Beyond fast food and slow motion: weighty contributors to the obesity epidemic.

Decreased physical activity and marketing-driven increased consumption of "junk" food, dubbed "The Big Two", are generally regarded as the most important contributors to the obesity epidemic. However, the full picture contains many more pieces of the puzzle. We address several additional issues and review current clinical developments in obesity research. In spite of dramatic advancements in our understanding of the adipose organ and its endocrine and immune products, the ultimate causes of the obesity epidemic remain elusive. Treatment is plagued by poor adherence to life style modifications, and available pharmacological options are marginally effective, often also associated with major side effects. Surgical treatments, albeit effective in decreasing body weight, are invasive and expensive. Thus, our approaches to finding the causes, improving the existing treatments, and inventing novel therapies must be manifold.

Rising incidence and challenges of childhood diabetes. A mini review.

Approximately 215,000 people younger than 20 yr of age, or 1 in 500 children and adolescents, had diabetes in the United States in 2010--and the incidence is rising. We still have insufficient knowledge about the precise mechanisms leading to the autoimmune mediated ß-cell destruction in Type 1 diabetes, and the ß-cell failure associated with insulin resistance in Type 2 diabetes. Long-term complications are similar: micro- and macrovascular disease occurs prematurely and presents an enormous burden on affected individuals, often as early as in middle age. In Type 1 diabetes, technological advances have clearly improved blood glucose management, but chronic peripheral over-insulinization remains a problem even with the most advanced systems. Thus, in Type 1 diabetes our research must focus on 1) finding the stimulus that ignites the immune response and 2) developing treatments that avoid hyperinsulinemia. In Type 2 diabetes in youth, the challenges start much earlier: most young patients do not even benefit from existing therapies due to non-compliance. Therefore, prevention of Type 2 diabetes and improvement of compliance, especially with non-pharmacological interventions, are the greatest challenges.

Human leptin levels are pulsatile and inversely related to pituitary-adrenal function.

Leptin communicates nutritional status to regulatory centers in the brain. Because peripheral leptin influences the activity of the highly pulsatile adrenal and gonadal axes, we sought to determine whether leptin levels in the blood are pulsatile. We measured circulating leptin levels every 7 minutes for 24 hours, in six healthy men, and found that total circulating leptin levels exhibited a pattern indicative of pulsatile release, with 32.0 +/- 1.5 pulses every 24 hours and a pulse duration of 32.8 +/- 1.6 minutes. We also show an inverse relation between rapid fluctuations in plasma levels of leptin and those of adrenocorticotropic hormone (ACTH) and cortisol that could not be accounted for on the basis of glucocorticoid suppression of leptin. As leptin levels are pulsatile, we propose that a key function of the CNS is regulated by a peripheral pulsatile signal. In a separate pilot study we compared leptin pulsatility in 414 plasma samples collected every 7 minutes for 24 hours from one obese woman and one normal-weight woman. We found that high leptin levels in the obese subject were due solely to increased leptin pulse height; all concentration-independent pulsatility parameters were almost identical in the two women. Leptin pulsatility therefore can be preserved in the obese.

Chronic sleep deprivation and seasonality: implications for the obesity epidemic.

Sleep duration has progressively fallen over the last 100 years while obesity has increased in the past 30 years. Several studies have reported an association between chronic sleep deprivation and long-term weight gain. Increased energy intake due to sleep loss has been listed as the main mechanism. The consequences of chronic sleep deprivation on energy expenditure have not been fully explored. Sleep, body weight, mood and behavior are subjected to circannual changes. However, in our modern environment seasonal changes in light and ambient temperature are attenuated. Seasonality, defined as cyclic changes in mood and behavior, is a stable personality trait with a strong genetic component. We hypothesize that the attenuation in seasonal changes in the environment may produce negative consequences, especially in individuals more predisposed to seasonality, such as women. Seasonal affective disorder, a condition more common in women and characterized by depressed mood, hypersomnia, weight gain, and carbohydrate craving during the winter, represents an extreme example of seasonality. One of the postulated functions of sleep is energy preservation. Hibernation, a phenomenon characterized by decreased energy expenditure and changes in the state of arousal, may offer useful insight into the mechanisms behind energy preservation during sleep. The goals of this article are to: a) consider the contribution of changes in energy expenditure to the weight gain due to sleep loss; b) review the phenomena of seasonality, hibernation, and their neuroendocrine mechanisms as they relate to sleep, energy expenditure, and body weight regulation.

