1 Developmental
Neuroendocrinology Laboratory, High-fat feeding induces insulin resistance
and increases the risk for the development of diabetes and coronary
artery disease. Glucocorticoids exacerbate this hyperinsulinemic state,
rendering an individual at further risk for chronic disease. The
present studies were undertaken to determine whether dietary
fat-induced increases in corticosterone (B) reflect alterations in the
regulatory components of the hypothalamic-pituitary-adrenal (HPA) axis.
Adult male rats were maintained on a high-fat (20%) or control (4%) diet for varying periods of time. Marked elevations in light-phase spontaneous basal B levels were evident as early as 7 days after fat
diet onset, and B concentrations remained significantly elevated up to
21 days after fat diet onset compared with controls. In contrast, there
were no significant effects on any parameters of spontaneous growth
hormone secretory profiles, thus providing support for the specificity
of the effects on the HPA axis. In a second study, all groups of rats
fed the high-fat diet for 1, 9, or 12 wk exhibited significantly
elevated levels of plasma adrenocorticotropic hormone, B, fatty acid,
and glucose before, during, and/or at 20, 60, and/or
120 min after the termination of a restraint stress. Furthermore, 12-wk
fat-fed animals showed a significant resistance to insulin compared
with normally fed controls. There were no differences in negative
feedback efficacy in high-fat-fed rats vs. controls. Taken together,
these results suggest that dietary fat intake acts as a background form
of chronic stress, elevating basal B levels and enhancing HPA responses
to stress.
glucocorticoids; adrenocorticotropic hormone; corticosterone; fatty
acid; glucose
HIGH-FAT DIETS contribute to insulin resistance (37,
42), impaired glucose metabolism (15), type 2 or non-insulin-dependent diabetes mellitus (NIDDM) (2, 19, 24), stroke, and coronary artery
disease (28), although the mechanisms underlying these effects are not
completely understood. Dietary cholesterol is associated with increased
low-density-lipoprotein (LDL) concentrations and the elevated
triglyceride levels in very low-density lipoproteins (vLDL). Dietary
fat not only lowers glucose uptake but also stimulates inappropriate
glucose production (6), resulting in elevations in both circulating
insulin and glucose (15, 37). High-fat diets decrease the number of
insulin receptors in liver, skeletal muscle, and adipose tissue,
decrease glucose uptake into skeletal muscle and adipose tissue, and
decrease hepatic glycolysis and glycogen synthesis (6). Glycogen
accumulation and glucose oxidation are also lower with high-fat diets,
and the rate of gluconeogenesis is increased in the liver (3), a common
problem for many diabetics. In sum, high-fat diets are associated with
a Syndrome X-like state that includes hypertriglyceridemia, decreased
high-density lipoproteins, high LDL and vLDL, abnormal glucose
production, hyperinsulinemia, and insulin resistance (36).
High-fat diets may also influence hypothalamic-pituitary-adrenal (HPA)
activity, elevating adrenal glucocorticoid (GC) production (11, 21,
35). This is of considerable interest here because increased levels of
GCs also stimulate secretion of triglycerides from the liver in vLDL,
as demonstrated in perfused liver and monolayer cultures of hepatocytes
(7, 30). Furthermore, GCs decrease levels of lipoprotein lipase, which
controls the hydrolysis of vLDL; this decrease has been shown to
exaggerate hypertriglyceridemia (44). Normally, most LDL formed after
the degradation of vLDL is removed from the circulation via
receptor-mediated endocytosis (16). The binding and degradation of LDL
by rat hepatocytes are decreased by dexamethasone, a synthetic GC,
which could result in elevations in LDL levels.
A prolonged excess in GC levels leads to various adjustments, altering
the balance between insulin and GCs. Elevated GCs antagonize most of
insulin's actions and result in increased basal and glucose-stimulated insulin levels and pancreatic In the present study, we tested the hypothesis that elevations in HPA
activity could modulate some of the effects of high-fat feeding. To
accomplish this, we examined both basal and stress-induced alterations in HPA axis functioning as well as carbohydrate and fatty
acid metabolism after short- and long-term exposure to a high-fat diet.
