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Chronic Stress and Energy Balance: Role of the Hypothalamo‐Pituitary‐Adrenal Axis

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Regulation of Function in the Hypothalamo‐Pituitary‐Adrenal Axis
1.1 Corticosteroid Receptors: Feedback Control of the Hypothalamo‐Pituitary‐Adrenal Axis by Exogenous Corticosteroid Treatment
1.2 Stressor‐Induced Endogenous Corticosteroid Secretion and Feedback Control
1.3 Chronic or Repeated Stressors Induce Facilitated Responses
1.4 Diurnal Rhythms and Responsivity
2 Acute Versus Chronic Stressors: Effects on Activity in the Hypothalamo‐Pituitary‐Adrenal Axis
2.1 Acute Responses to Stress
2.2 Adaptations to Intermittent Stimuli
2.3 Adaption to Chronic, Sustained Stimuli
3 Corticosteroids, Stress, and Energy Balance
3.1 Energy Acquisition
3.2 Energy Disposition
4 Chronic Stress in Humans
Figure 1. Figure 1.

The circadian excursion in corticosterone adjusts to exogenous steroid. A: A typical circadian rhythm in plasma corticosterone in rats provided 5 days previously with a subcutaneous wax pellet (control, solid lines and symbols). Trough values occur at lights‐on and peak values at lights‐off. A subcutaneous corticosterone pellet was provided 5 days previously that caused plasma corticosterone concentrations of 4 μg/dl at lights‐on (exogenous B, dashed lines, open symbols). Elevations in trough corticosterone levels cause the Hypothalamo‐Pituitary‐Adrenal axis to reduce endogenous corticotropin secretion so that the mean 24 h corticosterone level in both groups is ∼5 μg/dl. B: Treatment of rats with 20%, 40%, or 80% corticosterone in 100 mg pellets containing corticosterone:cholesterol (w/w) 5 days previously causes graded increases in plasma corticosterone concentrations measured in the morning within 1 h of lights‐on. At the right is an estimate of the circulating total corticosterone concentrations (both free and bound to transcortin) that are sufficient to occupy the mineralocorticoid receptor (MR) and both the mineralocorticoid and glucocorticoid receptors (GR). Although the graph stops at 10 μg/dl, this is just the lower part of the dynamic range of plasma corticosterone, which extends to at least 60 μg/dl.

From Akana et al. , with permission
Figure 2. Figure 2.

Effects of elevations in trough plasma corticosterone by implantation of pellets 5 days previously. Biological effects of elevated trough corticosterone concentrations on end points within the Hypothalamo‐Pituitary‐Adrenal axis are more sensitive to small increases in corticosterone (left panels, adrenal weight and stress‐induced corticotropin concentrations) than are end points in other systems (right panels, thymus and body weights). Central feedback regulation of the Hypothalamo‐Pituitary‐Adrenal axis by occupancy of both mineralocorticoid (MR) and glucocorticoid (GR) receptors confers greater sensitivity to corticosterone than is exhibited by the peripheral targets of corticosterone. ACTH, corticotropin; BW, body weight.

From Akana et al. , with permission
Figure 3. Figure 3.

The plasma corticotropin (ACTH) response to restraint stress exhibits similar temporal dynamics in intact rats and in adrenalectomized (ADX) rats with clamped, steady‐state corticosterone concentrations, showing that changes in corticosterone in response to stress do not acutely alter corticotropin secretion.

From Viau et al. , with permission
Figure 4. Figure 4.

Facilitation of corticotropin (ACTH) responses to acute stress occurs in chronically stressed rats. Rats were exposed to cold (5° C) or remained at room temperature (control) for 5 days and then were acutely restrained in the morning of day 5. Intact rats (left) had corticotropin responses of equal magnitude (P = not significant) whether or not they had been chronically exposed to cold stress. Adrenalectomized rats, replaced with a constant corticosterone signal of ∼6 μg/dl (right), had significantly greater corticotropin responses to restraint (P < 0.001) if they had been chronically exposed to cold. Constraining corticosterone in the control and cold groups makes the facilitated corticotropin responses in the chronically stressed rats apparent.

