| | Altered “set-point” of the hypothalamus determines effects of cortisol on food intake, adiposity, and metabolic substrates in sheepReceived 14 May 2009; received in revised form 1 July 2009; accepted 14 July 2009. published online 04 September 2009. Abstract Chronic elevation of glucocorticoid concentrations is detrimental to health. We investigated effects of chronic increase in plasma cortisol concentrations on energy balance and endocrine function in sheep. Because food intake and reproduction are regulated by photoperiod, we performed experiments in January (JAN) and August (AUG), when appetite drive is either high or low, respectively. Ovariectomized ewes were treated (intramuscularly) daily with 0.5 mg Synacthen Depot® (synthetic adrenocorticotropin: ACTH) or saline for 4 wk. Blood samples were taken to measure plasma concentrations of cortisol, luteinising hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH), leptin, insulin, and glucose. Adrenocorticotropin treatment increased concentrations of cortisol. During JAN, treatment reduced food intake transiently, but increased food intake in AUG. Leptin concentrations were reduced and glucose concentrations were greater in AUG, and insulin concentrations were similar throughout the year. Treatment with ACTH increased leptin concentrations in AUG only, whereas insulin concentrations increased in JAN only. Synacthen treatment increased glucose concentrations, with a greater effect in JAN. Changes in truncal adiposity and ACTH-induced cortisol secretion were positively correlated in JAN and negatively correlated in AUG. Treatment reduced the plasma LH pulse frequency in JAN and AUG, with an effect on pulse amplitude in JAN only. Treatment did not affect plasma GH or FSH concentrations. We conclude that chronically elevated cortisol concentrations can affect food intake, adiposity, and reproductive function. In sheep, effects of chronically elevated cortisol concentrations on energy balance and metabolism depend upon metabolic setpoint, determined by circannual rhythms. 1. Introduction  Activation of the hypothalamo-pituitary-adrenal (HPA) axis is a hallmark response to stress, which culminates in increased secretion of glucocorticoids from the adrenal gland. In humans and sheep, the predominant glucocorticoid secreted is cortisol. In various animal models and in humans, prolonged activation of the HPA axis, or chronically increased concentrations of glucocorticoids, is detrimental to a variety of physiological systems. Persistent and uncontrolled secretion of glucocorticoids results in the development of affective disorders, impairs fertility, and influences energy homeostasis [1], [2] In humans, chronic elevation in cortisol concentrations has been associated with the development of obesity. A classic example is Cushing's disease, which is characterized by enhanced secretion of cortisol and increased adiposity, particularly truncal or central adiposity [3]. In addition, in non-Cushingoid patients, the degree of cortisol responsiveness following stress influences the metabolic response such that subjects classified as “high-cortisol responders” exhibit increased caloric consumption after a stressful episode compared to subjects classified as “low-cortisol responders” [4]. In contrast, others [5] have found that increasing levels of stress reduce food intake in a subgroup (around 30%) of human patients. Hitherto, defining the effects of stress and increased concentrations of cortisol on feeding behavior and body weight has proven difficult owing to the dichotomous findings. It has proven difficult to develop an animal model to study glucocorticoid-induced feeding. In some cases, such as genetic forms of obesity including the ob/ob mouse and the fatty Zucker rat, animals display both profound obesity and elevated concentrations of corticosterone [6], [7]. Adrenalectomy attenuates or may even reverse the obese phenotype in these models [6], [7]. In sheep, hypothalamo-pituitary disconnection (HPD), results in a number of neuroendocrine perturbations including elevated basal (non-stressed) circulating concentrations of cortisol [8], and these animals gain adiposity [9]. These animals, however, have other complications such as loss of growth hormone and thyroid stimulating hormone secretion and loss of the arcuate nucleus resulting from the operative procedure. In spite of the aforementioned cases, it still remains controversial as to whether increased glucocorticoid concentrations in normal animals can trigger weight gain through increased adiposity. In humans, prednisolone treatment increases food intake within 7 d [10], whereas dexamethasone reduces food intake in rodents [11]. Repeated-restraint stress (5 d) also reduces total daily food intake and body weight in rats, despite the animals exhibiting preference for palatable lard and sugar diets [12]. A central objective of the current study was to establish a model of glucocorticoid-induced feeding and weight gain in a different species. We investigated the effects of chronic elevation in plasma cortisol (4 wk) on metabolic output and the endocrine systems controlling metabolism and reproduction in sheep, and we replicated the study at 2 times of the year, when inherent appetite drive is either high or low [13], [14]. 