We also monitored spontaneous growth hormone (GH) secretory profiles,
to assess the specificity of the response, and assessed dietary-induced
alterations in exogenous corticosterone (B) negative feedback efficacy.
Animals.
Because of the multicenter nature of this study, different rat strains
were used. Adult male Long-Evans hooded rats (Charles River Canada, St.
Constant, QC, Canada) were used in most experiments. In both the
negative feedback experiment [M. F. Dallman Lab, University of
California at San Francisco (UCSF)] and the experiment on the effects of high-fat diets on spontaneous basal B and GH levels (G. S. Tannenbaum Lab, McGill University), adult male Sprague-Dawley rats
(Harlan-Holtzman, Madison, WI and Charles River, Canada) were employed.
Long-Evans rats were housed on a 12:12-h light-dark cycle (lights on at
0800) and were group housed until
catheterization. In the negative feedback and basal B/GH
studies, the rats were individually housed on arrival and kept on a
12:12-h light-dark cycle (lights on at 0600) in a humidity- and
temperature-controlled environment. In the basal study, body weight was
monitored daily, and 24-h food intake was assessed daily over several
days. The rats used in these experiments weighed 260-320 g (basal
and feedback experiments) and 175-225 g (stress experiment) at the
onset of the experiment and were assigned randomly to groups fed either the control or high-fat diet for 5 days or 1, 3, 9, or 12 wk. A subset
of these rats was implanted with indwelling jugular catheters; those
selected for negative feedback and glucocorticoid receptor binding were
not catheterized.
Diets.
Both the control (4% fat) and high-fat (20% fat) diets were obtained
from ICN Biomedical (Mississauga, ON, Canada). The same source of diet
was used in both the McGill and UCSF studies. The diets had been
formulated in a previous study (11) and were modified slightly for the
present studies (Table 1). Diets were balanced for protein as a percentage of energy intake and for essential
vitamins and minerals. The fat source in both the control and high-fat
diets was corn oil. The high-fat diet contained 4.8 kcal/g and the 4%
fat control diet, 4.0 kcal/g. In place of fat (corn oil), the 4% fat
diet contained a slightly greater amount of cornstarch.
ABSTRACT
Top
Abstract
Introduction
Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References
-cell hyperplasia (27, 31). Insulin
inhibits the secretion of triacylglycerol, phospholipid, cholesterol
ester, and apolipoproteins B and E associated with vLDL (10). GCs
antagonize these effects by increasing the breakdown of protein,
glycogen, and triacylglycerol. Amino acids that are released from
proteins can be used for gluconeogenesis. Other enzymes that are
released from this pathway are increased in activity by GCs. Thus the
effects of increased GCs mimic those of a high-fat diet, raising the
possibility that some of the effects of high fat might be mediated by
increases in circulating GC levels.
METHODS
Top
Abstract
Introduction
Methods
Results
Discussion
References
Table 1.
Composition of 20% fat (high-fat) and 4% fat (control) diets
Basal blood sampling experiments. To assess basal levels of B and GH, chronic intracardiac venous cannulas were implanted under pentobarbital sodium anesthesia (50 mg/kg ip), as described previously (43). After surgery, the rats were placed directly in isolation test chambers and given free access to regular Purina rat chow (Ralston-Purina, St. Louis, MO) and tap water until their body weights returned to preoperative levels. During this time (5-7 days), all rats were weighed and handled daily. At the end of the recovery period, the rats were randomly divided into a group fed the high-fat diet and a group fed the control diet. All animals were presented with the same amount of either the high-fat or control diet each day, and their intake was measured the following day by subtracting uneaten food plus spillage from total food given; spillage was collected on a diaper under the rat cages. In this experiment, rats were fed the control or high-fat diet for either 1 or 3 wk before testing.
