Hypothalamic-pituitary-adrenal axis function and the metabolic syndrome X of obesity

Obesity has negative health consequences related to fat distribution, particularly the central or visceral accumulation of fat. The major complications associated with visceral obesity, termed the "Metabolic Syndrome of Obesity," or "Syndrome X," are type II diabetes, hypertension, and dyslipidemia. As with certain mood disorders, the syndrome may be a consequence of neuroendocrine perturbations typically associated with chronic stress. Our work with bonnet macaque monkeys provides an animal model for the relationship between early stress, behavioral and hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and Syndrome X. During their infant's first half-year, mothers face a variable foraging demand (VFD), in which ample food varies unpredictably in the difficulty of its acquisition, and the offspring show persistent abnormalities in systems known to modulate stress and affective regulation. Early work on the bonnet macaque noted the emergence of a sample of spontaneously obese subjects as they matured. Using the VFD model, the current study showed that there was a clear relationship between early cerebrospinal fluid corticotropin-releasing factor levels and subsequently measured body mass index, supporting the hypotheses regarding the interactive roles of early experience and HPA axis dysregulation in the ontogeny of both metabolic and mood disorders.     

Chronic psychosocial stress induces visceral hyperalgesia in mice

Experimental and clinical evidence has shown that chronic stress plays an important role in the onset and/or exacerbation of symptoms of functional gastrointestinal disorders. Here, we aimed to investigate whether exposure to a chronic and temporally unpredictable psychosocial stressor alters visceral and somatic nociception as well as anxiety-related behaviour. In male C57BL/6J mice, chronic stress was induced by repeated exposure to social defeat (SD, 2?h) and overcrowding (OC, 24?h) during 19 consecutive days. Visceral and somatic nociception was evaluated by colorectal distension and a hot plate, respectively. The social interaction test was used to assess social anxiety. Mice exposed to psychosocial stress developed visceral hyperalgesia and somatic hypoalgesia 24?h following the last stress session. SD/OC mice also exhibited social anxiety-like behaviour. All these changes were also associated with physiological alterations, measured as a decreased faecal pellet output and hypothalamic-pituitary-adrenal (HPA) axis disruption. Taken together, these data confirm that this mouse model of chronic psychosocial stress may be useful for studies on the pathophysiological mechanisms underlying such stress-associated disorders and to further test potential therapies.     

Investigations of HPA function and the enduring consequences of stressors in adolescence in animal models

Developmental differences in hypothalamic–pituitary–adrenal (HPA) axis responsiveness to stressors and ongoing development of glucocorticoid-sensitive brain regions in adolescence suggest that similar to the neonatal period of ontogeny, adolescence may also be a sensitive period for programming effects of stressors on the central nervous system. Although research on this period of life is scarce compared to early life and adulthood, the available research indicates that effects of stress exposure during adolescence differ from, and may be longer-lasting than, effects of the same stress exposure in adulthood. Research progress in animal models in this field is reviewed including HPA function and the enduring effects of stress exposures in adolescence on sensitivity to drugs of abuse, learning and memory, and emotional behaviour in adulthood. The effects of adolescent stress depend on a number of factors, including the age, gender, the duration of stress exposure, the type of stressor, and the time between stress exposure and testing.     

IQ in childhood and the metabolic syndrome in middle age: Extended follow-up of the 1946 British Birth Cohort Study

IQ in early adulthood has been inversely associated with risk of the metabolic syndrome in midlife. We tested this association in the British 1946 birth cohort, which assessed IQ at age eight years and ascertained the metabolic syndrome at age 53 years based on modified (non-fasting blood) ATPIII criteria. Childhood IQ was inversely associated with risk of the metabolic syndrome, but this association was almost entirely mediated by educational attainment and achieved occupational social class. This may be consistent with a pattern where childhood IQ is strongly associated with outcomes that reflect neurological disorder, such as the degenerative dementias, but less so with common chronic physical diseases of ageing.     

