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Obesity and Insulin Resistance in Human Growth Hormone Transgenic Rats¹

Department of Veterinary Physiology, Veterinary Medical Science, University of Tokyo (A.I., K.-T.C., Y.F., M.N., M.T.), 1–1-1 Yayoi, Bunkyo-ku, Tokyo 113; and the Department of Anatomy, Osaka Prefecture University College of Agriculture (Y.M., F.S.), 1-1 Gakuen-cho, Sakai, Osaka 591, Japan

Address all correspondence and requests for reprints to: Dr. Michio Takahashi, Department of Veterinary Physiology, Veterinary Medical Science, University of Tokyo, 1–1-1 Yayoi, Bunkyo-ku, Tokyo 113, Japan. E-mail: amtaka{at}hongo.ecc.u-tokyo.ac.jp

A line of transgenic rats (heterozygotes) carrying a chimeric gene comprising a regulatory portion of murine whey acidic protein and a structural portion of human GH (hGH) genes developed severe obesity with age. To characterize physiological mechanisms that lead to fat accumulation, an array of parameters related to obesity were studied. Blood hGH levels were continuously low, endogenous rat GH secretion was suppressed, and the pulsatility in peripheral GH levels was absent. Plasma glucose, insulin, triglyceride, and FFA levels in the male transgenic rats significantly exceeded those in nontransgenic littermates at 12 and 17 weeks, but not at 7 weeks, of age. All symptoms except hyperlipidemia were restored to normal by treatment with an antidiabetic agent, thiazolidinedione (troglitazone), for 1 week from 17 weeks of age. As phenotypic expression of obesity was already evident before aberration of physiological parameters, it was assumed that animals had a condition in which obesity or hyperlipidemia caused hyperinsulinemia. Gene expression and enzymatic activity of lipoprotein lipase in the adipose tissue in the transgenic rats were not different from those in normal rats. In contrast, the gene expression level of glycerol-3-phosphodehydrogenase was markedly elevated, suggesting that glycerol synthesis was much enhanced in the adipocytes of the transgenic rats. In an ip glucose tolerance test, the transgenic rats were not hyperglycemic at 7 weeks of age; however, the animal became hyperglycemic at 15–17 weeks of age. Finally, treatment with recombinant hGH for 1 week to produce pulsatile secretion reduced the size of epididymal and kidney fat pads and restored normal weight gain. These observations suggest that continuously low peripheral GH levels with the lack of pulsatile secretion resulted in obesity and noninsulin-dependent diabetes mellitus.

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