On the day of testing, food was removed 1.5-2 h before the start of sampling and was returned at the end. Blood samples (0.4 ml) were withdrawn every 15 min for periods of 6 h (1000-1600). All blood samples were centrifuged immediately, and the plasma was separated and stored atStress testing. After 1, 9, or 12 wk on the diets and 3 days before testing, another set of animals was anesthetized under methoxyflurane (Metofane; MTC Pharmaceuticals, Mississauga, ON, Canada) and implanted with indwelling Silastic jugular catheters (Dow Corning), which were led subcutaneously and externalized to the nape of the neck. The catheter was filled with heparinized (100 U/ml) isotonic saline and closed off with a stainless steel obturator. Animals were housed singly for the remaining 3 days of the study (while being maintained on the high-fat or control diets).
Restraint stress was performed between 1000 and 1300 with the use of tubular, plastic restrainers lined with foam rubber. This period was chosen to avoid the elevated basal B levels and peak HPA responses to stress associated with the dark phase of the cycle (8). A blood sample (0.15 ml) was taken immediately before the rat was placed in the restrainer and within 10 s after removal from the home cage. The animals were restrained for 20 min, and blood samples were taken at both 5 and 10 min after the onset of restraint. Additional blood samples were obtained at the termination of restraint and at 20, 60, and 120 min thereafter. Blood samples for B, fatty acid (FA), and glucose measurement were collected into tubes coated with EDTA, placed on ice, and then centrifuged and stored atBasal plasma glucose and FA levels.
To assess basal plasma glucose and FA levels, separate sets of animals
(noncatheterized) were fed the high-fat diets for 1, 9, or 12 wk. After
termination of the dietary periods, the animals were killed rapidly
(i.e., <10 s) by decapitation after removal from the home cage
between 1000 and 1300. Trunk blood was collected and stored at
20°C until assayed. Plasma FAs were determined with a
nonesterified fatty acid (NEFA-C) test kit (Wako, Richmond, VA). The
assay protocol followed the manufacturer's instructions but was
miniaturized, and absorbancies were measured with a microtitration test
reader. Plasma glucose concentrations were measured by an automated
glucose oxidase method with a Beckman Glucose Analyzer 2 (Beckman
Instruments, Fullerton, CA).
Adrenalectomies, brain dissections, and GC receptor binding.
At the end of 1, 9, and 12 wk of exposure to the diet, two additional
groups of control and high-fat-fed rats (noncatheterized) were
bilaterally adrenalectomized (ADX). These animals were killed by rapid
decapitation 12-14 h after ADX, a time period that allows for
clearance of the endogenous steroid (32). The brain was removed quickly
and placed on ice, and the hippocampus, frontal cortex, hypothalamus,
and pituitary were dissected, frozen on dry ice, and stored at
80°C. On the day of the GC receptor (GR) binding assay,
brain tissue was homogenized in 30 mM
tris(hydroxymethyl)aminomethane, 1 mM EDTA, 1 mM dithiothreitol,
10% (vol/vol) glycerol, and 10 mM sodium molybdate (TEDGM; pH adjusted
to 7.4), and the homogenates were centrifuged at 4°C for 45 min at
105,000 g. Binding in all tissues was
measured by single point assays in which aliquots (225 µl) of the
soluble fraction from a single animal were incubated for 18-24 h
[a time that has been shown to be sufficient for maximal exchange
to occur and during which binding is stable (22)] with 150 µl
of TEDGM containing a saturating, 10 nM concentration of [3H]dexamethasone
(88.7 Ci/mmol; Amersham, Oakville, ON, Canada). Nonspecific binding was
determined in parallel incubations containing a 500-fold excess of
unlabeled RU-28362. RU-28362 binds selectively to the GR, with very
little affinity for the mineralocorticoid receptor (39).
Insulin sensitivity tests.
At the end of 12 wk of exposure to either the high-fat or control diet,
animals were food deprived for 12 h overnight, and blood was collected
via the tail vein at 0800 the following day for measurement of basal
plasma glucose levels. Two hours later, animals were injected with
0.125 U/kg ip of insulin (Humulin R, Eli Lilly, Indianapolis, IN).
Samples were then taken at 15, 30, 60, 120, and 180 min after
injection. All samples were collected in tubes containing EDTA,
centrifuged, and stored at 20°C until assayed for plasma
glucose.