Cardiovascular reactivity and central adiposity in older African Americans.

This study examined central adiposity, as measured by waist circumference (WC), in relation to mental-stress induced systolic (SBP) and diastolic blood pressure (DBP) and heart rate (HR) responses, body composition, the metabolic syndrome, and health practices in 22 older, African American men and women (ages 52-79 years). The high WC (> 100 cm) group showed significantly greater SBP, DBP, and HR reactivity, greater fasting insulin levels, lower high density lipoprotein cholesterol levels, greater fat mass in both truncal and peripheral regions, and greater body mass index as compared to the low WC (< 100 cm) group. Groups were comparable with respect to fat-free mass, peak oxygen consumption (VO2), leisure time activity, dietary intake, resting blood pressure, and other metabolic variables. The findings support a clustering of metabolic and mental stress risk factors that may predispose older African Americans to increased cardiovascular and metabolic disease.     

Cultural influences in somatosensory amplification and their association with negative affective states

Previous research has indicated that, reflecting East Asians’ holistic attentional style, they are likely to emphasize more somatic symptoms and perceive their internal visceral states less accurately as compared with Westerners. Based on these findings, comparing representative samples of Americans and Japanese participants, this research examined whether somatosensory amplification would vary across cultures. Moreover, by controlling confounding factors, including neuroticism and chronic disorders, the possibility that the association between somatosensory amplification and negative affective states differs across cultures also was tested. The results showed that Japanese exhibit higher somatosensory amplification than do Americans. In both cultures, as neuroticism and the number of chronic disorders increased, negative affective states also increased, leading to higher somatosensory amplification. Whereas negative affective states completely mediated the paths of neuroticism and chronic disorders to somatosensory amplification in the United States, such mediation was partial in Japan. Moreover, the association between somatosensory amplification and negative affective states was weaker in Japanese than in Americans.     

The adolescent brain

Adolescence is a developmental period characterized by suboptimal decisions and actions that give rise to an increased incidence of unintentional injuries and violence, alcohol and drug abuse, unintended pregnancy and sexually transmitted diseases. Traditional neurobiological and cognitive explanations for adolescent behavior have failed to account for the nonlinear changes in behavior observed during adolescence, relative to childhood and adulthood. This review provides a biologically plausible conceptualization of the neural mechanisms underlying these nonlinear changes in behavior, as a heightened responsiveness to incentives while impulse control is still relatively immature during this period. Recent human imaging and animal studies provide a biological basis for this view, suggesting differential development of limbic reward systems relative to top-down control systems during adolescence relative to childhood and adulthood. This developmental pattern may be exacerbated in those adolescents with a predisposition toward risk-taking, increasing the risk for poor outcomes.     

Long-term associations of stress and chronic diseases in ageing and retired employees

Long-term associations of prolonged stress symptoms and work-related stressors with chronic diseases were assessed in a sample of ageing and retired food industry workers (N = 100, mean age 62 years) using independent samples t-test, chi-squared test and binary logistic regression analyses. Data was gathered at health checkups and using self-report questionnaires in 1989 and 2000. Prolonged stress symptoms were associated with overall morbidity. Higher scores of stress symptoms predicted musculoskeletal disorders, diseases of the nervous system, eye and ear, endocrine and metabolic diseases, and mental disorders. Of work-related stressors, only job dissatisfaction had a long-term association with endocrine and metabolic diseases. Importantly, prolonged stress symptoms could not be explained by job strain and demands. Identification of prolonged stress symptoms along with traditional and potential risk factors, and combining this knowledge with stress reduction and management is essential for disease prevention and in postponing subsequent onset of disease.     

