Advanced lipodystrophy reverses fatty liver in mice lacking adipocyte hormone-sensitive lipase

Modulation of adipocyte lipolysis represents an attractive approach to treat metabolic diseases. Lipolysis mainly depends on two enzymes: adipose triglyceride lipase and hormone-sensitive lipase (HSL). Here, we investigated the short- and long-term impact of adipocyte HSL on energy homeostasis using adipocyte-specific HSL knockout (AHKO) mice. AHKO mice fed high-fat-diet (HFD) progressively developed lipodystrophy accompanied by excessive hepatic lipid accumulation. The increased hepatic triglyceride deposition was due to induced de novo lipogenesis driven by increased fatty acid release from adipose tissue during refeeding related to defective insulin signaling in adipose tissue. Remarkably, the fatty liver of HFD-fed AHKO mice reversed with advanced age. The reversal of fatty liver coincided with a pronounced lipodystrophic phenotype leading to blunted lipolytic activity in adipose tissue. Overall, we demonstrate that impaired adipocyte HSL-mediated lipolysis affects systemic energy homeostasis in AHKO mice, whereby with older age, these mice reverse their fatty liver despite advanced lipodystrophy. Pajed et al. investigate the role of adipocyte hormone-sensitive lipase (HSL) in whole body energy homeostasis. They show that adipocyte-specific HSL Knockout (AHKO) mice fed high fat diet develop fatty liver. Interestingly, this phenotype reverses in aged AHKO mice, possibly due to blunted lipolytic activity in adipose tissue with pronounced lipodystrophy.