Test of feedback with exogenous B.
In this study, rats were bilaterally ADX and implanted with 0, 25, or
50% B pellets. The pellets remained implanted for 5 days while the
rats were exposed to either the high fat or the control diet. At the
end of 5 days, and within 2 h of lights on, rats were exposed to 30 min
of restraint stress. Blood was collected immediately before (0 min) and
at 15 min into restraint. At the termination of restraint (30 min),
animals were rapidly decapitated, and trunk blood was collected
at this time point as well. Trunk blood was collected into plastic
tubes, and the plasma was separated and stored at 20°C for
subsequent assay of ACTH and B.
Radioimmunoassays. Plasma B was measured by the radioimmunoassay (RIA) of Krey et al. (25), with a highly specific B antiserum (B3-163, Endocrine Sciences, Tarzana, CA), [3H]B (101 Ci/mmol; NEN, Boston, MA) as tracer, and 10 µl of plasma. The minimum level of detection of the assay was 10 pg/ml. The antiserum cross-reacts slightly with deoxycorticosterone (4%) but not with cortisol (<1%). Separation of bound from unbound hormone was achieved using dextran-coated charcoal. Samples were then decanted into miniscintillation vials filled with 4.5 ml of Liquiscint (National Diagnostics, Sommerville, NJ), and radioactivity was determined in a Packard scintillation counter at 56% efficiency. The intra- and interassay coefficients of variation were 3.2 and 3.9%, respectively.
Plasma ACTH was measured by the RIA described by Walker et al. (47) with an ACTH antiserum (immunoglobulin G, Nashville, TN) and 125I-labeled ACTH (Incstar, Stillwater, MN) as tracer. The ACTH antibody cross-reacts 100% with ACTH-(1Statistical analyses. The results were analyzed by repeated-measures and factorial analyses of variance and by paired and unpaired Student's t-tests. Scheffé post hoc tests were performed when appropriate. Integrated hormone levels were determined with the trapezoidal rule, and the data were expressed over time of sampling. P < 0.05 was considered significant.
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RESULTS |
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Effects of high-fat diet on spontaneous plasma B and GH profiles. Plasma B levels measured every 15 min over 6 h and averaged over 2-h blocks (1000-1200, 1200-1400, and 1400-1600) are shown in Fig. 1. All rats displayed the typical circadian elevation in basal plasma B, with increasing levels observed during the latter hours of the day; spontaneous basal plasma B values obtained in the 1000-1200 time period were significantly (P < 0.05) lower in all groups compared with their respective profiles from either the 1200-1400 or 1400-1600 period. However, compared with normal-fed controls, mean 2-h plasma B levels were markedly elevated in both groups of high-fat-fed rats (Fig. 1). Rats fed a high-fat diet for 1 wk showed two- to threefold increases in plasma B levels throughout the sampling period. After 3 wk of exposure to high fat, significant elevations in B were observed in the 1200-1400 and 1400-1600 sampling periods compared with those of normal-fed controls. Interestingly, mean plasma B profiles obtained from rats fed the high-fat diet for 7 days were significantly (P < 0.05) higher at both the 1000-1200 and 1200-1400 phases than the profiles obtained from rats fed the high-fat diet for 21 days.
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Effects of high-fat diet on plasma ACTH and B responses to restraint. Plasma ACTH and B responses immediately before, during, and up to 2 h after the termination of restraint are shown in Figs. 2 and 3. Compared with animals fed the control diet, rats fed the high-fat diet for 1 wk showed elevated levels of ACTH throughout the sampling period that reached significance 60 min after termination of stress (P < 0.05; see Fig. 2A). Overall, the integrated levels of plasma ACTH were significantly (P < 0.05) increased in animals fed the high-fat diet for 1 wk compared with controls (Fig. 3A). One-week high-fat-fed rats also showed a significant elevation in plasma B at 60 min after the termination of restraint (Fig. 2B) in addition to significantly (P < 0.05) higher integrated levels of B compared with controls (Fig. 3B).
