Interaction of genetic and environmental programming of the leptin system and of obesity disposition

Possible adverse interactions between an usually inconspicuous genetic trai t and early environmental factors favoring the development of obesity were investigated in rats heterozygous for the leptin receptor defect "fatty"( f a). Pups were exposed to early postnatal overfeeding by reducing litter siz e from normally 10-12 to only 4. Rearing +/+ and +/fa pups from day 3 to 21 in small litters increased fat-free dry mass and body fat, but only in the latter did a significant interaction with genotype occur. Pronounced diffe rences in the responsiveness of +/+ and +/fa pups to "prophylactic" leptin treatment (from day 1 to 21) were observed, with +/fa females from small li tters being nearly as fat and unresponsive as previously reported for norma lly reared fa/fa pups. Clear heterozygous differences in total hypothalamic leptin binding, but no litter size effect, paralleling the differences in leptin responsiveness, were observed. By early postnatal overfeeding an usu ally inconspicuous genetic trait may thus become etiologic for the developm ent of obesity via physiological changes other than the decreased leptin bi nding characterizing the genetic defect.