Surviving Starvation

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Starvation is a major cause of death in the world, killing more than 6 million children each year. Throughout evolution famine has been a constant threat to all animal species. As a result, evolution has selected for powerful mechanisms to maintain life even under conditions in which nutrients are severely limited. When body fat disappears, it is essential that the body maintain levels of plasma glucose that are sufficient to nourish the brain. The famous French scientist Claude Bernard was the first to call attention to this compensation with his famous quotation: "La fixité du milieu intérieur est la condition d'une vie libre et indépendante"

Recently, our laboratory found that a peptide hormone, ghrelin, is essential to the survival of chronically starved mice. Ghrelin was discovered in 1999 by Kojima and Kangawa in Japan. It is a peptide of 28 amino acids that has a unique modification, namely, an 8 carbon fatty acid, octanoate, attached in thioester linkage to a serine at position three. The octanoate modification is essential for ghrelin activity, and it is conserved in all vertebrate species.

Most ghrelin is produced primarily in the stomach. Its concentration in plasma rises steeply before meals, and it declines dramatically following eating. Administration of excess ghrelin to rodents and humans increases food intake. Itwas therefore postulated that ghrelin provides the signal that makes animals hungry prior to meals. This hypothesis was disproven when the gene for ghrelin and its receptor were eliminated in mice through homologous recombination. When deprived of food, the ghrelin-deficient mice became just as hungry as wild-type mice. Moreover, when fed a high-calorie diet the ghrelin-deficient mice became just as obese as wild-type mice.

Ghrelin was discovered because of its ability to release growth hormone from pituitary cells. Nevertheless, ghrelin-deficient mice grew normally and had no signs of growth hormone deficiency. Therefore, the true function of ghrelin was an enigma.

Our laboratory became interested in ghrelin because of the octanoate modification. Ghrelin is the only animal protein that is known to be modified by an 8 carbon fatty acid. We identified the unique enzyme that is responsible for the attachment of octanoate to ghrelin. We called the enzyme Ghrelin O-Acyltransferase(GOAT).

We eliminated the gene for GOAT in mice through homologous recombination. The GOAT-deficient mice produced no ghrelin. However, just like the ghrelin-deficient mice they grew normally, ate normally and gained weight normally on a high fat diet.

To search for another function for ghrelin, we subjected our GOAT-knockout mice to severe calorie restriction in a protocol that reproduces the effects of famine. The mice were fed only 40% of the calories that they would normally consume each day. After three days on this diet, the wild-type and GOAT-knockout mice both lost 80% of their body fat and 30% of their body weight. In both strains the fasting blood glucose level declined to the range of 60 mg/dL. Over the succeeding four days, the wild type mice maintained blood glucose above 40 mg/dL, and they showed normal physical activity. On the other hand, the GOAT-knockout mice exhibited a progressive fall in their fasting glucose levels. By day seven the blood glucose levels had fallen to the range of 20 mg/dL, and the animals began to die.

In wild-type mice, the calorie restriction led to an increase in plasma ghrelin levels that was progressive over seven days. Plasma growth hormone levels also rose markedly. These increases did not occur in the GOAT-knockout mice. Infusion of ghrelin or growth hormone prevented the fall in blood sugar in the GOAT-knockout mice.

Profound hypoglycemia in the GOAT-knockout mice was associated with reductions in plasma lactate levels and a reduced synthesis of glucose by the liver. Infusion of lactate restored glucose production and plasma glucose rose. We conclude that ghrelin is essential during famine to maintain viable levels of blood sugar. Ghrelin acts by causing major increases in growth hormone. The growth hormone maintains production of lactate that is sufficient to support normal glucose production. Ghrelin is therefore an essential hormone in the resistance of mice to chronic starvation.