2. Materials and Methods 2.2. Blood sampling and endocrine measurements 2.2.1. Blood sampling Serial blood samples (6mL) were taken prior to the initiation of treatment and again at the end of the 4-wk treatment regime. To facilitate the sampling, an indwelling cannula was inserted into one external jugular vein, extended with a manometer line (Portex Ltd., Kent, UK), and closed with a 3-way tap on the day prior to sampling. Samples were taken at 10-min intervals for 8h (9:00 AM-5:00 PM) into heparinized tubes, the blood was centrifuged, and the plasma was harvested. Plasma was stored at -20°C for radioimmunoassay to measure cortisol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH), and leptin. 2.2.2. Cortisol Samples (100μL) were assayed in duplicate in accordance with the method of Bocking et al. [16]. For 20 assays, the interassay coefficient of variation (CV) was 9.8%, the intra-assay CV was 8.0%, and the sensitivity of the assay was 0.4ng/mL. 2.2.8. Pulse and endocrine analyses The mean plasma concentration was used to assess effects of chronic elevation in cortisol on plasma concentrations of FSH and leptin. The secretory profiles of LH and GH were characterized using pulse analysis techniques. For LH, standard pulse analysis techniques were performed [22]. The mean GH concentration, GH pulse amplitude, and GH interpulse interval were characterized using the pulse analysis program TURBOPULSAR [23], using previously defined G-parameters [21]. 2.3. Metabolic and morphometric analyses 2.3.1. Plasma glucose concentrations Plasma concentrations of glucose were measured in 25-μL samples of plasma using a YSI2300 STAT glucose/lactate analyzer (Yellow Springs Instrument Co., Yellow Springs, OH). 2.3.2. Food intake, body weight, and adiposity Animals were fed 2kg of lucerne chaff daily at 9:00 AM; food intake was calculated by weighing refusal. Food intake was determined for 1 wk prior to the commencement and for the duration of the experiment. Animals were weighed weekly, and truncal and visceral adiposity was estimated in 2 ways. Truncal adiposity was assessed using dual energy x-ray absorptiometry (DXA) prior to and at 4 wks of treatment. In addition, at the end of the experiment the animals were killed and the visceral fat was removed and weighed. 2.4. Statistical analysis All data were analyzed by repeated measures analysis of variance (ANOVA) using SPSS version 14.0 (SPSS Inc., Cary, NC, USA) incorporating the factors treatment, season and time. Homogeneity of variance was determined prior to analysis. Direct comparisons of means were made using single-factor ANOVA, and post-hoc analyses were performed using least significant differences. Regression analysis was used to determine the correlation between cortisol responsiveness (area under the curve) and gain in truncal adiposity. 3. Results 3.2. Effect of chronic elevation in cortisol concentrations on food intake, body weight, omental fat, and truncal adiposity Baseline food intake was greater (P<0.01) in animals in JAN (1999.8±18.9g) than in AUG (1744.5±21.9g). The effect of chronic elevation of cortisol on food intake was dependent on the time of year. During JAN, when food intake is highest, there was a transient effect of cortisol to reduce (P<0.05) food intake, but there was a return to baseline concentrations within 1 wk of treatment. During AUG, when food intake is at a nadir, elevation in cortisol caused an increase (P<0.05) in food intake for the first 3 wk of the study (Fig. 2). In spite of the differential effect of elevated cortisol concentrations on food intake in JAN and AUG, there was no effect of increased cortisol concentrations on body weight (Fig. 3) or adiposity (as determined by omental fat weight and DXA; Fig. 3). Total truncal adiposity (% adiposity) was reduced (P<0.05) during AUG compared to JAN. Nonetheless, the degree of cortisol responsiveness, determined by analysis of the area under the curve after ACTH injection, was correlated to the propensity of individual animals to gain truncal fat, and the direction of this correlation was dependent on the season studied (Fig. 4). In JAN, cortisol responsiveness was positively correlated (P<0.05) to the propensity to gain truncal fat across the injection period, whereas in AUG this was a negative (P=0.06) correlation (Fig. 4). 3.4. Effect of chronic elevation in cortisol secretion on the secretory profiles of GH and gonadotropins To characterize the secretory profile of GH, we analyzed the mean GH concentration, the interpulse interval, and the GH pulse amplitude. The secretion of GH was similar in JAN and AUG (Fig. 6). There was no effect of chronic elevation in cortisol concentration on any of the GH parameters studied (Fig. 6). Chronic elevation in cortisol had minimal effects on the secretion of gonadotropins. There was no effect of chronic elevation in cortisol concentrations on the mean plasma concentration of either LH or FSH in either JAN or AUG (Fig. 7). Cortisol treatment reduced the pulse frequency of LH, as indicated by an increase in the interpulse interval; an effect that occurred in both JAN and AUG (Fig. 7). Furthermore, increased cortisol concentration reduced the LH pulse amplitude in JAN only (Fig. 7). 