Pathways to resilience: maternal nurturance as a buffer against the effects of childhood poverty on metabolic syndrome at midlife

Children raised in families with low socioeconomic status (SES) go on to have high rates of chronic illness in adulthood. However, a sizable minority of low-SES children remain healthy across the life course, which raises questions about the factors associated with, and potentially responsible for, such resilience. Using a sample of 1,205 middle-aged Americans, we explored whether two characteristics--upward socioeconomic mobility and early parental nurturance--were associated with resilience to the health effects of childhood disadvantage. The primary outcome in our analyses was the presence of metabolic syndrome in adulthood. Results revealed that low childhood SES was associated with higher prevalence of metabolic syndrome at midlife, independently of traditional risk factors. Despite this pattern, half the participants raised in low-SES households were free of metabolic syndrome at midlife. Upward social mobility was not associated with resilience to metabolic syndrome. However, results were consistent with a buffering scenario, in which high levels of maternal nurturance offset the metabolic consequences of childhood disadvantage.     

腹内脂肪与胰岛素抵抗

腹内脂肪与胰岛素抵抗的关系密切,它在形态、脂解等方面不同于皮下脂肪。脂肪细胞分泌的细胞因子在胰岛素抵抗的发生发展中有着重要的作用。明确腹内脂肪致胰岛素抵抗的机制有益于代谢综合征的防治。     

Risk Factors for Adolescent Suicide and Suicidal Behavior: Mental and Substance Abuse Disorders,Family Environmental Factors,and Life Stress

This review focuses on psychopathologic risk factors for adolescent suicide and suicidal behavior, namely, affective, disruptive, substance abuse, psychotic, and personality disorders. The interaction of psychopathology with age and gender is discussed. The role of family environmental risk factors and stress events in suicide and suicidal behavior, both alone, and in interaction with psychopathology are reviewed. Research reviewed will include psychological; autopsy studies, longitudinal studies examining predictors of suicide, and epidemiologic studies of suicide attempts.     

Family interaction and the course of adolescent psychopathology: An analysis of adolescent and parent effects

This study focused on evaluating the utility of three family measures for predicting outcome in a sample of disturbed but nonpsychotic adolescents: (a) the affective quality of the adolescents' voice tone when communicating with his/her parents; (b) the predominant affective quality of the parents' voice tones when communicating with the adolescent, and (c) the affective quality of the content of the parents' verbalizations to the adolescent. These measures were derived from 5-minute face to face discussions between parents and their disturbed adolescent. Results indicated that adolescents using positive or neutral voice tones during emotionally laden discussions with their parents tended to show relatively adequate levels of psychosocial adjustment as young adults, while adolescents using exclusively negative voice tones tended to show sufficient adjustment difficulties in early adulthood to warrant diagnoses within the extended schizophrenia spectrum. Although adolescent voice tone was associated with outcome, considering both adolescent and parent affective response led to improved prediction, with consideration of adolescent and parent variables leading to accurate prediction of outcome for 30 of the 33 sample cases.     

Chronic stress, metabolism, and metabolic syndrome

The prevalence of obesity has rapidly escalated and now represents a major public health concern. Although genetic associations with obesity and related metabolic disorders such as diabetes and cardiovascular disease have been identified, together they account for a small proportion of the incidence of disease. Environmental influences such as chronic stress, behavioral and metabolic disturbances, dietary deficiency, and infection have now emerged as contributors to the development of metabolic disease. Although epidemiological data suggest strong associations between chronic stress exposure and metabolic disease, the etiological mechanisms responsible remain unclear. Mechanistic studies of the influence of chronic social stress are now being conducted in both rodent and nonhuman primate models, and phenotypic results are consistent with those in humans. The advantage of these models is that potential neural mechanisms may be examined and interventions to treat or prevent disease may be developed and tested. Further, circadian disruption and metabolic conditions such as diabetes mellitus could increase susceptibility to other stressors or serve as a stressor itself. Here, we review data from leading investigators discussing the interrelationship between chronic stress and development of metabolic disorders.     

