Consensus on the key characteristics of metabolism disruptors

Abstract

Metabolism-disrupting agents (MDAs) are chemical, infectious or physical agents that increase the risk of metabolic disorders. Examples include pharmaceuticals, such as antidepressants, and environmental agents, such as bisphenol A. Various types of studies can provide evidence to identify MDAs, yet a systematic method is needed to integrate these data to help to identify such hazards. Inspired by work to improve hazard identification of carcinogens using key characteristics (KCs), we developed 12 KCs of MDAs based on our knowledge of processes underlying metabolic diseases and the effects of their causal agents: (1) alters function of the endocrine pancreas; (2) impairs function of adipose tissue; (3) alters nervous system control of metabolic function; (4) promotes insulin resistance; (5) disrupts metabolic signalling pathways; (6) alters development and fate of metabolic cell types; (7) alters energy homeostasis; (8) causes inappropriate nutrient handling and partitioning; (9) promotes chronic inflammation and immune dysregulation in metabolic tissues; (10) disrupts gastrointestinal tract function; (11) induces cellular stress pathways; and (12) disrupts circadian rhythms. In this Consensus Statement, we present the logic that revealed the KCs of MDAs and highlight evidence that supports the identification of KCs. We use chemical, infectious and physical agents as examples to illustrate how the KCs can be used to organize and use mechanistic data to help to identify MDAs.

Figure 1 |. The key characteristics of metabolism disrupting agents.

Red circles are metabolism-disrupting agents (MDAs). The plus or minus symbol indicates that an MDA can increase or decrease processes and effects; the blocked lines indicate that an MDA can interfere with or block an effect, and the arrows indicate that an MDA can influence a process. KC1: an MDA can alter the function of the endocrine pancreas by, for example, interfering with glucagon and insulin secretion by pancreatic α-cells and β-cells, respectively, leading to disruption of steady-state glucose control. KC2: an MDA can impair the function of adipose tissue by, for example, impairing differentiation, resulting in an altered balance between white, beige and brown adipocytes and the development of a dysfunctional adipocyte with impaired glucose uptake. KC3: an MDA can alter nervous system control of metabolic function by, for example, acting on food intake and satiety neurons to stimulate food intake. KC4: an MDA can promote insulin resistance. KC5: an MDA can disrupt metabolic signalling pathways. KC6: an MDA can alter the development and fate of metabolic cell types by, for example, affecting proliferation, differentiation and apoptosis. KC7: an MDA can alter energy homeostasis by, for example, impairing thyroid hormone synthesis. KC8: an MDA can cause inappropriate nutrient handling and partitioning by, for example, impairing glucose storage as glycogen in the liver. KC9: an MDA can promote chronic inflammation and immune dysregulation in metabolic tissues by, for example, promoting metabolic inflammation in adipose tissue that increases the number of inflammatory M1 macrophages. KC10: an MDA can disrupt gastrointestinal tract function by, for example, disrupting and/or opening the tight junctions in the intestinal barrier. KC11: an MDA can induce cellular stress pathways by, for example, increasing the levels of reactive oxygen species (ROS) in adipocytes resulting in a net increase in triglyceride stores. KC12: an MDA can disrupt circadian rhythms by impairing the hypothalamic suprachiasmatic nucleus or nuclei clock leading to downstream effects on peripheral clocks and the induction of obesity and diabetes mellitus. AKT-phos, AKT phosphorylation; TCA, tricarboxylic acid cycle.