The study reports evidence that a premature surge of the hormone leptin in newborn mice of underfed mothers leads to a remodeling of key brain circuits that contributes to obesity in the animals later in life. Moreover, the researchers found that the early leptin surge alone was enough to cause the accelerated weight gain.
The findings offer one mechanism whereby metabolic disease can originate from early developmental experiences, the researchers said.
"Obesity has increased at an alarming rate in Western countries and is now a worldwide public health problem," said Shingo Fujii of the Kyoto University Graduate School of Medicine in Japan. "Genetic and environmental factors, such as a high-calorie diet, are thought to contribute to the prevalence of obesity.
"The present study suggests that a premature surge of leptin as a result of fetal undernourishment can alter energy regulation by the brain and contribute to developmental origins of health and disease."
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.
In the new study, mice born of mothers who ate 30 percent less than normal were small at birth and had less fat. However, the undernourished newborns caught up with normal mice after ten days and, when fed a high-fat diet, developed pronounced weight gain and increased leptin levels compared to normal mice on the same diet.
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," 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 suggest that the leptin surge may be a target for therapeutic intervention in the developmental origins of health and disease, the researchers said.
cellmetabolism/