From Akana et al. , with permission
Figure 5. Figure 5.

Effect of clamped corticosterone levels in adrenalectomized rats on plasma corticosterone, insulin, and triglyceride concentrations. Corticosterone pellet composition was chosen to provide moderate (near normal) and high plasma concentrations. Corticosterone had a marked dose‐related stimulatory effect on insulin in control rats and inhibited insulin in rats made diabetic with streptozotocin. Triglycerides increased with corticosterone in control rats, and the increase was markedly exacerbated in the diabetics.

From Strack et al. , with permission
Figure 6. Figure 6.

Reciprocal interactions between corticosterone and insulin on food intake but not body weight. A: Effects of corticosterone. All rats were adrenalectomized, and half were made diabetic with streptozotocin and studied 5 days later (same rats as in Fig. ). In nondiabetic rats, both corticosterone pellets increased food intake equally; by contrast, in diabetic rats, in the absence of insulin secretion, there was a marked corticosterone dose‐related increase in food intake, with intake/body weight (BW) more than doubling at the higher dose of corticosterone (top). Body weight was initially the same in all groups, and only the high (80%) corticosterone dose resulted in a significant decrease in weight gain (bottom). B: Effects of insulin. All rats were adrenalectomized and made diabetic with streptozotocin; half were replaced with a moderate (40%) and half with a high (80%) corticosterone pellet. Low doses of insulin (which did not reduce plasma glucose below a mean of 300 mg/dl) were infused by minipump, and the rats were studied 5 days later. Both doses of insulin reduced food intake in the moderate steroid group (P < 0.05), and only the higher dose of insulin reduced food intake in the high steroid group (P < 0.05). Initial body weight was the same in all groups, and at these low doses, insulin infusion had no significant effect on body weight.

From Strack et al. , with permission
Figure 7. Figure 7.

The interaction between corticosterone and insulin on the weight of white adipose tissue (WAT) depots is site‐selective (data from the same rats as in Figs. and ). There is no interaction between the hormones on caloric efficiency; corticosterone inhibits and insulin promotes caloric efficiency (top). Epididymal fat pads increase in weight in a corticosterone dose‐related manner in the presence of insulin and decrease in weight in a dose‐related manner in the absence of insulin. Perirenal fat pads significantly increase or decrease in weight only at the high dose of corticosterone. The magnitude of the increase in perirenal fat weight is 2.5‐fold compared to a 0.5‐fold increase in epididymal fat weight at the same dose of corticosterone. At constant body weight (BW), accrual of fat represents a shift in caloric storage sites in the rats treated with high corticosterone in the presence of high insulin.

From Strack et al. , with permission
Figure 8. Figure 8.

Effect of insulin infusion in adrenalectomized, corticosterone‐treated, diabetic rats depends on the dose of corticosterone and is site‐selective on white adipose tissue (WAT) depots. A maximal effect of insulin on caloric efficiency was achieved at the lower dose in rats with moderate (40%) corticosterone pellets. By contrast, caloric efficiency increased with increasing insulin infusion rate in the high (80%) corticosterone pellet group. Insulin infusion rate had a greater effect on epididymal fat weight in the high‐dose steroid group than the medium‐dose group, again showing the marked positive interaction between the hormones on fat deposition. Although insulin increased perirenal adipose depot weight in a dose‐related fashion in rats with moderate corticosterone, the highest rate of insulin infusion was required to increase perirenal adipose weight in rats with high corticosterone, again showing a differential effect of the steroids on intraabdominal compared to more peripheral fat depots. BW, body weight.

From Strack et al. , with permission
Figure 9. Figure 9.

Effects of stimulus‐induced increases in endogenous corticosterone secretion on epididymal (eWAT) and perirenal (pWAT) white adipose tissue depots under conditions of concurrently low (A) and high (B) plasma insulin concentrations. A: Rats were placed in cold (5° C) for 5 days or remained at room temperature (control). Although corticosterone secretion was stimulated, insulin was inhibited in the cold‐exposed rats, which lost weight and fat mass; the relative loss in perirenal fat is greater than that in epididymal fat mass. B: Rats were prepared with intracerebroventricular (icv) cannulae and Ginfused for 5 days with either neuropeptide Y (NPY, 6 μg/day) or artificial cerebrospinal fluid (aCSF). Both corticosterone and insulin were stimulated by NPY infusion, and the rats increased food intake and fat mass; the relative gain in perirenal fat is greater than that in epididymal fat mass. BW, body weight.

