Prenatal stress-immune programming of sex differences in comorbidity of depression and obesity/metabolic syndrome

Abstract

Major depressive disorder (MDD) is the number one cause of disability worldwide and is comorbid with many chronic diseases, including obesity/metabolic syndrome (MetS). Women have twice as much risk for MDD and comorbidity with obesity/MetS as men, although pathways for understanding this association remain unclear. On the basis of clinical and preclinical studies, we argue that prenatal maternal stress (ie, excess glucocorticoid expression and associated immune responses) that occurs during the sexual differentiation of the fetal brain has sex-dependent effects on brain development within highly sexually dimorphic regions that regulate mood, stress, metabolic function, the autonomic nervous system, and the vasculature. Furthermore, these effects have lifelong consequences for shared sex-dependent risk of MDD and obesity/MetS. Thus, we propose that there are shared biologic substrates at the anatomical, molecular, and/or genetic levels that produce the comorbid risk for MDD-MetS through sex-dependent fetal origins.

Keywords: depression; depression-cardiometabolic comorbidity; fetal programming; inflammation; obesity/metabolic syndrome; prenatal stress model; sex difference.

Figure 1.. Sexually dimorphic subcortical (A) and cortical (B) regions in stress and mood circuitries. Shared neural circuitry implicated in mood, stress, metabolic function, and the autonomic nervous system, highlighting regions with relatively dense distribution of gonadal and/or adrenal hormone receptors. In women, regions larger in volume relative to cerebrum size include orbitofrontal cortex, anterior cingulate cortex, and hippocampus, whereas in men, regions larger relative to cerebrum size include amygdala and hypothalamus. OFC, orbitofrontal cortex; vmPFC, ventromedial prefrontal cortex. Based on reference 11: Goldstein JM, Seidman LJ, Horton NJ, et al. Normal sexual dimorphism of the adult human brain assessed by in vivo magnetic resonance imaging. Cereb Cortex. 2001;11(6):490-497.

Figure 2.. Fetal antecedents to sex differences in comorbidity of depression and metabolic syndrome. This figure illustrates a prenatal stress-immune model of sex differences in the comorbidity of depression and metabolic syndrome emphasizing maternal hypothalamic-pituitary-adrenal-axis dysregulation (elevated glucocorticoids and proinflammatory expression) during gestation that impacts development of hypothalamic-pituitary-adrenal circuitry in the fetus in sex-dependent ways, with lifelong consequences for mood/anxiety, the endocrine and autonomic nervous systems, growth and metabolism, vascular structure and function, and insulin resistance. F, female; HPA, hypothalamic-pituitary-adrenal; M, male.