Adipotropic effects of heavy metals and their potential role in obesity

Abstract

Epidemiological studies demonstrated an association between heavy metal exposure and the incidence of obesity and metabolic syndrome. However, the particular effects of metal toxicity on adipose tissue functioning are unclear. Therefore, recent findings of direct influence of heavy metals (mercury, cadmium, and lead) and metalloid (arsenic) on adipose tissue physiology are discussed while considering existing gaps and contradictions. Here, we provide a literature review addressing adipose tissue as a potential target of heavy metal toxicity. Experimental in vivo studies demonstrated a significant influence of mercury, cadmium, lead, and arsenic exposure on body adiposity. In turn, in vitro experiments revealed both up- and downregulation of adipogenesis associated with aberrant expression of key adipogenic pathways, namely CCAAT/enhancer-binding protein (C/EBP) and peroxisome proliferator-activated receptor gamma (PPARγ). Comparison of the existing studies on the basis of dose and route of exposure demonstrated that the effects of heavy metal exposure on adipose tissue may be dose-dependent, varying from increased adipogenesis at low-dose exposure to inhibition of adipose tissue differentiation at higher doses. However, direct dose-response data are available in a single study only for arsenic. Nonetheless, both types of these effects, irrespective of their directionality, contribute significantly to metabolic disturbances due to dysregulated adipogenesis. Particularly, inhibition of adipocyte differentiation is known to reduce lipid-storage capacity of adipose tissue, leading to ectopic lipid accumulation. In contrast, metal-associated stimulation of adipogenesis may result in increased adipose tissue accumulation and obesity. However, further studies are required to reveal the particular dose- and species-dependent effects of heavy metal exposure on adipogenesis and adipose tissue functioning.

Keywords: adipocyte; adipogenesis; cadmium; lead; mercury.

Figure 1.. A schematic representation of biphasic adipogenic response to heavy metal exposure.

Briefly, low-dose exposure (left) may upregulate key adipogenic factors C/EBPs and PPARγ, thus promoting excessive adipogenesis and contributing to obesity and diabetes mellitus. In turn, “high-dose” metal exposure (right) may inhibit adipogenesis through downregulation of C/EBPs and PPARγ that may be associated with toxic effects of the metals because of pro-inflammatory and pro-oxidant activity. Under positive caloric balance, reduced adipogenic capacity results in increased ectopic lipid accumulation and lipotoxicity, including that in non-alcoholic fatty liver disease (NAFLD). However, in vivo and in vitro dose-response studies are required to clarify the association between toxic metal exposure and adipogenesis. C/EBP, CCAAT/enhancer-binding protein; PPARγ, peroxisome proliferator-activated receptor gamma.