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Basal and stress-induced plasma FA and blood glucose concentrations.
Figure 4A
illustrates basal FA levels in 1-, 9-, and 12-wk high-fat-fed and
control animals. Basal FA levels were significantly (P < 0.03) elevated in 1- and 9-wk
high-fat-fed animals compared with controls, but no significant
differences were found at 12 wk. Plasma FA responses before and after
exposure to a 20-min period of restraint are shown in Fig.
4B. High-fat-fed animals maintained on
the diet for 1 wk showed significant
(P < 0.03) elevations in FA
immediately before and at 5 and 10 min after the onset of restraint
compared with controls. On termination of restraint, rats fed the
high-fat diet maintained significantly (P < 0.03) elevated FA levels
compared with controls. Integrated FA levels were augmented twofold
(P < 0.05) in fat-fed rats (1,110 ± 112 µeq · l1 · min
1)
vs. controls (585 ± 50 µeq · l
1 · min
1).
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Insulin sensitivity test.
Figure 6 shows plasma glucose levels
before and after an injection of 0.125 U/kg of insulin in rats exposed
to the high-fat or control diets for 12 wk. No significant differences
in plasma glucose concentrations were found before insulin
administration. Control-fed rats demonstrated a significant decrease in
blood glucose in response to insulin administration. In contrast,
fat-fed rats failed to respond to insulin at 1015, and this resulted in plasma glucose levels being significantly
(P < 0.02) higher at 15 and 30 min after injection in high-fat-fed animals compared with
controls. High-fat-fed animals showed significantly
(P < 0.05) elevated integrated
plasma glucose levels (95 ± 4 mg · dl1 · min
1)
compared with controls (75 ± 6 mg · dl
1 · min
1).
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GR binding densities. Examination of GR binding in brain regions known to be implicated in GC negative feedback regulation of HPA activity revealed no significant differences in GR binding densities in either hippocampus, frontal cortex, or pituitary after 1 wk on the diet, although GR binding in the hypothalamus was significantly lower (P < 0.05) in high-fat-fed animals on the diet compared with controls (Fig. 7A). After 9 (Fig. 7B) and 12 (Fig. 7C) wk of exposure to the high-fat or control diet, GR binding densities were similar in all brain areas studied.
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Feedback of exogenous B. Table 3 shows both basal plasma ACTH and B concentrations, as well as stress-induced ACTH levels, in rats that were ADX and replaced with 0, 25, or 50% B pellets and exposed to both diets. Replacement with B pellets effectively decreased plasma ACTH levels after ADX. However, there were no significant differences in either basal ACTH or B levels, or stress-induced ACTH, between ADX rats fed the high-fat diet and control-fed animals.
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DISCUSSION |
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These results demonstrate that both basal and stress-induced HPA activity was altered by both short- and long-term exposure to a high-fat diet. Free-moving high-fat-fed animals maintained on the diet for 1 and 3 wk and sampled throughout the day showed two- to threefold increases in plasma B concentrations between 1000 and 1600 compared with controls. Rats fed the high-fat diet for 1, 9, and 12 wk also showed significant elevations in plasma ACTH, B, and FA levels at 20, 60, and 120 min after the termination of restraint and significant augmentation in the overall integrated ACTH, B, and FA responses to restraint stress, compared with normally fed controls. In contrast, there were no significant alterations in any parameters of the spontaneous GH secretory profiles after 1 and 3 wk on the high-fat diet, providing support for the specificity of the effects on the HPA axis.
