Oral Subacute Exposure to Cadmium LOAEL Dose Induces Insulin Resistance and Impairment of the Hormonal and Metabolic Liver-Adipose Axis in Wistar Rats

Abstract

Cadmium is a nonessential transition metal considered one of the more hazardous environmental contaminants. The population is chronically exposed to this metal at low concentrations, designated as the LOAEL (lowest observable adverse effect level) dose. We aimed to investigate whether oral subacute exposure to cadmium LOAEL disrupts hormonal and metabolic effects of the liver-adipose axis in Wistar rats. Fifty male Wistar rats were separated into two groups: control (standard normocalorie diet + water free of cadmium) and cadmium (standard normocalorie diet + drinking water with 32.5 ppm CdCl₂). After 1 month, zoometry, a serum lipid panel, adipokines, and proinflammatory cytokines were evaluated. Tests of glucose and insulin tolerance (ITT) and insulin resistance were performed. Histological studies on structure, triglyceride distribution, and protein expression of the insulin pathway were performed in the liver and retroperitoneal adipose tissue. In both tissues, the cadmium, triglyceride, glycogen, and proinflammatory cytokine contents were also quantified. The cadmium group developed dyslipidemia, glucose intolerance, hyperinsulinemia, hyperleptinemia, inflammation, and selective insulin resistance in the liver and adipose tissue. In the liver, glycogen synthesis was diminished, while de novo lipogenesis increased, which was associated with low GSK3β-pS9 and strong expression of SREBP-1c. Dysfunctional adipose tissue was observed with hypertrophy and lipolysis, without changes in SREBP-1c expression and low glycogen synthesis. Both tissues accumulated cadmium and developed inflammation. In conclusion, oral subacute cadmium LOAEL dose exposure induces inflammation, insulin signaling modifications, an early insulin resistance stage (insensibility), and impairment of the hormonal and metabolic liver-adipose axis in Wistar rats.

Keywords: Adipocyte dysfunction; Adipokines; Cadmium; Insulin resistance; Liver-adipose axis; Metabolic disruption.