Pharmacological Inhibition of Hormone Sensitive Lipase (HSL) Improves Lipid and Glucose Homeostasis in the Obese Zucker Rat.

Fledelius, Christian; Vinterby, Aase; Damgaard, Jesper; De Jong, Johannes C.; Sturis, Jeppe; Jacobsen, Poul

Elevation of plasma free fatty acids (FFA), especially when it is postprandial, is believed to be causally linked to insulin resistance and the development of the metabolic syndrome. Inhibition of lipolysis in adipose tissue may provide a mechanism to decrease plasma FFA, thereby improving insulin sensitivity. The enzyme hormone sensitive lipase (HSL) is an important regulator of FFA and glycerol release from adipocyte lipid stores. In this study we investigated the chronic effects of treatment with the HSL inhibitor NNC0079-0000-0079 (76-0079) on lipid and glucose metabolism in the obese Zucker rat, a non-diabetic animal model for the metabolic syndrome. Six-week-old male obese Zucker rats were treated p.o. with vehicle or 760079 (30 mg/kg), a highly selective inhibitor of HSL, twice daily for ten weeks. The rats had free access to food and water during the study. Blood was collected and an oral glucose tolerance test (OGTT) was performed at baseline and at the end of study for determination of clinical parameters related to lipid and glucose homeostasis. The insulin/glucose ratio determined using area-under-the-curve estimates derived from the OGTT profiles was used as an index of insulin resistance. Both groups developed severe insulin resistance, dyslipidemia, and obesity during the study. Compared with vehicle, however, 76-0079 significantly improved plasma lipids (FFA 24%,↓ ; TG 23%↓ HDL-C 23%↑ TG/HDL-C 38%↓), glucose homeostasis (HbA 1c 7%↓), and the degree of insulin resistance (39%↓). Body weight and glucose tolerance were similar in both groups at the end of study. To our knowledge, this is the first report published investigating the pharmacological effects of chronic HSL inhibition on lipid and glucose metabolism in an animal model. We have shown that treatment with the HSL inhibitor 76-0079 improves lipid and glucose metabolism in the obese Zucker rat. Taken together, these data support a connection between adipose tissue lipolysis and dyslipidemia, glucose homeostasis, and insulin resistance.

LIPASES; FATTY acids; GLUCOSE; LIPOLYSIS; INSULIN resistance; ADIPOSE tissues; METABOLIC syndrome; LABORATORY rats

Diabetes, 2007, Vol 56, pA357

0012-1797

Academic Journal