Abstract
Author SummaryIn periods of energy demand, mobilization of fat stores in mammals (i.e., adipose tissue lipolysis) is essential to provide energy in the form of fatty acids. In excess, however, fatty acids induce resistance to the action of insulin, which serves to regulate glucose metabolism in skeletal muscle and liver. Insulin resistance (or low insulin sensitivity) is believed to be a cornerstone of the complications of obesity such as type 2 diabetes and cardiovascular diseases. In this study, our clinical observation of natural variation in fat cell lipolysis in individuals reveals that a high lipolytic rate is associated with low insulin sensitivity. Furthermore, partial genetic and pharmacologic inhibition of hormone-sensitive lipase, one of the enzymes involved in the breakdown of white adipose tissue lipids, results in improvement of insulin sensitivity in mice without gain in body weight and fat mass. We undertake a series of mechanistic studies in mice and in human fat cells to show that blunted lipolytic capacity increases the synthesis of new fatty acids from glucose in fat cells, a pathway that has recently been shown by others to be a major determinant of whole body insulin sensitivity. In conclusion, partial inhibition of adipose tissue lipolysis is a plausible strategy in the treatment of obesity-related insulin resistance.
Highlights
White adipose tissue (WAT) is the main energy store of the body in mammals
Partial genetic and pharmacologic inhibition of hormone-sensitive lipase, one of the enzymes involved in the breakdown of white adipose tissue lipids, results in improvement of insulin sensitivity in mice without gain in body weight and fat mass
We undertake a series of mechanistic studies in mice and in human fat cells to show that blunted lipolytic capacity increases the synthesis of new fatty acids from glucose in fat cells, a pathway that has recently been shown by others to be a major determinant of whole body insulin sensitivity
Summary
White adipose tissue (WAT) is the main energy store of the body in mammals. Under the influence of insulin, WAT stores excess energy as triacylglycerols (TGs) in the lipid droplet of adipocytes. When energy is needed between meals or during physical exercise, WAT delivers fatty acids (FAs) to be oxidized in peripheral tissues. Lipolysis is the process by which stored TGs are released as nonesterified FA (NEFA) [1]. It involves different regulators such as lipases, co-lipases, and proteins that coat the lipid droplet. It is largely accepted that the enzymatic breakdown of TG is initiated by adipose triglyceride lipase
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