Abstract
Early-life stress is associated with depression and metabolic abnormalities that increase the risk of cardiovascular disease and diabetes. Such associations could be due to increased glucocorticoid levels. Periodic maternal separation in the neonate and rearing in social isolation are potent stressors that increase hypothalamus-pituitary-adrenal axis activity. Moreover, social isolation promotes feed intake and body weight gain in rats subjected to periodic maternal separation; however, its effects on metabolic risks have not been described. In the present study, we evaluated whether periodic maternal separation, social isolation rearing, and a combination of these two stressors (periodic maternal separation + social isolation rearing) impair glucose homeostasis and its relation to the hypothalamus-pituitary-adrenal axis and depressive-like behavior. Periodic maternal separation increased basal corticosterone levels, induced a passive coping strategy in the forced swimming test, and was associated with a mild (24%) increase in fasting glucose, insulin resistance, and dyslipidemia. Rearing in social isolation increased stress reactivity in comparison to both controls and in combination with periodic maternal separation, without affecting the coping strategy associated with the forced swimming test. However, social isolation also increased body weight gain, fasting glucose (120%), and insulin levels in rats subjected to periodic maternal separation. Correlation analyses showed that stress-induced effects on coping strategy on the forced swimming test (but not on metabolic risk markers) are associated with basal corticosterone levels. These findings suggest that maternal separation and postweaning social isolation affect stress and metabolic vulnerability differentially and that early-life stress-related effects on metabolism are not directly dependent on glucocorticoid levels. In conclusion, our study supports the cumulative stress hypothesis, which suggests that metabolic risk markers arise when vulnerable individuals are exposed to social challenges later in life.
Highlights
The prevalence of obesity has rapidly increased over the past two decades and represents a major public health concern
We evaluated HPA axis reactivity in rats subjected to MS180 that were housed under normal and social isolation rearing (SIR) conditions, and correlated the results with depresive-like behavior and metabolic risk parameters
The lack of association between CORT levels and body weight observed in the present study suggest that SIR-induced body weight gain in MS180 animals could be related to both hyperphagia and increased peripheral fat deposition, but is not directly modulated by GC
Summary
The prevalence of obesity has rapidly increased over the past two decades and represents a major public health concern. Hyperlipidemia, hypertension, and diabetes mellitus type 2 are common comorbidities in patients with depression. Patients with a history of depression have a higher risk of developing type 2 diabetes and this association cannot be entirely attributed to the use of antidepressant drugs or obesity [3]. Recent evidence suggests that impaired insulin sensitivity in women with major depression can be improved after successful treatment with antidepressants [4]. These findings suggest that a common etiology could increase the risk of both conditions, rather than depression being the sole complication of a metabolic imbalance in the brain
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