Interestingly, the pattern of effects of the high-fat diet is similar to that observed after chronic stress. Basal HPA activity is increased in rat models of chronic stress, such as continuous cold exposure or streptozotocin-induced diabetes, and this effect is most apparent in the light phase of the cycle, i.e., the nadir in HPA activity (41). Moreover, chronic stress facilitates HPA responses to subsequent acute stressors (1). High-fat diets clearly augmented both ACTH and B responses to acute stress. The effects of chronic stress (enhanced ACTH and B responses to stress) are not associated with alterations in delayed GC negative-feedback sensitivity. Accordingly, high-fat-fed rats of the present study also did not differ from controls in delayed feedback sensitivity. Thus, in terms of HPA activity, sustained periods of increased fat consumption appear to function as a chronic stressor. The lack of effect of increased fat consumption on GH secretory profiles is consistent with earlier reports demonstrating that plasma GH concentrations are not altered in conditions of chronic stress (18, 26).
As in other chronic stress models, there appeared to be a small amount of adaptation to high-fat feeding. After 12 wk of exposure to high fat, animals failed to show a significantly elevated ACTH response to stress despite a significantly augmented B response to the restraint. Animals fed the high-fat diet for 12 wk also did not differ in basal FA levels compared with controls. However, although it is possible that these particular responses adapted after longer exposures to fat feeding, adrenal GC responses remained elevated. Moreover, these animals were clearly nonresponsive to insulin challenge; rats tested after 12 wk of exposure to high fat demonstrated a significant resistance to insulin, as evidenced by a lower decline in blood glucose levels after the administration of insulin. This finding supports the severity of the effects of long-term (12-wk) fat feeding on insulin and glucose dynamics and underscores the functional significance of this high-fat model in rodents. Although high-fat diet-induced insulin insensitivity has been shown in models in which exposure to the diet has been more prolonged, our results suggest that relatively short exposures to high-fat diets can induce severe changes in insulin dynamics without any major change in circulating basal blood glucose levels, a phenomenon often seen in the clinical setting (36).
High-fat diets have been reported to increase serum FA concentrations, which in turn may act to antagonize the action of insulin (38). Feeding experimental animals with high-fat diets induces insulin resistance and impairs intracellular glucose metabolism by a variety of mechanisms. The binding of insulin to its receptor initiates glucose transport into fat and muscle cells. Insulin stimulates glycogen synthesis, glycolysis, and glucose oxidation; high-fat diets impair all of the intracellular routes of glucose disposal (14, 20). High FA may act directly to reduce the number of insulin receptors in certain tissues (4). High-fat diets also decrease the activities of the key enzymes involved in glycolysis (5) while at the same time stimulating gluconeogenesis (38). The present findings show that high-fat-fed rats exhibit elevations in both basal and stress-induced FA. FA levels were elevated before, during, and immediately after the termination of restraint in the high-fat-fed animals; this elevation in FAs may mediate changes in both insulin sensitivity and HPA function. The high FA levels appeared to coincide with higher basal and stress-induced ACTH. Because ACTH has been shown to be a stimulus for lipolysis, the ACTH response to stress may best predict the FA levels.
Widmaier et al. (49) showed that elevations in FA, achieved by infusions of intralipid, raise plasma levels of ACTH and B. Fatty acids have direct electrophysiological effects on cells of the central nervous system and are taken up by cells in the brain (29, 34). Oomura (34) demonstrated that electroapplication of FA into the ventromedial hypothalamus (VMH) inhibited neuronal firing rates in that area, and Dallman (13) showed that the cells of the VMH exert an inhibitory control on the HPA. Thus FA may act to alter hypothalamic regulation of the HPA axis. We propose that high fat-induced elevations in FA may be partly responsible for the elevation in basal B, as well as the increased stress-induced hypersecretion of both B and ACTH. Furthermore, because GCs tend to stimulate lipolysis, elevations in B may further stimulate the production of FA, which are already elevated because of the fat content of the diet. This may render the animal even more resistant to insulin, because elevations in FA tend to reduce the number of insulin receptors on various tissues, thereby increasing the dependence on GCs for homeostasis and stimulating gluconeogenesis. Taken together, these findings suggest a feed-forward cascade involving FA, GC, and insulin dynamics.