Depression and osteoporosis: a research synthesis with meta-analysis.

Major depressive disorder has been associated with low bone mineral density. The strength of this association, however, varies greatly among studies; the direction of the causative link is still controversial, and the etiology remains unclear. We aimed to confirm this association, assess its magnitude and estimate its clinical relevancy. A total of 535 articles were initially identified and the research synthesis was based on 33 qualified articles. Of these, 25 articles (or 76%) showed an inverse relationship between major depression or minor depression or depressive symptoms and bone mineral density or bone turnover. Meta-analysis could be performed on 20 of the initially selected 33 articles. Standardized weighted differences in mean AP spine, total femur and femoral neck bone mineral density, each from at least 10 studies, were computed in g/cm (2) and transformed into percent differences. At each site, bone mass was lower in subjects with depression as compared to controls: AP spine bone mineral density was 4.73% lower (95% CI -7.28% to -2.19%, p<0.0001; n=16 studies), total femur bone mineral density was 3.53% lower (95% CI -5.66% to -1.41%, p<0.001; n=13 studies), and femoral neck bone mineral density was 7.32% lower (95% CI -10.67% to -3.96%; p<0.0005; n=8 studies). In conclusion, major depressive disorder was associated with lower bone mineral density at the AP spine, femoral neck, and total femur. The deficits in bone mineral density in subjects with depression are of clinical significance and likely to increase fracture risk over the lifetime of these subjects.

The contribution of psychosocial stress to the obesity epidemic: an evolutionary approach.

The Thrifty Gene hypothesis theorizes that during evolution a set of genes has been selected to ensure survival in environments with limited food supply and marked seasonality. Contemporary environments have predictable and unlimited food availability, an attenuated seasonality due to artificial lighting, indoor heating during the winter and air conditioning during the summer, and promote sedentariness and overeating. In this setting the thrifty genes are constantly activated to enhance energy storage. Psychosocial stress and sleep deprivation are other features of modern societies. Stress-induced hypercortisolemia in the setting of unlimited food supply promotes adiposity. Modern man is becoming obese because these ancient mechanisms are efficiently promoting a positive energy balance. We propose that in today's plentifully provisioned societies, where sedentariness and mental stress have become typical traits, chronic activation of the neuroendocrine systems may contribute to the increased prevalence of obesity. We suggest that some of the yet unidentified thrifty genes may be linked to highly conserved energy sensing mechanisms (AMP kinase, mTOR kinase). These hypotheses are testable. Rural societies that are becoming rapidly industrialized and are witnessing a dramatic increase in obesity may provide a historical opportunity to conduct epidemiological studies of the thrifty genotype. In experimental settings, the effects of various forms of psychosocial stress in increasing metabolic efficiency and gene expression can be further tested.

Plasma CRP levels in premenopausal women with major depression: a 12-month controlled study.

C-reactive protein (CRP), an inflammatory marker of cardiovascular risk, is often elevated in major depressive disorder (MDD). The magnitude and consistency of this elevation have not been previously characterized in premenopausal women with MDD. The aim of the study was to prospectively assess plasma CRP levels, body composition, endocrine and metabolic parameters, and depressive status in premenopausal women with MDD (n=77) and controls (n=41), aged 21 to 45. Women were enrolled in a 12-month, controlled study of bone turnover, the P.O.W.E.R. ( Premenopausal, Osteoporosis, Women, Al Endronate, Dep Ression) Study. Blood samples were taken at Baseline, Month 6, and Month 12. Most subjects with MDD were in clinical remission. These women tended to have consistently higher CRP levels than controls over 12 months (p=0.077). BMI was positively related to log[CRP] in women with MDD only. Nine women with MDD had CRP levels greater than 10 mg/l, a value associated with a very high cardiovascular risk. This subset was obese and had significantly higher triglycerides, total cholesterol, LDL-cholesterol, fasting insulin, and HOMA-IR than the rest of women with MDD. The variations in CRP levels over time were high (intra- and inter-individual coefficients of variations of approximately 30-50% and approximately 70-140%, respectively). No control had CRP levels greater than 10 mg/l. Depression was associated with increased plasma CRP in women with MDD. The clinical significance of abnormal plasma CRP for cardiovascular risk needs to be assessed in large prospective studies of women with depression.

Decreased stress responsivity of central and peripheral catecholaminergic systems in aged 344/N Fischer rats.

