Background & Aims Non‐alcoholic fatty liver disease (NAFLD) is a major health problem and occurs frequently in the context of metabolic syndrome and type 2 diabetes mellitus. Hepatocyte‐specific Pten‐deficiency in mice was shown previously to result in hepatic steatosis due to hyperactivated AKT2. However, the role of peripheral insulin‐sensitive tissues on PTEN‐ and AKT2‐dependent accumulation of hepatic lipids has not been addressed. Methods Effects of systemically perturbed PTEN/AKT2 signalling on hepatic lipid content were studied in Pten‐haplodeficient (Pten+/−/Akt2+/+) mice and Pten‐haplodeficient mice lacking Akt2 (Pten+/−/Akt2−/−). The liver and skeletal muscle were characterized by histology and/or analysis of insulin signalling. To assess the effects of AKT2 activity in skeletal muscle on hepatic lipid content, AKT2 mutants were expressed in skeletal muscle of Pten+/+/Akt2+/+ and Pten+/−/Akt2+/+ mice using adeno‐associated virus 8. Results Pten+/−/Akt2+/+ mice were found to have a more than 2‐fold reduction in hepatic lipid content, at a level similar to that observed in Pten+/−/Akt2−/− mice. Insulin signalling in the livers of Pten+/−/Akt2+/+ mice was enhanced, indicating that extrahepatic factors prevent lipid accumulation. The skeletal muscle of Pten+/−/Akt2+/+ mice also showed enhanced insulin signalling. Skeletal muscle‐specific expression of constitutively active AKT2 reduced hepatic lipid content in Pten+/+/Akt2+/+ mice, and dominant negative AKT2 led to an increase in accumulation of hepatic lipids in both Pten+/+/Akt2+/+ and Pten+/−/Akt2+/+ mice. Conclusion Our results demonstrate that AKT2 activity in skeletal muscle critically affects lipid accumulation in the livers of Pten+/+/Akt2+/+ and Pten+/−/Akt2+/+ mice, and emphasize the role of skeletal muscle in the pathology of NAFLD.