Lifetime reproduction of giant transgenic mice: the energy stress paradigm

Abstract

Lifetime reproduction of female transgenic rat growth hormone (TRrGH) mice and their normal siblings was evaluated on a high-protein (38%) diet, a standard diet (23% protein), and the standard diet supplemented with sucrose cubes. Compared with those on the standard diet, normal mice fed the high-protein diet showed significant increases in litter size, number of litters, and lifetime fecundity. Number of litters and lifetime fecundity were also enhanced in normal mice fed sucrose. TRrGH mice showed no significant improvements in reproduction on the high-protein diet, but they were significantly smaller. Sucrose dramatically improved reproduction of TRrGH mice, with no reduction in mature mass. The percentage of fertile TRrGH mice increased from 45% on standard chow to 71% with sucrose. The number and size of litters of TRrGH mice also significantly increased with sucrose, mean lifetime fecundity doubling from 9 pups on standard food to 18 pups on sucrose. However, TRrGH mice did not attain the reproductive success of normal mice on any diet. These results suggest that TRrGH mice are energetically stressed by enforced channelling of energy into growth. An immense literature addresses infertility due to energy limitation and stress generally. We synthesize these aspects with growth hormone transgenesis to derive an integrated view of neuroendocrine energy regulation relevant to restoring fertility of transgenic GH animals.

Transgenic growth hormone mice exposed to lifetime constant illumination: gender-specific effects

“…Increased growth of TG females in LL was associated with improved reproduction and longevity. These results resemble those reported in studies of TG females fed sucrose supplements (Rollo et al , 1997b, suggesting that LL altered the energy balance of TG females. Possible mechanisms mediating these effects are discussed.…”

“…Similar results were obtained by supplementing the diet fed to TG females with sucrose (Rollo et al 1997b). Sucrose, however, also improved fertility of TG females (72% of TG females fed supplements having a litter compared with about 45% of TG females not fed supplements), whereas LL did not improve this indicator (43% fertile).…”

“…TG males are fertile but may have lower libido. Although TG females have few litters, pregnancy and maternal care are otherwise normal (Rollo et al 1997b; Bartke et al 1999).…”

“…Only females that lived a full lifetime specific to their genotype were analyzed (Rollo et al , 1997b. This ensured that lifetime reproduction was encompassed, since mice live for a considerable time after reproductive senescence.…”

“…This mainly involves more efficient conversion of food into tissue Rollo 1994, 1996;Rollo et al 1999a), although mass-specific feeding is also elevated in a specific size range (first documented here). TG mice express decreased longevity, low fertility, reduced physical activity, increased sleep, altered cognition, changes in feeding, and hypothermia (Rollo et al , 1997a(Rollo et al , 1997b(Rollo et al , 1999a(Rollo et al , 1999b(Rollo et al , 2004Bartke et al 1999;Hajdu et al 2002;Lemon et al 2003). Our guiding hypothesis has been that exaggerated allocation of resources to growth results in trade-offs with other functions mediated by relative energetic stress, a prediction of the "principle of allocation" (Rollo 1994).…”