We investigated the effects of stress on central and peripheral sympatho-adrenal and sympatho-neural functions in healthy, intact young (3-4 mo) and aged (24 mo) male Fischer 344/N rats. Extracellular fluid (ECF) levels of the catecholamines norepinephrine (NE), dihydroxyphenylglycol (DHPG), methoxyhydroxyphenylglycol (MHPG), and dihydroxyphenylacetic acid (DOPAC) were obtained by microdialysis in the paraventricular nucleus (PVN) of the hypothalamus at baseline and during immobilization (IMMO). The baseline levels of these substances were similar in both age groups, and their concentrations increased significantly in response to IMMO. The IMMO-induced increases of NE and MHPG, however, were significantly smaller in old than in young rats. Plasma levels of the catecholamines NE, DHPG, MHPG, DOPAC, dihydroxyphenylalanine (DOPA), epinephrine (EPI), dopamine (DA), and HVA were also determined in young and old rats during IMMO. Basal levels of these substances were significantly higher in old than in young rats. The magnitude of the IMMO-induced increases in the majority of these compounds however, was significantly smaller in old than in young rats. We conclude that, at the basal state, aging in the Fischer rat is associated with normal PVN ECF, but high plasma catecholamine levels; at stress state, however, old rats have substantially lesser activation of their central and peripheral catecholaminergic systems than young rats.

Depression: a major, unrecognized risk factor for osteoporosis?

Existing studies of the relationship between depression and osteoporosis have been heterogeneous in their design and use of diagnostic instruments for depression, which might have contributed to the different results on the comorbidity of these two conditions. Nevertheless, these studies reveal a strong association between depression and osteoporosis. Endocrine factors such as depression-induced hypersecretion of corticotropin-releasing hormone and hypercortisolism, hypogonadism, growth hormone deficiency and increased concentration of circulating interleukin 6, might play a crucial role in the bone loss observed in subjects suffering from major depression.

Low body mass index is an important risk factor for low bone mass and increased bone loss in early postmenopausal women. Early Postmenopausal Intervention Cohort (EPIC) study group.

Thinness (low percentage of body fat, low body mass index [BMI], or low body weight) was evaluated as a risk factor for low bone mineral density (BMD) or increased bone loss in a randomized trial of alendronate for prevention of osteoporosis in recently postmenopausal women with normal bone mass (n = 1609). The 2-year data from the placebo group were used (n = 417). Percentage of body fat, BMI, and body weight were correlated with baseline BMD (r = -0. 13 to -0.43, p < 0.01) and 2-year bone loss (r = -0.14 to -0.19, p < 0.01). Women in the lowest tertiles of percentage of body fat or BMI had up to 12% lower BMD at baseline and a more than 2-fold higher 2-year bone loss as compared with women in the highest tertiles (p

Endogenous glucocorticoids restrain catecholamine synthesis and release at rest and during immobilization stress in rats.

Cardiovascular and metabolic adjustments during stress involve participation of the sympatho-adrenal and hypothalamic-pituitary-adrenocortical systems, which interact at several levels. The present study investigated the effects of removal of endogenous glucocorticoids on indices of norepinephrine release and metabolism and of catecholamine biosynthesis in sympathetic nerves, at baseline and in response to immobilization stress (IMMO) in rats. Plasma levels of the catecholamine precursor dihydroxyphenylalanine, norepinephrine (NE), the NE metabolites dihydroxyphenylglycol and methoxyhydroxyphenylglycol, dopamine, and the dopamine metabolites dihydroxyphenylacetic acid and homovanillic acid were measured in adrenalectomized, adrenal-medullectomized, or sham-operated conscious rats, with or without glucocorticoid treatment (25 mg/kg.24 h cortisol for 7 days by osmotic minipumps), at rest and after 5, 20, 60, and 120 min of IMMO. Adrenalectomy eliminated plasma levels of epinephrine and corticosterone and augmented IMMO-induced increments in levels of NE, dihydroxyphenylglycol, methoxyhydroxyphenylglycol, dihydroxyphenylalanine, dihydroxyphenylacetic acid, and homovanillic acid. Adrenal-medullectomy reduced plasma epinephrine, but not corticosterone, to undetectable levels at baseline and did not augment stress-induced responses of any of the measured compounds. Cortisol administration (plasma levels approximately 600 pmol/ml) reversed the augmentation of catecholaminergic responses in adrenalectomized rats. The results indicate that adrenalectomy stimulates several aspects of sympatho-neural function, including stress-induced increments in NE release, reuptake, metabolism, and turnover and in catecholamine biosynthesis. This augmentation was absent in adreno-medullectomized rats, indicating that the loss of adrenomedullary hormones after adrenalectomy does not appear to contribute to the augmentation. Since cortisol treatment reversed or prevented this augmentation, loss of feedback inhibition by endogenous glucocorticoids appears to be the basis of the enhanced responses. Thus, the results suggest that endogenous glucocorticoids restrain responses of catecholamine turnover, synthesis, release, reuptake, and metabolism in sympathetic nerves in this stress model.

