Modulation of the effects of a cholesterol-supplemented high-fat diet by aryl hydrocarbon receptor (AHR) activation and/or tryptophan reduction in male mice

Abstract

<p>Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor whose role in energy metabolism is obscure. Most of its physiological ligands are derived from tryptophan (TRP). Here, fifty male C57BL/6JRccHsd mice were assigned to one of five feeding groups, control diet (CD), high-fat diet (HFD; 45 % of energy from fat), HFD with only 70 % of the regular TRP concentration (HFDtrp), HFD supplemented with a weakly toxic AHR agonist C2 (HFDc2), or HFDtrp with C2 (HFDtrp-c2). All diets contained 2 % cholesterol and were fed for 18 weeks. On weeks 14-16, the mice were tested for gas exchange and locomotor activity, and on weeks 15-17 for glucose tolerance (GTT) and insulin sensitivity (ITT). At termination, tissue samples were collected for biochemical and AI-assisted histological analyses. Body weight gain (BWG) was only 28-38 % higher in the HFD groups than in the CD group, but the HFD-fed mice accumulated 43-61 % more fat. Calorie intake was greater in the two low-TRP groups than in the two other HFD groups, while BWG remained similar. C2 induced <em>Cyp1a1</em> expression (an index of AHR activity) in all tissues examined and increased the ratio of micro-/macrosteatosis in the liver. The HFDs tended to reduce insulin sensitivity, CO₂ production, and the ability to respond appropriately to a low-temperature challenge. These findings suggest that the effects of AHR activity modulation on energy balance are strongly context-dependent. A sensitive response to long-term AHR activation appears to be elevated micro-/macrosteatosis ratio in the liver when exposed to HFD.</p>