4. Discussion The current study demonstrates that effects of cortisol treatment on food intake and adiposity were dependent on the set-point of the hypothalamus, typified by different responses in JAN and AUG. Furthermore, effects of treatment on plasma concentrations of leptin were seen in AUG (when adiposity and leptin concentrations are low), but effects of cortisol on concentrations of glucose and insulin were greater in JAN (when food intake and levels of adiposity are high). In contrast, elevated cortisol concentrations had minimal effect on the secretion of GH, LH, and FSH in either JAN or AUG. These studies demonstrate that long-term elevation of plasma cortisol concentrations in ovariectomized ewes has a greater impact on food intake and metabolic function than on pituitary hormone secretion and that effects are dependent on the metabolic set-point of the hypothalamus, which is determined by season (photoperiod). Sheep, like other seasonal mammals, exhibit distinct photoperiodic-driven cycles in feeding behavior and adiposity [14], [24], [25]. Under conditions of natural photoperiod, we have previously demonstrated that sheep exhibit a circannual cycle in voluntary food intake (VFI). At our location with our breed of sheep, intake is maximal during summer/autumn and then declines to reach a nadir in late winter/early spring [14], [26], [27]. These natural shifts in food intake coincide with endogenous changes in the expression of appetite-regulating peptides in the hypothalamus. For example, the expression of neuropeptide Y (NPY) mRNA is highest when food intake is at the zenith and lowest when food intake is at the nadir [14]. These innate changes in the set-point of the hypothalamus appear to influence the way that increased plasma cortisol concentrations change food intake and other metabolic variables. When VFI was highest (JAN), treatment to elevate cortisol concentrations had a transient effect to inhibit food intake, but VFI was increased at the time of year (AUG) when lowered NPY expression causes reduced baseline VFI. In rodents, NPY has been shown to be integral to the glucocorticoid-associated effects on feeding, since adrenalectomy abolishes NPY-induced feeding and the subsequent manifestation of obesity [28]. Given the well-documented interaction between NPY and the glucocorticoid system in regulating food intake and metabolism, it is not surprising that seasonal differences in hypothalamic NPY activity are associated with different cortisol-induced feeding responses in sheep. Thus, at the time of the year when NPY expression is low and VFI is low, up-regulation can be achieved with increased cortisol concentrations. In the current study, we found that chronic cortisol treatment did not affect body weight or adiposity in either experimental setting. It is possible that 4 wk of treatment was not sufficient to reveal any morphometric change. In this limited cohort of animals, however, the degree of cortisol responsiveness to ACTH injection was correlated to the propensity of individual animals to gain truncal fat. During JAN, animals that exhibited increased cortisol responsiveness displayed greater tendency to accumulate truncal adiposity. Interestingly, during AUG there was an inverse correlation between cortisol responsiveness and truncal adiposity, again highlighting the importance of the hypothalamic set-point in cortisol-induced changes in energy balance and adiposity. In addition to changes in NPY expression, season (photoperiod) influences gene expression for melanin-concentrating hormone (MCH) and orexin in the lateral hypothalamus [13]. Expression of MCH and orexin mRNA is high when NPY expression and food intake are high, and there is little effect of season on the expression of POMC in the ARC [13], [14]. There is a clear association between levels of adiposity and the expression of orexin and MCH mRNA [13]. This positive correlation exists regardless of gene expression in the ARC and may not be associated with changes in food intake [13]. The current study clearly demonstrates effects of season on both food intake and predisposition to gain adipose tissue, yet these effects are divergent in that cortisol responsiveness was positively associated with fat gain without an effect on food intake (JAN), but was negatively associated with fat gain when food intake was increased (AUG). This dichotomy may be caused by changes in orexin and MCH that lead to altered rates of energy expenditure [30], [31], [32]. It has been hypothesized that the glucocorticoid-induced inhibition of GH secretion in humans leads to weight gain under conditions where cortisol concentrations are increased [3]. In ruminants, glucocorticoid-induced inhibition is less apparent, as acute isolation restraint stress (15min) has been shown to increase plasma GH concentrations in sheep [35], and acute but sustained increases in cortisol also increase GH release in