Central hypothyroidism is associated with advanced age in male Fischer 344/N rats: in vivo and in vitro studies.

We investigated age-related alterations in hypothalamic-pituitary-thyroid function in a series of in vivo and in vitro studies in 2-, 8-, 18-, and 24-month-old male Fischer 344/N (F344/N) rats. Thyroid histology showed progressive follicular loss with advancing age; this was associated with significant and progressive decrements in plasma levels of free T4 and free T3, but not immunoreactive TSH, which remained unchanged with age. This was accompanied by a progressive age-dependent loss in in vivo responsivity of the thyrotroph to synthetic TRH and a paradoxically augmented response of GH to this peptide in the oldest rats. Steady state levels of prepro-TRH mRNA in the hypothalamic paraventricular nucleus were decreased with age, whereas TRH content in and in vitro secretion by whole hypothalami remained unchanged. Both anterior pituitary steady state TSH beta-subunit mRNA levels and TSH content were decreased with age. Taken together, these data suggest that aging in male F344/N rats is associated with a progressive, centrally mediated decrease in thyroid function. The relative contributions to this phenomenon of age-related alterations in supra-hypothalamic and/or hypothalamic vs. pituitary thyrotropic function remain to be determined, as do the relationships between changes in hypothalamic-pituitary-thyroid function and those in aging per se.

Male Fischer 344/N rats show a progressive central impairment of the hypothalamic-pituitary-adrenal axis with advancing age.

We investigated the effects of aging on the regulation of hypothalamic-pituitary-adrenal function and hippocampal steroid receptors in a series of in vivo and in vitro studies conducted in healthy intact 2-, 8-, 18-, and 24-month-old male Fischer 344/N rats. Basal plasma ACTH levels were similar among age groups, and basal plasma corticosterone levels showed a significant aging-associated decline. Two i.v. doses (2 and 20 micrograms/kg BW) of rat CRF elicited significantly greater and delayed ACTH and greater corticosterone responses in older rats, consistent with the pattern encountered in hypothalamic CRF deficiency. In contrast, the i.v. injection of a muscarinic agonist, arecoline, elicited similar ACTH and corticosterone responses in all age groups. An i.v. injection of ACTH-(1-24) evoked lower corticosterone responses in the older (18- and 24-month-old) than in the younger (2- and 8-month-old) groups of rats, consistent with an impairment of hypothalamic-pituitary-adrenal axis function in older animals. Steady state mRNA levels of mineralocorticoid and glucocorticoid receptors were significantly decreased in the hippocampus of the 8-, 18-, and 24-month-old rats, compatible with maturational, rather than senescent, changes. CRF mRNA levels in the paraventricular nucleus of the hypothalamus, CRF content, and in vitro secretion by whole explanted hypothalami were progressively and significantly reduced with age, whereas the steady state levels of arginine vasopressin mRNA were significantly increased with age. Steady state levels of POMC mRNA were decreased, and ACTH content and in vitro secretion by corticotrophs were increased with age in the anterior pituitary. We conclude that male Fischer 344/N rats show a progressive hypothalamic CRH deficiency with advancing age, which appears to be associated with elevated production of arginine vasopressin in the hypothalamus.

Decreased central and peripheral catecholaminergic activation in obese Zucker rats.

