Introduction: 

Adenosine is well known to inhibit lipolysis mediated by adenosine A1-receptors. However, it is yet unknown, whether this effect is functionally relevant under in vivo conditions and whether adenosine formed extracellularly by CD73 is involved. We therefore aimed to characterize the metabolic consequences of impaired extracellular adenosine formation by using CD73-deficient (CD73^-/-) mice.

Methods: 

Adult male C57/Bl6 wildtype (WT) and CD73^-/- mice at the age of 6–8 months were fed a standard chow diet and received tap water ad libitum. In vivo¹H MRI and ¹H/¹³C MRS at 9.4 T were used for analysis of all-over body fat content and composition as well as hepatic and myocellular lipid distribution.

Results: 

Analysis of fat-selective MR images from WT and CD73^-/- animals showed that the mutant is characterized by a distinctly altered fat pattern in particular within the subcutaneous areas. The classification of the subcutaneous fat in deep and superficial areas revealed that this was predominantly caused by a decrease in the superficial fat fraction (WT: 2.6±0.9 au; CD73^-/-: 1.4±0.5 au (n=10)) and only to a minor extent by alterations in the deep subcutaneous fat. However, no differences were found between the groups in the content of saturated, mono- and polyunsaturated fatty acids as well as the average fatty acid chain length. Similarly, no significant differences in intrahepatic lipid accumulation and composition between WT and the mutant were observed. To further characterize the consequences of CD73 deficiency on the lipid distribution we analyzed intra- and extramyocellular (IMCL + EMCL) lipid contents. Localized ¹H MR spectra acquired from the tibialis anterior (TA) muscle revealed an almost 50% increase in IMCL levels for the transgenic group, whereas EMCL levels were not significantly altered. Analysis of blood parameters unveiled significant increases in blood glucose and serum insulin levels (WT: 1.20±1.15 vs. 7.06±5.51 mg/l (CD73^-/-)) accompanied by increased serum free fatty acids and triglycerides in the mutant.

Conclusions: 

Taken together, these results indicate an enhanced lipolysis in mice lacking CD73 resulting in an accumulation of lipids in muscle cells. Increased insulin and glucose levels provide additional evidence for insulin resistance suggesting that impaired extracellular adenosine formation may be critically involved in associated diseases like diabetes mellitus and metabolic syndrome.