The adipose tissue keeps the score: priming of the adrenal-adipose tissue axis by early life stress predisposes women to obesity and cardiometabolic risk

Abstract

Adverse Childhood Experiences (ACEs) refer to early life stress events, including abuse, neglect, and other psychosocial childhood traumas that can have long-lasting effects on a wide range of physiological functions. ACEs provoke sex-specific effects, whereas women have been shown to display a strong positive correlation with obesity and cardiometabolic disease. Notably, rodent models of chronic behavioral stress during postnatal life recapitulate several effects of ACEs in a sex-specific fashion. In this review, we will discuss the potential mechanisms uncovered by models of early life stress that may explain the greater susceptibility of females to obesity and metabolic risk compared with their male counterparts. We highlight the early life stress-induced neuroendocrine shaping of the adrenal-adipose tissue axis as a primary event conferring sex-dependent heightened sensitivity to obesity.

Keywords: HPA axis; adverse childhood experience; aldosterone; obesity; sex differences.

Figure 1

Progressive stress exposure during the stress hyporesponsive period alters HPA function. In rodent models, SHRP is characterized by decreased ACTH and corticosterone production despite increased CRH expression in the hypothalamus. A first hit of stress during this period elicits a modest elevation in AVP and ACTH, coupled with a significant increase in aldosterone. After early life stress exposure, a subsequent hit of stress leads to increased activation in the PVN accompanied by increased AVP expression and decreased CRH expression. This “second hit” elicits an increase in ACTH, followed by elevated corticosterone and significant increases in aldosterone. Priming of the HPA axis during this period of altered stress response mechanisms may underlie the predisposition for a hyper-aldosteronogeneic response to stressors such as high fat diet in adulthood.

Figure 2

Neuroendocrine mechanism linking early life stress with increased susceptibility of women to obesity. Women have heightened HPA axis activation and responsiveness, which is exacerbated by early life stress, predisposing to obesity. Females have increased activation of the hypothalamus, delineated by increased CRH and AVP expression, compared to males. Both women and female rodents have elevated ACTH in plasma, as well as aldosterone and cortisol/corticosterone. Increased cortisol/corticosterone is attributed to an expanded zona fasciculata in the adrenal glands, which are larger in females than males. Exposure to early life stress leads to sensitization of the HPA axis, which increases CRH in the hypothalamus of rodent models and increased plasma ACTH and AVP in women and female rodents. These secretagogues elicit an elevated basal corticosterone/cortisol, but moreso, elevated aldosterone from the adrenal glands via binding to MC2R and V1R. Adrenal aldosterone acts on the mineralocorticoid receptor in adipose tissue to exacerbate production of adipokines leptin and AngII production, which stimulate further aldosterone production via LepR and AT1R, respectively.