The Zucker rat is an animal model of autosomal recessive obesity characterized by excessive hypothalamic-pituitary-adrenal (HPA) axis and parasympathetic activities and deficient sympathetic outflow. Alterations in norepinephrine (NE) release, reuptake, and metabolism in the hypothalamic paraventricular nucleus (PVN) could also contribute to dysregulation of the HPA axis in obese Zucker rats via effects on corticotropin-releasing hormone neurons or could be secondary to some other primary defect. The present study assessed whether the obese phenotype defect. The present study assessed whether the obese phenotype (fa/fa) compared to the lean phenotype (Fa/?) of this strain was also associated with alterations in basal and immobilization (IMMO) stress-induced noradrenergic activation in the PVN, using in vivo microdialysis. To evaluate concurrent activity of the peripheral sympathetic nervous system and the HPA axis, we also measured plasma concentrations of catecholamines, ACTH, and corticosterone. IMMO-induced increases in PVN NE levels were significantly lower in obese Zucker rats, as were elevations in plasma concentrations of dihydroxyphenylglycol and epinephrine. Basal and IMMO-stimulated plasma ACTH concentrations were similar in obese and lean rats. Basal plasma corticosterone concentrations were also similar in obese and lean rats; however, IMMO-stimulated corticosterone levels were significantly greater in obese than in lean animals. Basal plasma free corticosterone levels, measured by ultrafiltration, were significantly higher in obese than in lean rats, confirming the state of chronic hypercorticosteronism in these animals. These findings indicate that obese Zucker rats have diminished central noradrenergic and peripheral sympathetic nervous system responses to IMMO stress along with a chronically hyperactive HPA axis. We suggest that defective regulation of PVN NE reflects and contributes to the development and/or maintenance of obesity in Zucker rats via central hypoactivity of the sympathetic system. The hypercorticosteronism of these animals, apparently sustained by some nonadrenergic stimulatory input, might participate in the suppression of the sympathetic system.

Plasma leptin levels do not change in patients with Cushing's disease shortly after correction of hypercortisolism.

In the present study, we characterized the changes in plasma leptin levels in patients with pituitary Cushing's disease and in age- and sex-matched controls. Plasma levels of ACTH, cortisol, and leptin were measured before and after iv administration of ovine CRH in controls once and in patients twice (while they had active hypercortisolism and 10 days after successful surgery). Cushing's patients had elevated body mass indexes (34 +/- 1.9 vs. 22.9 +/- 0.8) and plasma leptin levels (35.6 +/- 3.4 vs. 9.2 +/- 1.9 ng/mL) compared to controls, which remained unchanged 10 days after successful transsphenoidal surgery and directly proportional to the body mass index. Plasma leptin levels were not affected by CRH infusion in either the controls or the patients despite clear-cut elevations in plasma ACTH and cortisol. These findings suggest that although acute changes in plasma cortisol do not affect plasma leptin, chronic hypercortisolism results in elevated leptin levels, probably by causing visceral obesity.

Factitious Cushing syndrome.

There have been few reports of factitious Cushing syndrome. To characterize the clinical and laboratory features leading to this unusual diagnosis, we describe 6 patients (5 women, 1 man), ages 31-44, identified retrospectively among 860 patients evaluated for hypercortisolism at the National Institutes of Health Clinical Center. All six patients had multiple surgeries unrelated to Cushing syndrome and a history of depression or anxiety. Four patients had close contact with the medical profession, three a history of drug abuse, and three had undergone previous treatment for Cushing syndrome. The physical features of Cushing syndrome were variable and not helpful in the differential diagnosis with endogenous Cushing syndrome. Four patients had striking variability in urine-free cortisol (UFC) and 17-hydroxysteroid (17-OHCS) values from low to high. Adrenal computed tomography, performed in two patients, showed small adrenal glands (n = 1) or a left-sided mass (n = 1), and adrenal magnetic resonance imaging, performed in one patient, showed atrophic glands. Pituitary magnetic resonance imaging, carried out in four patients, was either normal (n = 1) or exhibited questionable signs of microadenoma (n = 3). Determination of synthetic glucocorticoids by high pressure liquid chromatography (HPLC) was positive in the four patients in whom it was performed. Factitious Cushing syndrome is a difficult diagnosis. To conserve time and resources, high pressure liquid chromatography analysis of urine steroids, the most definitive test for the factitious disorder, should be performed whenever there is clinical suspicion of glucocorticoid abuse.

Monitoring of alendronate treatment and prediction of effect on bone mass by biochemical markers in the early postmenopausal intervention cohort study.

To establish whether biochemical markers could be used to monitor alendronate (ALN) treatment and predict long-term response in bone mass, we used results from an ongoing, randomized trial of ALN treatment for prevention of postmenopausal osteoporosis (n = 1202). In women treated with ALN (5 mg), change from baseline at month 6 in urine N-telopeptide cross-links of type I collagen (NTX) and osteocalcin (OC) correlated with change from baseline at month 24 in spine, hip, and total body bone mineral density (BMD) [r = -0.28 to -0.31 (NTX) and r = -0.16 to -0.25 (OC), P<0.001]. This corresponded to a 4- to 5-fold greater increase at month 24 in BMD in the tertiles, with the greatest decrease at month 6 in NTX or OC. In women treated with ALN (5 mg) who had a change at month 24 in spine BMD of at least 0%, 86% (NTX) and 79% (OC) had a decrease at month 6 of at least 40% (NTX) or 20% (OC) (sensitivity). The corresponding specificities were 48% (NTX) and 53% (OC). In conclusion, change at month 6 in NTX and OC, in groups of women treated with ALN, indicated the numeric long-term response in BMD within these groups. In individual women, a decrease at month 6, in NTX or OC below the cut-point, validly identified women who responded, on ALN treatment, with a stabilization or an increase in bone mass. However, lack of decrease below the cut-point in NTX or OC could not be used to identify women with a bone loss during ALN treatment.

