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Abstract
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.
Highlights
Modulation of adipocyte lipolysis represents an attractive approach to treat metabolic diseases
We found that adipocyte-specific hormonesensitive lipase (HSL) knockout (AHKO) mice progressively develop a partial lipodystrophy despite reduced lipolytic activity
Inhibition of adipocyte lipolysis has been demonstrated in numerous studies to counteract obesity and obesity-related disorders such as insulin resistance, type 2 diabetes, and nonalcoholic fatty liver disease[6,9,11]
Summary
Modulation of adipocyte lipolysis represents an attractive approach to treat metabolic diseases. 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. Adipocytes evolved to store large amounts of fatty acids in form of energy dense triglycerides and to release them upon energy demand. Besides their function as systemic energy substrates, fatty acids serve as building blocks for cellular membranes, signaling molecules, and key mediators of various cellular processes. Diglycerides, and monoglycerides, HSL hydrolyzes cholesteryl esters and retinyl esters, representing the main hydrolase for diglycerides, cholesteryl esters, and retinyl esters in adipose tissue[3,4,5]
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