P2Y6 depletion enhances metabolic activity and ameliorates outcome of high fat diet induced obesity in mice

J. Merz, P. Stachon, P. Albrecht, F. Ünal, S. von Garlen, A. Heidenreich, N. Hoppe, B. Duffner, C. Bode, A. Zirlik (Freiburg, Deutschland)

Basic Science
Date: 16.02.2017,
Time: 11:00 - 12:00

Objective: With 17.3 million deaths per year cardiovascular diseases are the major cause of death worldwide. A prolonged obese body composition is strongly related with a higher risk of cardiovascular disease (CVD) incidence and mortality. Extracellular nucleotides are known to modulate metabolic pathways such as glucose homeostasis, cholesterol homeostasis, and adipocyte differentiation. These extracellular nucleotides signal through purinergic receptors, e.g. P2Y6, which fine-tune metabolic processes providing a potential target in the treatment of obesity induced metabolic syndrome. We hypothesized a role of P2Y6 in the outcome of high-fat diet induced obesity.

Methods: P2Y6 deficient (ko) 8 week old male mice and C57Bl6/N wildtype (wt) mice were fed for 20 weeks a high-fat or normal diet. Metabolic activity was assessed by metabolic caging at week 17. After 20 weeks mice were euthanized and whole body composition analyzed by necropsy. Blood plasma was analyzed by enzyme-linked immunosorbent assay.

Results: We observed a decelerated gain of body weight in P2Y6 deficient animals (after 12 weeks wt: 45.4 ± 0.9g (n=13) and P2Y6 ko: 40.6 ± 1.0g (n=13), p=0.0022). After necropsy P2Y6 ko mice revealed reduced fat depositions (e.g. pericardial adipose tissue of P2Y6 ko mice: 58.3 ± 5.4mg (n=13) versus wt animals: 75.2 ± 4.8mg (n=9), p < 0.05). Brown adipose tissue was elevated in P2Y6 ko animals under HFD (P2Y6 ko: 380 ± 27.9mg (n=8) versus wt: 303.3 ± 23.2mg (n=10), p < 0.05). P2Y6 deficient mice have a higher O2 consumption (P2Y6 ko: 2666 ± 79ml/h/kg (n=6) versus wt: 2315 ± 62ml/h/kg (n=6), p=0.0059), increased CO2 exhalation (P2Y6 ko: 2006 ± 66ml/h/kg (n=6) versus wt: 1724 ± 44ml/h/kg (n=6), p=0.0051) and increased heat (P2Y6 ko: 12.64 ± 0.38kcal/h/kg (n=6) versus wt: 11.16 ± 0.42kcal/h/kg (n=6), p<0.05) but no difference in movement or food intake. Plasma cholesterol levels were decreased in P2Y6 ko animals (100.2 ± 28.6mg/dl (n=5)) compared to wt animals under HFD (219.5 ± 41.4mg/dl (n=3), p<0.05).

Conclusion: In conclusion our data showed a reduction of HFD induced fat deposition in P2Y6 ko mice due to an increased metabolic activity. These effects make P2Y6 a promising target for the treatment of obesity induced metabolic syndrome and prevention of CVDs.