Stress-induced changes in brain-derived neurotrophic factor expression are attenuated in aged Fischer 344/N rats.

Aging and stress can sometimes result in a decline in brain function. We addressed the question whether changes in the expression of neurotrophic factors, which are necessary for the survival and maintenance of neurons, might occur during aging and stress. Therefore, we used in situ hybridization to investigate the effects of aging and stress on neurotrophic factor expression in young (3-4 month) and old (24 month) male Fischer 344/N rats. The ability of acute immobilization stress (2 h) to modulate BDNF mRNA levels in old rats was significantly reduced both in the hippocampus (a smaller decrease in BDNF) and the PVN (a smaller increase in BDNF) compared to young rats. In contrast, the induction of nerve growth factor and neurotrophin 3 (NT-3) by stress was not influenced by age. The diminished BDNF responses to stress in aged rats may be relevant to difficulties in adaptation to stress encountered during old age.

Long-term acetyl-L-carnitine treatment in Alzheimer's disease.

In a double-blind, placebo-controlled, parallel-group, randomized clinical trial, we studied the efficacy of long-term (1-year) oral treatment with acetyl-L-carnitine in 130 patients with a clinical diagnosis of Alzheimer's disease. We employed 14 outcome measures to assess functional and cognitive impairment. After 1 year, both the treated and placebo groups worsened, but the treated group showed a slower rate of deterioration in 13 of the 14 outcome measures, reaching statistical significance for the Blessed Dementia Scale, logical intelligence, ideomotor and buccofacial apraxia, and selective attention. Adjusting for initial scores with analysis of covariance, the treated group showed better scores on all outcome measures, reaching statistical significance for the Blessed Dementia Scale, logical intelligence, verbal critical abilities, long-term verbal memory, and selective attention. The analysis for patients with good treatment compliance showed a greater drug benefit than for the overall sample. Reported adverse events were relatively mild, and there was no significant difference between the treated and placebo groups either in incidence or severity.

Regulation of plasma osteocalcin by corticosterone and norepinephrine during restraint stress.

Osteocalcin (OC), an extracellular calcium-binding protein of bone origin, is synthesized by osteoblasts and binds with high specificity to bone mineral crystals. A small, but relatively consistent portion of newly synthesized OC which is released to circulation has been well correlated with histological indices of osteoblastic activity. Synthesis of OC is regulated by numerous hormones including glucocorticoids. We previously reported that mild mental stressors such as cage change or cold exposure decreased rat plasma OC by up to 40% within 1 h. A similar response was induced in a time- and dose-related manner by injection of physiological levels of corticosterone (CS), the active glucocorticoid in rats. Prone immobilization by foot restraint of conscious rats for up to 2 h (IMMO) is a well-characterized model of classic "fight-or-flight" response. This model induces an immediate and prolonged elevation of CS, as well as the catecholamines epinephrine (E) and norepinephrine (NE). In marked contrast to milder stressors, immobilization induced an immediate increase of plasma OC, greater than 50% within 5-20 min, which returned toward normal after 2 h of restraint. Selective ablation of the hormones by adrenal medulectomy, adrenalectomy, or blockade of sympathetic ganglia did not abolish the initial rapid rise of plasma OC. Even before IMMO, plasma OC was increased by about 50% in the absence of sympathetic neural function or adrenal CS production. The presence of both CS and NE, but not E, was required to return plasma OC concentrations to basal levels. This strongly suggests interaction of CS and NE to regulate plasma OC and its release from bone. As expected, prior cold exposure lowered plasma OC, but did not abolish a subsequent increase in response to IMMO, nor did IMMO repeated daily for 7 days. The stimulus for the initial rapid elevation of OC is unknown, but likely to be of importance in the role OC plays in response to stress. Further investigation of the OC under mental stress should help to understand the function of this abundant and highly conserved bone protein.