Binge eating proneness emerges during puberty in female rats: a longitudinal study

Puberty is a critical risk period for binge eating and eating disorders characterized by binge eating. Previous research focused almost entirely on psychosocial risk factors during puberty to the relative exclusion of biological influences. The current study addressed this gap by examining the emergence of binge eating during puberty in a rat model. We predicted that there would be minimal differences in binge eating proneness during pre-early puberty, but significant differences would emerge during puberty. Two independent samples of female Sprague-Dawley rats (n = 30 and n = 36) were followed longitudinally across pre-early puberty, mid-late puberty, and adulthood. Binge eating proneness was defined using the binge eating resistant (BER)/binge eating prone (BEP) model of binge eating that identifies BER and BEP rats in adulthood. Across two samples of rats, binge eating proneness emerged during puberty. Mixed linear models showed little difference in palatable food intake between BER and BEP rats during pre-early puberty, but significant group differences emerged during mid-late puberty and adulthood. Group differences could not be accounted for by changes in nonpalatable food intake or body weight. Similar to patterns in humans, individual differences in binge eating emerge during puberty in female rats. These findings provide strong confirming evidence for the importance of biological risk factors in developmental trajectories of binge eating risk across adolescence.     

Does War Hurt? Effects of Media Exposure After Missile Attacks on Chronic Pain

This study focused on the effects of exposure to terrorist missile attacks on the physical and mental well being of chronic pain patients. In this prospective and longitudinal design, 55 chronic pain patients treated at a specialty pain clinic completed self-report questionnaires regarding their pain, depression and anxiety pre- and post a three week missile attack on the southern region of Israel. In addition, levels of direct and indirect exposure to the attacks were measured. Results of regression analyses showed that exposure to the attacks through the media predicted an increase in pain intensity and in the sensory component of pain during the pre-post war period, but did not predict depression, anxiety or the affective component of pain. These findings contribute to the understanding of the effects of terrorism on physical and emotional distress and identify chronic pain patients as a vulnerable population requiring special attention during terrorism-related stress.     

Developmental effects of acute, chronic, and withdrawal from chronic nicotine on fear conditioning

Pre-adolescence and adolescence are developmental periods associated with increased vulnerability for tobacco addiction, and exposure to tobacco during these periods may lead to long-lasting changes in behavioral and neuronal plasticity. The present study examined the short- and long-term effects of nicotine and nicotine withdrawal on fear conditioning in pre-adolescent, adolescent, and adult mice, and potential underlying substrates that may mediate the developmental effects of nicotine, such as changes in nicotinic acetylcholine receptor (nAChR) binding, CREB expression, and nicotine metabolism. Age-related differences existed in sensitivity to the effects of acute nicotine, chronic nicotine and nicotine withdrawal on contextual fear conditioning (no changes in cued fear conditioning were seen); younger mice were more sensitive to the acute effects and less sensitive to the effects of nicotine withdrawal 24 h post treatment cessation. Developmental differences in nAChR binding were associated with the effects of nicotine withdrawal on contextual learning. Developmental differences in nicotine metabolism and CREB expression were also observed, but were not related to the effects of nicotine withdrawal on contextual learning 24 h post treatment. Chronic nicotine exposure during pre-adolescence or adolescence, however, produced long-lasting impairments in contextual learning that were observed during adulthood, whereas adult chronic nicotine exposure did not. These developmental effects could be related to changes in CREB. Overall, there is a developmental shift in the effects of nicotine on hippocampus-dependent learning and developmental exposure to nicotine results in adult cognitive deficits; these changes in cognition may play an important role in the development and maintenance of nicotine addiction.     

Maternal separation in early life impairs tumor immunity in adulthood in the F344 rat