Exposure to high-fat diets did not alter B negative feedback sensitivity. We did find differences in hypothalamic GR levels after 1 wk, but not after 9 or 12 wk, of high-fat feeding. The absence of differences at 9 and 12 wk of feeding might be attributable to the poor resolution of our technique used for the binding assays. We cannot, therefore, preclude the possibility of differences in other forms of feedback, such as fast feedback. Fast feedback represents a process whereby rapidly increasing levels of B dampen ACTH release (23). FA may play a role here. The binding of dexamethasone (DEX) to the rat cytosolic GR can be modified by FA; for example, FAs inhibit the binding of DEX to GR in the liver as a function of increasing dose (45). Because GCs stimulate lipolysis, FA could exert a feedback control on GC by modulating binding of the hormone to the receptor. Also, recent work shows that the binding of GC in vivo to GR is reduced in immature rats after plasma FA is increased by stimulating lipase activity (17). The elevations in FA levels occur under more dynamic conditions of stress, and these conditions would be expected to alter fast, but probably not delayed, forms of feedback. Although this idea clearly remains to be tested, it does provide another potential mechanism whereby high-fat diets could modulate HPA responses to stress.
GCs can antagonize the effects of insulin, produce insulin insensitivity, and decrease glucose uptake in tissues. However, the combination of elevated GCs with concurrent increases in insulin further enhances energy deposition through FA and glycogen synthesis and the activity of lipoprotein lipase in adipose tissue (12). An increased GC control of metabolism is characteristic of many of the risk factors for premature atherosclerosis. The GC-insulin antagonism stimulates the secretion of vLDL and decreases hepatic uptake of LDL (48). High-fat-fed rats are insulin resistant and therefore may be at greater risk for the development of Syndrome X and NIDDM.
A strong correlation exists between consumption of a diet high in fat and many cancers, such as breast, colorectal, pancreatic, prostatic, and uterine cancer (40). Munck et al. (33) demonstrated that GCs inhibit production of interferon, which augments natural killer (NK) cell activity and activates macrophages for clearance of bacterial pathogens and antibody tagged host cells. Thus, in addition to obvious implications for heart disease, increased GC production may mediate some of the effects of high-fat diets on tumor development in addition to the onset and progression of related pathologies. If one considers that high-fat feeding increases GCs and FAs and decreases insulin sensitivity in an atherosclerosis-prone animal (e.g., a human), then these stress-induced changes should aggravate the atherosclerosis.
In summary, the results of the present study demonstrate that high-fat feeding augments both the ACTH and B responses to acute stress, as well as increases in basal B secretion, without any significant alterations in B negative feedback efficacy. Furthermore, we have shown that high-fat feeding results in insulin resistance and elevations in both basal and stress-induced FA and blood glucose concentrations. Taken together, these findings provide initial support for the view that enhanced exposure to counterregulatory hormones can mediate the effects of high-fat diets. These findings may be of considerable clinical importance, because stressful events not only stimulate HPA activity but may also increase fat consumption, leading to a potentially dangerous metabolic cascade.
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ACKNOWLEDGEMENTS |
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We gratefully acknowledge the assistance of Erika Rutenberg in the basal B and GH studies, and we thank the National Institute of Diabetes and Digestive and Kidney Diseases Hormone Distribution Program for the generous provision of rat GH RIA materials.
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FOOTNOTES |
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This work was supported by research grants from the MacArthur Foundation to M. J. Meaney, D. N. Brindley, and M. F. Dallman and from the Medical Research Council of Canada (MRC) to G. S. Tannenbaum. M. J. Meaney is an MRC Scientist. D. N. Brindley is a Medical Scientist of the Alberta Heritage Foundation for Medical Research. G. S. Tannenbaum is a Chercheur de Carrière of the Fonds de la Recherche en santé du Quebec.
Address for reprint requests: B. M. Tannenbaum, Developmental Neuroendocrinology Laboratory, Douglas Hospital Research Centre, 6875 Lasalle Blvd., Montreal, QC, Canada H4H-1R3.
Received 9 January 1997; accepted in final form 22 August 1997.
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