Gene-environment interactions controlling energy and glucose homeostasis and the developmental origins of obesity

Abstract

Obesity and type 2 diabetes mellitus (T2DM) often occur together and affect a growing number of individuals in both the developed and developing worlds. Both are associated with a number of other serious illnesses that lead to increased rates of mortality. There is likely a polygenic mode of inheritance underlying both disorders, but it has become increasingly clear that the pre- and postnatal environments play critical roles in pushing predisposed individuals over the edge into a disease state. This review focuses on the many genetic and environmental variables that interact to cause predisposed individuals to become obese and diabetic. The brain and its interactions with the external and internal environment are a major focus given the prominent role these interactions play in the regulation of energy and glucose homeostasis in health and disease.

FIGURE 1.

Major routes for regulation of feeding and energy balance. These simplified schematics illustrate the possible neural networks relaying metabolic signals from the periphery to the brain. The regulatory effects of peripheral hormones and nutrients involve a complex, distributed, and interconnected neuronal network involving neurons in the forebrain, midbrain, and hindbrain. The arcuate (ARC) and ventromedial (VMN) nuclei in the hypothalamus have high densities of neurons that directly respond to peripheral signals such as leptin, insulin, ghrelin, and glucose. In turn, neurons in the ARC and VMN send projections to other parts of the hypothalamus inculding the dorsomedial (DMN) and paraventicular (PVN) nuclei of the hypothalamus and the lateral hypothalamic area (LHA). Of particular importance are projections to PVN because it contains neurons that mediate autonomic and neuroendocrine responses associated with energy homeostasis. In addition to a direct action in the hypothalamus, peripheral metabolic signals also act on neurons located in the hindbrain, specifically on neurons located in the nucleus of the tractus solitarius (NTS). The NTS appears primarily involved in the short-term control of feeding control in response to satiety, such as peptide YY (PYY), cholecystokinin (CCK), and glucagon-like peptide-1 (GLP-1), and mechanical signals originating from the gastrointestinal (GI) tract. The central regulation of feeding also involves the neurons in the ventral tegmental area (VTA), which modulates behaviors and both our need to and desire to eat. This figure was created in part using illustrations from “Servier Medical Art” with permission.

FIGURE 2.

Developmental origins of metabolic disease. The developmental programming of key regulatory systems by the perinatal environment and/or genetic background represents a possible mechanism by which alterations in maternal and/or early postnatal nutrition predispose the offspring to obesity and type 2 diabetes. This figure was created in part using illustrations from “Servier Medical Art” with permission.