Molecular and cellular actions of a structural domain of human growth hormone (AOD9401) on lipid metabolism in Zucker fatty rats

A lipolytic domain (AOD9401) of human growth hormone (hGH) which resides in the carboxyl terminus of the molecule and contains the amino acid residues 177-191, has been synthesized using solid-phase peptide synthesis techniqu es. AOD9101 stimulated hormone-sensitive lipase and inhibited acetyl coenzy me A carboxylase (acetyl CoA carboxylase) in isolated rat adipose tissues, in a similar manner to the actions of the intact hGH molecule. The syntheti c lipolytic domain mimicked the effect of the intact growth hormone on diac ylglycerol release in adipocytes. Chronic treatment of obese Zucker rats wi th AOD9401 for 20 days reduced the body weight gain of the animals, and the average cell size of the adipocytes of the treated animals decreased from 110 to 80 mum in diameter. Unlike hGH. synthetic AOD9401 did not induce ins ulin resistance or glucose intolerance in the laboratory animals after chro nic treatment. The results suggest that AOD9401 has the potential to be dev eloped into a therapeutic agent for the control of obesity.