Abstract
Elevation of plasma free fatty acids has been linked with insulin resistance and diabetes. Inhibition of lipolysis may provide a mechanism to decrease plasma fatty acids, thereby improving insulin sensitivity. Hormone-sensitive lipase (HSL) is a critical enzyme involved in the hormonally regulated release of fatty acids and glycerol from adipocyte lipid stores, and its inhibition may thus improve insulin sensitivity and blood glucose handling in type 2 diabetes. In rat adipocytes, forskolin-activated lipolysis was blocked by in vitro addition of a potent and selective HSL inhibitor or by prior treatment of the animals themselves. Antilipolytic effects also were demonstrated in overnight-fasted mice, rats, and dogs with species-dependent effects on plasma free fatty acid levels but with similar reductions in plasma glycerol being observed in all species. Inhibition of HSL also reduced hyperglycemia in streptozotocin-induced diabetic rats. The data support a connection between adipose tissue lipolysis and plasma glucose levels.
Footnotes
-
Parts of this work have been presented previously as an abstract and poster at the 62nd Scientific Sessions of the American Diabetes Association [Claus TH, Lowe DB, Yang L, Burns M, Daly M, Keiper C, Qi N, Kupcho JR, Salhanick AI, Magnuson S, et al. (1992) An inhibitor of hormone sensitive lipase (HSL) reduces plasma FFA and glycerol levels, and prevents CL316,24-induced insulin secretion. Diabetes 51 (Suppl 2):A335; and Liang Y, Zhu J, Lemoine L, Salhanick AI, Lowe DB, and Clairmont KB (1992) Inhibition of hormone sensitive lipase (HSL) reduces glucagon-like peptide 1, CCK and acetylcholine stimulated insulin release from isolated rat pancreatic islets. Diabetes 51 (Suppl 2):A359–A360]; 2002 Jun 14–18; San Francisco, CA.
-
doi:10.1124/jpet.105.086926.
-
ABBREVIATIONS: FFA, free fatty acid; HSL, hormone-sensitive lipase; NEFA, nonesterified fatty acid; BAY, 4-isopropyl-3-methyl-2-{[(3S)-3-methylpiperidin-1-yl] carbonyl}isoxazol-5(2H)-one; MOPS, 4-morpholinepropanesulfonic acid; BAY G, 4-bromo-N,3-dimethyl-5-oxo-N-phenylisoxazol-2(5H)carboxamide; BAY P, N,N,3-trimethyl-5-oxo-4-(phenylthio)isoxazol-2(5H)carboxamide; GLP, glucagon-like peptide.
-
↵1 Current affiliation: Endocrine Therapeutics and Metabolic Disorders, Johnson and Johnson Pharmaceutical Research and Development, L.L.C., Raritan, NJ.
- Received March 28, 2005.
- Accepted September 8, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|