Obesity and elevated plasma leptin concentration in oMT1A-o growth hormonetransgenic mice

Objective: This study was undertaken to evaluate plasma leptin concentratio n in the regulatable ovine metallothionein-ovine growth hormone (oMT1a-oGH) transgenic (TG) mouse model of obesity. Research Methods and Procedures: Transgene stimulus (zinc) was provided at 21 days of age to male and female wild-type (WT) and TG mice. Plasma leptin concentrations were measured by radioimmunoassay at 42, 63, 84, and 105 da ys of age and from inactivated TG mice at 84 and 105 days. Results: WT and TG mice did not differ significantly in plasma leptin conce ntration at any of the ages examined (42, 63, 84, and 105 days), although f emales showed consistently higher plasma leptin concentrations than males r egardless of genotype throughout the duration of the study. Male and female TG mice in which the transgene was inactivated at 63 days had a 1.5-fold t o 3.5-fold increase in plasma leptin concentration over WT mice and continu ously activated TG mice at 84 and 105 days of age. The elevated plasma lept in concentration seen in the inactivated TG mice at 84 and 105 days of age reflects the >300% increase in white adipose tissue seen in this model and correlated with all adipose depot weights and overall body lipid at these l ater ages. When plasma leptin was expressed per gram of total body fat, the leptin adjusted for body lipid was significantly higher in WT mice than ei ther continuously activated TG or activated and then inactivated TC groups. Discussion: The inactivated TG mice in this study had higher plasma leptin levels with increasing total body adiposity, but the relative proportion of circulating leptin, on a total body lipid basis, was reduced when compared with the WT mice. This reduction was also observed in activated TG mice at the older ages. Although the absolute levels of circulating leptin were el evated in the inactivated TG animals, the amount of leptin produced per gra m of fat was lowered. With the inactivation of the transgene, the leptin re mained depressed after the removal of the elevated growth hormone. This rep resents a potential explanation for the ensuing hypertrophy of the fat depo ts and the abnormal phenotypic response of inactivated TG mice to elevated plasma leptin concentrations resulting in the development of obesity.