Neonatal stress alters the hypothalamic-pituitary-adrenal (HPA) axis in rodents, such that, when these animals are exposed to stress as adults they hypersecrete corticosterone. Given that glucocorticoids are immunosuppressive, we examined the impact of maternal separation on HPA axis reactivity, natural killer (NK) cytotoxicity, and tumor growth in Fischer 344 rats following chronic restraint stress in adulthood. Pups underwent a chronic stress protocol whereby they were separated from their dams for 3 h on postnatal days 1-21. In adulthood, corticosterone responses were assessed following exposure to chronic (6 days for 10 h) restraint stress. Rats allocated to the chronic stress condition were inoculated with MADB106 tumor cells on day 4 of the restraint protocol. Blood was assessed for NK cytotoxicity on the final day of the chronic restraint protocol, and tumor colonization was assessed 3 weeks thereafter. Maternal separation impaired developmental weight gain (P < 0.05), depressed NK cytotoxicity (P < 0.05), and increased tumor colonization in the presence of chronic restraint stress in adulthood (P < 0.00 l). These findings occurred independently of circulating plasma corticosterone as only adult stress exposure potentiated corticosterone responses (P < 0.05). Our findings indicate that maternal separation and chronic stress can impair NK cytotoxicity and hence tumor immunity, but these effects are not directly mediated by perturbations in HPA axis function.     

Adolescent personality disorders and conflict with romantic partners during the transition to adulthood

Longitudinal data were used to investigate the association of adolescent personality disorders with conflict between romantic partners during the transition to adulthood (i.e., age 17 to 27). Findings indicated that adolescent personality disorders (PDs) assessed at mean age 16 were associated with subsequent elevated partner conflict. Cluster B PD was associated with sustained elevations in partner conflict throughout the transition to adulthood. Cluster A and C PDs were associated with elevated partner conflict before age 23. Paranoid, schizoid, schizotypal, borderline, narcissistic, and obsessive-compulsive PD symptoms were independently associated with sustained elevations in partner conflict.     

The hypothalamo-pituitary-adrenal axis in chronic fatigue syndrome and fibromyalgia syndrome

The hypothalamo-pituitary-adrenal (HPA) axis plays a major role in the regulation of responses to stress. Human stress-related disorders such as chronic fatigue syndrome (CFS), fibromyalgia syndrome (FMS), chronic pelvic pain and post-traumatic stress disorder are characterized by alterations in HPA axis activity. However, the role of the HPA axis alterations in these stress-related disorders is not clear. Most studies have shown that the HPA axis is underactive in the stress-related disorders, but contradictory results have also been reported, which may be due to the patients selected for the study, the methods used for the investigation of the HPA axis, the stage of the syndrome when the tests have been done and the interpretation of the results. There is no structural abnormality in the endocrine organs which comprise the HPA axis, thus it seems that hypocortisolemia found in the patients with stress-related disorder is functional. It may be also an adaptive response of the body to chronic stress. In this review, tests used in the assessment of HPA axis function and the HPA axis alterations found in CFS and FMS are discussed in detail.     

Parent-Offspring Transmission of Internalizing and Sensory over-Responsivity Symptoms in Adolescence

Reactions to sensory experiences are an overlooked correlate of affective regulation, despite the importance of bodily states on psychological processes. Children who display sensory over-responsivity (i.e., adverse reactions to typical sensations) are at greater risk for developing affective disorders. We extended this literature to adolescents and their middle-aged parents. Participants in a birth record-based study of families of adolescent twins (N = 506 families; 1012 adolescents; 53% female) completed a subset of items from the Adult Sensory Profile. We derived adolescent self-reported internalizing disorder symptoms and parent affective diagnoses from structured diagnostic interviews. Structural equation models tested the relationship between parent sensory over-responsivity symptoms and affective diagnoses and their adolescent offspring’s sensory over-responsivity and internalizing symptoms. Adolescent sensory over-responsivity symptoms were correlated with internalizing disorder symptoms. Parents with a diagnosis of anxiety or depression (mothers only) reported more frequent SOR symptoms than parents without a diagnosis. Parent depression was significantly related to adolescent sensory over-responsivity symptoms, over and above parent sensory over-responsivity symptoms (β = 0.26, p < 0.001 for mothers; β = 0.13, p = 0.004 for fathers). Father alcohol abuse/dependency also predicted offspring sensory over-responsivity symptoms. Offspring of parents with affective disorders were at additional risk for sensory dysregulation via parents’ influence on offspring internalizing problems.