Impaired glucose and lipid metabolism in ageing aryl hydrocarbon receptor deficient mice

Abstract

Disturbed homeostasis of glucose and lipid metabolism are dominant features of the so-called metabolic syndrome (MetS) and can increase the risk for the development of type 2 diabetes (T2D), a severe metabolic disease. T2D prevalence increases with age. The aryl hydrocarbon receptor (AHR) is a sensor of small molecules including dietary components. AHR has been identified as potential regulator of glucose homeostasis and lipid metabolism. Epidemiologically, exposure to xenobiotic AHR ligands such as polycyclic aromatic hydrocarbons is linked to T2D. We assess here the potential role of the AHR in disturbances of glucose and lipid metabolism in young (age 2-5 months) and old (age > 1,5 years) AHR-deficient (AHR KO) mice. Fasted young wildtype (WT) and AHR-KO mice displayed similar blood glucose kinetics after challenge with intra-peritoneal glucose injection. However, old AHR-KO mice showed lower tolerance than WT to i.p. administered glucose, i.e. glucose levels rose higher and returned more slowly to normal levels. Old mice had overall higher insulin levels than young mice, and old AHR-KO had a somewhat disturbed insulin kinetic in the serum after glucose challenge. Surprisingly, young AHR-KO mice had significantly lower triglycerides, cholesterol, high density lipoprotein values than WT, i.e., a dyslipidemic profile. With ageing, AHR-KO and WT mice did not differ in these lipid levels, except for slightly reduced levels of triglycerides and cholesterol. In conclusion, our findings in AHR KO mice suggest that AHR expression is relevant for the maintenance of glucose and lipid homeostasis in old mice.

Keywords: AHR; diet; dyslipidemia; metabolic syndrome; senescence.

Table 1. Lipids in serum^a

Figure 1. Glucose levels in fasted young and old WT and AHR-KO mice

WT (black bars) and AHR-KO (white bars) mice were fasted for 15 hours and then their blood glucose levels were measured. Mice were < 4 months (young) or > 15 months (old) of age. Student´s t-test *** P < 0.001; * P < 0.05. N = 4 (young mice) or 10-12 (old mice). Means +/- SD

Figure 2. Kinetics of blood glucose levels in young and old mice after GTT

C57BL/6 wildtype (black squares) and AHR-KO mice (white squares) were injected i.p with 2 g glucose/kg body weight and their blood glucose levels monitored for two hours at the indicated time points. (A) young mice (2-4 months), (B) old mice (18-24 months). Insert: Percent difference between the areas under the curve of WT versus AHR-KO for the young and old mice. Data shown are of two pooled independent experiments, N = 8 for young mice, N = 9 for old mice, each genotype. *P < 0.05; **P < 0.001

Figure 3. Insulin levels in old mice after GTT

C57BL/6 wildtype and AHR-KO mice were injected i.p. with 2 g glucose/kg body weight and insulin levels were monitored for up to two hours at the indicated time points. AHR-KO (white squares), WT (black circles). Differences in insulin levels between WT and AHR-KO are not statistically significant. (A) young mice, (B) old mice.

Figure 4. Lipid profile of young WT and AHR-KO

Serum lipid measurements of postprandial young WT and AHR-KO mice. TG: Triglycerides; Chol: cholesterol; HDL-C: High density lipoprotein; LDL-C: low density lipoprotein. N = 10 (WT, black bars) and 10 (AHR-KO, white bars), partly pooled for measurement. *P < 0.05, ***P < 0.0001; Insert: Body weight of young (1,2) and old (3,4) WT (black bars) or AHR-KO (white bars).