The scientists from Kyoto University restricted the food supply of mice in the last half of gestation by 30 per cent. Their offspring weighed 17 per cent less than those from females given normal nutrition during the same period, they reported in yesterday's issue of Cell Metabolism.
However although the offspring rapidly grew to the weight of normal offspring, when fed a high-fat diet they developed pronounced weight gain and increased leptin levels compared to normal mice on the same diet.
Researchers say that the premature surge of the hormone leptin in these mice to help them catch up on growth leads to a remodeling of key brain circuits that contributes to obesity in the animals later in life.
Moreover, the early leptin surge alone was enough to cause accelerated weight gain.
The findings offer one mechanism whereby metabolic disease can originate from early developmental experiences, the researchers said.
Leptin is a hormone produced by fat that normally decreases food intake and increases energy expenditure. In many species, including humans, the hormone acts to stabilize weight and glucose balance through its effects on leptin receptors in a portion of the brain called the hypothalamus.
Earlier studies have found that mice lacking leptin show marked obesity that is restored following leptin treatment. However, obese animals often exhibit resistance to leptin's usual effects and high blood concentrations of the hormone.
Evidence has also suggested that a neonatal surge of leptin may play an important role in the formation of energy-regulating brain circuits in the hypothalamus.
The undernourished mice had lower body temperatures than normal mice, suggesting that the prenatal nutritional deficiency "programmed" them to conserve energy, the researchers said. During the catch-up growth period, the transient rise in leptin levels normally seen in newborns occurred six to eight days earlier in undernourished animals.
When the researchers mimicked that premature leptin surge by administering the hormone to normally fed mice, those animals also became prone to obesity upon eating a diet high in fat.
"Unexpectedly, normal offspring treated with leptin as newborns were indistinguishable from those that were undernourished before birth," researcher Shingo Fujii said. "Premature onset of leptin surge is thus causally related to pronounced obesity in undernourished offspring on a high-fat diet."
The researchers further demonstrated that the mice experiencing a premature surge of fat hormone exhibited resistance to administered leptin, with impaired transport of the hormone to the brain and abnormalities in the hypothalamic brain region that governs leptin response.
The findings demonstrate the importance of maternal nutrition.