Fetal programming of body composition, obesity, and metabolic function: the role of intrauterine stress and stress biology

Abstract

Epidemiological, clinical, physiological, cellular, and molecular evidence suggests that the origins of obesity and metabolic dysfunction can be traced back to intrauterine life and supports an important role for maternal nutrition prior to and during gestation in fetal programming. The elucidation of underlying mechanisms is an area of interest and intense investigation. In this perspectives paper we propose that in addition to maternal nutrition-related processes it may be important to concurrently consider the potential role of intrauterine stress and stress biology. We frame our arguments in the larger context of an evolutionary-developmental perspective that supports roles for both nutrition and stress as key environmental conditions driving natural selection and developmental plasticity. We suggest that intrauterine stress exposure may interact with the nutritional milieu, and that stress biology may represent an underlying mechanism mediating the effects of diverse intrauterine perturbations, including but not limited to maternal nutritional insults (undernutrition and overnutrition), on brain and peripheral targets of programming of body composition, energy balance homeostasis, and metabolic function. We discuss putative maternal-placental-fetal endocrine and immune/inflammatory candidate mechanisms that may underlie the long-term effects of intrauterine stress. We conclude with a commentary of the implications for future research and clinical practice.

Figure 1

Intrauterine stress biology and programming of fetal targets of body composition and metabolic function. Adverse circumstances during pregnancy (physiological as well as psychological stressors, summarized here as “prenatal stress”) have the potential to induce changes in maternal-placental-fetal stress biology (e.g., increases in maternal and fetal cortisol, placental corticotrophin-releasing-hormone (CRH), and inflammatory mediators). The subsequent increase in stress hormones and proinflammatory cytokines in the fetal compartment during sensitive or critical developmental windows can impact the structure and function of the brain and peripheral targets (e.g., adipose tissue, pancreas, and liver) that are related to body composition, energy balance homeostasis, and metabolic function.