From Akana et al. , with permission


Figure 1.

The circadian excursion in corticosterone adjusts to exogenous steroid. A: A typical circadian rhythm in plasma corticosterone in rats provided 5 days previously with a subcutaneous wax pellet (control, solid lines and symbols). Trough values occur at lights‐on and peak values at lights‐off. A subcutaneous corticosterone pellet was provided 5 days previously that caused plasma corticosterone concentrations of 4 μg/dl at lights‐on (exogenous B, dashed lines, open symbols). Elevations in trough corticosterone levels cause the Hypothalamo‐Pituitary‐Adrenal axis to reduce endogenous corticotropin secretion so that the mean 24 h corticosterone level in both groups is ∼5 μg/dl. B: Treatment of rats with 20%, 40%, or 80% corticosterone in 100 mg pellets containing corticosterone:cholesterol (w/w) 5 days previously causes graded increases in plasma corticosterone concentrations measured in the morning within 1 h of lights‐on. At the right is an estimate of the circulating total corticosterone concentrations (both free and bound to transcortin) that are sufficient to occupy the mineralocorticoid receptor (MR) and both the mineralocorticoid and glucocorticoid receptors (GR). Although the graph stops at 10 μg/dl, this is just the lower part of the dynamic range of plasma corticosterone, which extends to at least 60 μg/dl.

From Akana et al. , with permission


Figure 2.

Effects of elevations in trough plasma corticosterone by implantation of pellets 5 days previously. Biological effects of elevated trough corticosterone concentrations on end points within the Hypothalamo‐Pituitary‐Adrenal axis are more sensitive to small increases in corticosterone (left panels, adrenal weight and stress‐induced corticotropin concentrations) than are end points in other systems (right panels, thymus and body weights). Central feedback regulation of the Hypothalamo‐Pituitary‐Adrenal axis by occupancy of both mineralocorticoid (MR) and glucocorticoid (GR) receptors confers greater sensitivity to corticosterone than is exhibited by the peripheral targets of corticosterone. ACTH, corticotropin; BW, body weight.

From Akana et al. , with permission


Figure 3.

The plasma corticotropin (ACTH) response to restraint stress exhibits similar temporal dynamics in intact rats and in adrenalectomized (ADX) rats with clamped, steady‐state corticosterone concentrations, showing that changes in corticosterone in response to stress do not acutely alter corticotropin secretion.

From Viau et al. , with permission


Figure 4.

Facilitation of corticotropin (ACTH) responses to acute stress occurs in chronically stressed rats. Rats were exposed to cold (5° C) or remained at room temperature (control) for 5 days and then were acutely restrained in the morning of day 5. Intact rats (left) had corticotropin responses of equal magnitude (P = not significant) whether or not they had been chronically exposed to cold stress. Adrenalectomized rats, replaced with a constant corticosterone signal of ∼6 μg/dl (right), had significantly greater corticotropin responses to restraint (P < 0.001) if they had been chronically exposed to cold. Constraining corticosterone in the control and cold groups makes the facilitated corticotropin responses in the chronically stressed rats apparent.

From Akana et al. , with permission


Figure 5.

Effect of clamped corticosterone levels in adrenalectomized rats on plasma corticosterone, insulin, and triglyceride concentrations. Corticosterone pellet composition was chosen to provide moderate (near normal) and high plasma concentrations. Corticosterone had a marked dose‐related stimulatory effect on insulin in control rats and inhibited insulin in rats made diabetic with streptozotocin. Triglycerides increased with corticosterone in control rats, and the increase was markedly exacerbated in the diabetics.

From Strack et al. , with permission


Figure 6.

