64).

In summary, we have shown that glucocorticoids function in a dose-related manner to increase caloric intake. By contrast, insulin appears both to reduce chow intake and increase lard intake, which is rich in calories. The combination of both B and insulin is required for the characteristic increase in mesenteric fat stores observed in those eating a high density fat diet.


   Acknowledgments
 
We thank Drs. N. Pecoraro, H. Houshyar, and F. Gomez for their assistance with collecting fat and brain tissue.


   Footnotes
 
This work was supported in part by University of California, San Francisco Research Evaluation and Allocation Committee, National Institutes of Health Grant DK-28172, and the Dutch Diabetes Research Foundation.

Abbreviations: ADX, Adrenalectomized, adrenalectomy; aWAT, abdominal white adipose tissue; B, corticosterone; B0, pellet containing 0% B; B35, pellet containing 35% B; B100, pellet containing 100% B; sWAT, sc white adipose tissue; STZ, streptozotocin.

Received October 9, 2003.

Accepted for publication February 5, 2004.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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