Sci. Aging Knowl. Environ., 7 April 2004
Vol. 2004, Issue 14, p. nf37
[DOI: 10.1126/sageke.2004.14.nf37]


Composed by Leptin

Early in life, appetite hormone sets up circuitry that controls food intake during adulthood

Mary Beckman

Like many bands remembered for one popular song, leptin has been thought of as a one-hit wonder for suppressing appetite in adults. Now, research shows that the hormone plays another tune: It orchestrates the routing of key circuits in developing mouse brains that it uses to suppress appetite later in life. The results reveal how appetite-regulating brain regions develop and might explain why low-birth-weight babies often grow up to be obese.

When mammals eat, their bodies crank out leptin to tell them they're full. Many obese animals resist leptin's signal and keep stuffing their faces; furthermore, mice that lack the gene for the hormone fatten up. Leptin controls appetite by tingling certain neurons in the arcuate nucleus of the hypothalamus (ARH), the entryway to the adult brain's food-intake and energy-expenditure station. However, no one knew which molecular cues guide the creation of the ARH. Previous research revealed a leptin surge in mice just after they're born, but this surge doesn't dampen feasting, so researchers postulated that baby-mouse brains don't respond to leptin. Developmental neurobiologist Richard Simerly and colleagues at Oregon National Primate Research Center in Beaverton noticed that the leptin rush looked peculiarly like the behavior of sex hormones, which establish the neuronal wiring that they exploit in adults. So the scientists wondered whether leptin helps build the ARH.

To investigate, the researchers injected neuron-coloring dye into normal mice and those that lack leptin. By performing this procedure at different times after birth, they found that the animals normally complete construction of the ARH by 16 days of age. Rodents missing leptin, however, lacked most of the ARH neurons, suggesting that the hormone controls formation of the structure. To further test that idea, the team injected 4-day-old leptin-deficient baby mice with the purified molecule daily until the rodents were 12 days old. The mice formed nearly normal-looking ARHs. When the researchers gave mutant adult animals leptin, the creatures did not complete the ARH. These results indicate that the rodents need leptin during a critical early period to complete the brain structure.

The results suggest that developing animals that are undernourished--and therefore fail to produce normal amounts of leptin--are insensitive to the hormone as adults due to a poorly constructed ARH. This phenomenon might explain the obesity problems that frequently afflict low-birth-weight human babies later in life, says endocrinologist Michael Schwartz of the University of Washington School of Medicine in Seattle. Neurologist Cliff Saper of Harvard Medical School in Boston calls that speculation a "stretch" because other studies have shown that leptin-deficient mice respond to hormone treatment: They lose weight. But neuroendocrinologist Joel Elmquist of Harvard Medical School says that questions remain about why those animals respond and for how long and that future work is needed to settle those issues. "The big picture [that emerges from this study] is that changes in nutrition that lower leptin levels--through fasting or malnutrition--could have long-lasting effects into adulthood, such as in diabetes or obesity," says Elmquist. Understanding more about leptin's versatility might help keep it on the antifat charts.

April 7, 2004
  1. S. G. Bouret, S. Draper, R. B. Simerly, Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 304, 108-110 (2004). [Abstract/Free Full Text]
Citation: M. Beckman, Composed by Leptin. Sci. Aging Knowl. Environ. 2004 (14), nf37 (2004).

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