Developmental origins of metabolic diseases

Abstract

Almost 2 billion adults in the world are overweight, and more than half of them are classified as obese, while nearly one-third of children globally experience poor growth and development. Given the vast amount of knowledge that has been gleaned from decades of research on growth and development, a number of questions remain as to why the world is now in the midst of a global epidemic of obesity accompanied by the "double burden of malnutrition," where overweight coexists with underweight and micronutrient deficiencies. This challenge to the human condition can be attributed to nutritional and environmental exposures during pregnancy that may program a fetus to have a higher risk of chronic diseases in adulthood. To explore this concept, frequently called the developmental origins of health and disease (DOHaD), this review considers a host of factors and physiological mechanisms that drive a fetus or child toward a higher risk of obesity, fatty liver disease, hypertension, and/or type 2 diabetes (T2D). To that end, this review explores the epidemiology of DOHaD with discussions focused on adaptations to human energetics, placental development, dysmetabolism, and key environmental exposures that act to promote chronic diseases in adulthood. These areas are complementary and additive in understanding how providing the best conditions for optimal growth can create the best possible conditions for lifelong health. Moreover, understanding both physiological as well as epigenetic and molecular mechanisms for DOHaD is vital to most fully address the global issues of obesity and other chronic diseases.

Keywords: developmental origins; environmental toxins; metabolic diseases; obesity; placenta.

Graphical abstract

FIGURE 1.

Schematic of potential preconception and maternal/placental health factors that can influence birth size and the impact on health in childhood that can influence adult health in the long term with underlying environmental disruptors that contribute to the developmental origins of metabolic diseases.

FIGURE 2.

Potential social, environmental, or physical exposure that promote poor growth in utero or childhood and associated physiological responses or adaptions (with references) that ultimately contribute to the developmental origins of metabolic diseases. CPT-A, carnitine palmitoyltransferase 1A; RFTN1, Raftlin, lipid raft linker 1; FAS, fatty acid aynthase; KLF13, Kruppel-like factor 13; UCP, uncoupling protein; PPAR, peroxisome proliferator-activated receptor.

FIGURE 3.

Illustration of physiological mechanisms to support association between poor growth in childhood and metabolic adaptations that promote chronic diseases in adulthood. AMPK, AMP-activated protein kinase.

FIGURE 4.

Placental anatomy and transporter localization in the syncytiotrophoblast: amino acid (AA) transport across the syncytiotrophoblast (ST) to the fetal capillary endothelial cell; glucose transport; and lipid transport. BM, basal plasma membrane; FATP, fatty acid transporting protein; GLUT, glucose transporter; MVM, microvillous plasma membrane; SNAT2, sodium-dependent amino acid transporter isoform 2; LAT1, leucine transporter isoform 1; TG, triglyceride; LPL, lipoprotein lipase; FABP, fatty acid binding protein; NEFA, non-esterified fatty acid.

FIGURE 5.

Placental mechanistic target of rapamycin (mTOR) is responsive to a wide variety of upstream inputs including macronutrient availability, oxygen, energy status, and hormonal growth signals and in turn regulates placental growth and nutrient transporter function, which leads to changes in fetal growth rate, body composition, and developmental programming. hCG, human chorionic gonadotropin; hPL, human placental lactogen; IGF, insulin-like growth factor; pGH, placental growth hormone.

FIGURE 6.

Summary of the metabolic deficits exhibited in the fetal growth-restricted offspring from dams exposed to uterine artery ligation/ablation. ER, endoplasmic reticulum; EWAT, epididymal adipose tissue; MHC, myosin heavy chain; mTOR, mechanistic target of rapamycin; ROS, reactive oxygen species.

FIGURE 7.

Proposed mechanisms by which metabolism-disrupting chemicals may contribute to metabolic diseases. BPA, bisphenol A.

FIGURE 8.

Ubiquitous exposure to select metabolism disrupting chemicals among pregnant women in National Health and Nutrition Examination Survey (NHANES). BPA, bisphenol A; DDE, dichlorodiphenyldichloroethylene; DDT, dichlorodiphenyltrichloroethane; MBP, monobutyl phthalate; MEP, monoethyl phthalate; PFAS, perfluoroalkyl substance; PFOA, perfluorooctanoic acid; PFOS, perfluorooctane sulfonate.