OBESITY AND INSULIN-RESISTANCE IN HUMAN GROWTH-HORMONE TRANSGENIC RATS

A line of transgenic rats (heterozygotes) carrying a chimeric gene com prising a regulatory portion of murine whey acidic protein and a struc tural portion of human GH (hGH) genes developed severe obesity with ag e. To characterize physiological mechanisms that lead to fat accumulat ion, an array of parameters related to obesity were studied. Blood hGH levels were continuously low, endogenous rat GH secretion was suppres sed, and the pulsatility in peripheral GH levels was absent. Plasma gl ucose, insulin, triglyceride, and FFA levels in the male transgenic ra ts significantly exceeded those in nontransgenic littermates at 12 and 17 weeks, but not at 7 weeks, of age. All symptoms except hyperlipide mia were restored to normal by treatment with an antidiabetic agent, t hiazolidinedione (troglitazone), for 1 week from 17 weeks of age. As p henotypic expression of obesity was already evident before aberration of physiological parameters, it was assumed that animals had a conditi on in which obesity or hyperlipidemia caused hyperinsulinemia. Gene ex pression and enzymatic activity of lipoprotein lipase in the adipose t issue in the transgenic rats were not different from those in normal r ats. In contrast, the gene expression level of glycerol-3-phosphodehyd rogenase was markedly elevated, suggesting that glycerol synthesis was much enhanced in the adipocytes of the transgenic rats. In an ip gluc ose tolerance test, the transgenic rats were not hyperglycemic at 7 we eks of age; however, the animal became hyperglycemic at 15-17 weeks of age. Finally, treatment with recombinant hGH for 1 week to produce pu lsatile secretion reduced the size of epididymal and kidney fat pads a nd restored normal weight gain. These observations suggest that contin uously low peripheral GH levels with the lack of pulsatile secretion r esulted in obesity and noninsulin-dependent diabetes mellitus.