Reciprocal interactions between corticosterone and insulin on food intake but not body weight. A: Effects of corticosterone. All rats were adrenalectomized, and half were made diabetic with streptozotocin and studied 5 days later (same rats as in Fig. ). In nondiabetic rats, both corticosterone pellets increased food intake equally; by contrast, in diabetic rats, in the absence of insulin secretion, there was a marked corticosterone dose‐related increase in food intake, with intake/body weight (BW) more than doubling at the higher dose of corticosterone (top). Body weight was initially the same in all groups, and only the high (80%) corticosterone dose resulted in a significant decrease in weight gain (bottom). B: Effects of insulin. All rats were adrenalectomized and made diabetic with streptozotocin; half were replaced with a moderate (40%) and half with a high (80%) corticosterone pellet. Low doses of insulin (which did not reduce plasma glucose below a mean of 300 mg/dl) were infused by minipump, and the rats were studied 5 days later. Both doses of insulin reduced food intake in the moderate steroid group (P < 0.05), and only the higher dose of insulin reduced food intake in the high steroid group (P < 0.05). Initial body weight was the same in all groups, and at these low doses, insulin infusion had no significant effect on body weight.

From Strack et al. , with permission


Figure 7.

The interaction between corticosterone and insulin on the weight of white adipose tissue (WAT) depots is site‐selective (data from the same rats as in Figs. and ). There is no interaction between the hormones on caloric efficiency; corticosterone inhibits and insulin promotes caloric efficiency (top). Epididymal fat pads increase in weight in a corticosterone dose‐related manner in the presence of insulin and decrease in weight in a dose‐related manner in the absence of insulin. Perirenal fat pads significantly increase or decrease in weight only at the high dose of corticosterone. The magnitude of the increase in perirenal fat weight is 2.5‐fold compared to a 0.5‐fold increase in epididymal fat weight at the same dose of corticosterone. At constant body weight (BW), accrual of fat represents a shift in caloric storage sites in the rats treated with high corticosterone in the presence of high insulin.

From Strack et al. , with permission


Figure 8.

Effect of insulin infusion in adrenalectomized, corticosterone‐treated, diabetic rats depends on the dose of corticosterone and is site‐selective on white adipose tissue (WAT) depots. A maximal effect of insulin on caloric efficiency was achieved at the lower dose in rats with moderate (40%) corticosterone pellets. By contrast, caloric efficiency increased with increasing insulin infusion rate in the high (80%) corticosterone pellet group. Insulin infusion rate had a greater effect on epididymal fat weight in the high‐dose steroid group than the medium‐dose group, again showing the marked positive interaction between the hormones on fat deposition. Although insulin increased perirenal adipose depot weight in a dose‐related fashion in rats with moderate corticosterone, the highest rate of insulin infusion was required to increase perirenal adipose weight in rats with high corticosterone, again showing a differential effect of the steroids on intraabdominal compared to more peripheral fat depots. BW, body weight.

From Strack et al. , with permission


Figure 9.

Effects of stimulus‐induced increases in endogenous corticosterone secretion on epididymal (eWAT) and perirenal (pWAT) white adipose tissue depots under conditions of concurrently low (A) and high (B) plasma insulin concentrations. A: Rats were placed in cold (5° C) for 5 days or remained at room temperature (control). Although corticosterone secretion was stimulated, insulin was inhibited in the cold‐exposed rats, which lost weight and fat mass; the relative loss in perirenal fat is greater than that in epididymal fat mass. B: Rats were prepared with intracerebroventricular (icv) cannulae and Ginfused for 5 days with either neuropeptide Y (NPY, 6 μg/day) or artificial cerebrospinal fluid (aCSF). Both corticosterone and insulin were stimulated by NPY infusion, and the rats increased food intake and fat mass; the relative gain in perirenal fat is greater than that in epididymal fat mass. BW, body weight.

From Akana et al. , with permission
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Mary F. Dallman, Seema Bhatnagar. Chronic Stress and Energy Balance: Role of the Hypothalamo‐Pituitary‐Adrenal Axis. Compr Physiol 2011, Supplement 23: Handbook of Physiology, The Endocrine System, Coping with the Environment: Neural and Endocrine Mechanisms: 179-210. First published in print 2001. doi: 10.1002/cphy.cp070410