cows [36]. In, another study of rams, infusion of cortisol (4h) did not change plasma GH concentrations but attenuated growth hormone-releasing hormone–stimulated GH secretion [37]. In the current study, we found that chronic elevation of plasma cortisol concentrations did not affect plasma GH concentrations. Although there was a reduction in the secretion of GH compared to pre-treatment, this effect occurred in both cortisol- and saline-treated animals. The current data, therefore, demonstrate a lack of association between cortisol responsiveness, GH inhibition, and the propensity to gain weight in ovariectomized ewes. Stress- or cortisol-induced inhibition of reproduction manifests as a reduction in the sensitivity of the gonadotrope to the stimulatory effect of gonadotropin-releasing hormone (GnRH) [38], [39], [40], [41], as well as a reduction in the secretion of GnRH [42], [43]. Chronic elevation in plasma concentrations of cortisol, however, had minimal effects on the secretion of LH or FSH; there was no effect of elevated cortisol concentrations on the mean concentration of LH or FSH, although the secretory dynamics of LH were altered. Typically, acute elevation in cortisol concentrations leads to a reduction in the pulse amplitude of LH [38], [39], [40], [41], whereas chronic elevation in plasma cortisol concentrations, as demonstrated by the current study, predominantly inhibits LH secretion by reducing the frequency of LH pulses regardless of photoperiod. This mode of reduction suggests that chronically elevated cortisol concentrations may reduce LH secretion indirectly by inhibiting pulsatile GnRH release from the hypothalamus. Furthermore, chronic elevation in cortisol concentrations was shown to reduce LH pulse amplitude, but the effect was restricted to the JAN period only. Previous studies using gonadectomized ewes have demonstrated that acute elevation in cortisol concentrations decreases LH pulse amplitude, regardless of season [44], whereas stress reduces LH pulse amplitude in intact animals only during the anestrous period [41]. The current data demonstrate inhibition of LH secretion by chronic treatment regardless of season. Whereas it is most likely that the chronic treatment reduces GnRH secretion in both seasons, a possible pituitary effect on the gonadotrope, to reduce pulse amplitude, is seen only in the breeding season. We have demonstrated that pretreatment plasma glucose concentrations were greater in AUG than in JAN, which was somewhat unexpected, since food intake and adiposity are lower in AUG. Nonetheless, elevation in cortisol concentrations led to increased plasma glucose concentrations in JAN and AUG. In sheep, dexamethasone treatment increases plasma glucose concentrations [45]. Similarly, in cows, acute infusion of cortisol increased plasma glucose concentrations [36]. The effects of chronic elevation of cortisol on plasma insulin concentrations, however, were clearly dependent on the hypothalamic set-point, which was increased by ACTH treatment in JAN only. To determine whether these differences translate to altered insulin sensitivity, glucose and insulin clamps or tolerance tests are required. The pretreatment plasma concentrations of leptin were reduced in animals in AUG, consistent with the lower levels of adiposity during this period [9], [13]. Dexamethasone treatment increases leptin concentrations in obese and non-obese humans [48], [49], but we found that treatment with ACTH increased leptin concentrations in sheep in AUG only. During JAN, leptin concentrations were reduced in the saline-treated control animals, but not those in the cortisol-treated group. Thus, in AUG, ACTH treatment and elevated cortisol concentrations increased leptin concentrations during periods when endogenous concentrations were low. In spite of elevated concentrations of leptin, animals in AUG exhibited increased food intake, indicating the development of a leptin-resistant state. In addition, photoperiod is known to influence leptin sensitivity, and it is thought that during JAN, animals are leptin resistant [27]. Nonetheless, changes in leptin concentrations were not indicative of the effects of cortisol on food intake. In summary, we have shown that effects of chronic elevation in plasma cortisol concentrations on food intake, adiposity, and metabolism in ovariectomized ewes are dependent on seasonal changes in metabolic set-point. Our results suggest that inherent differences in cortisol responsiveness to ACTH challenge may be a major determinant of the predisposition to obesity. 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a Department of Physiology, Building 13 F, Wellington Road, Monash University, VIC 3800, Australia b School of Animal Biology, University of Western Australia, Crawley, WA 6009, Australia c Melbourne School of Land and Environment, The University of Melbourne, Parkville, VIC 3010, Melbourne, Australia  Corresponding author. Tel.: +61 3 99052500; fax: +61 3 99052566.
PII: S0739-7240(09)00077-0 doi:10.1016/j.domaniend.2009.07.006 © 2009 Elsevier Inc. All rights reserved. | |
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