Leptin and biological basis for obesity — State of the Art Lecture

Presenter: Jeffrey Friedman (Howard Hughes Medical Institute and Rockefeller University)

This year’s (2011) State of the Art Lecture focused on leptin and the genetics of obesity. Obesity is one of the most inheritable traits at 0.8–0.9 (closer to 1.0, the more likely the trait is inheritable). For comparison, obesity is more likely to be inherited than diabetes, alcoholism, or heart disease. Only individual height (0.9) is more likely to be inherited than obesity. As such, there is likely to be a genetic explanation for obesity amongst the environmental and behavioral influences.

Leptin is a gene, whose correspondingly named protein product is produced by adipose tissue in a manner directly proportional to the amount of fat (fat mass) present. Leptin is a major molecule in the homeostatic mechanism that tells the brain how much to eat; more on that later on.

Dr. Friedman goes on to talk about the early days of linking obesity to genetic factors. Stephen O’Rahilly, a physician in the UK, noted a 4-year old child of 90 lbs who was pre-diabetic. He postulated that the young child had a deficiency in leptin — perhaps as a result of extensive consanguinity in the child’s family. As a result, the brain was unaware of the amount of fat mass in the child and resulted in uncontrollable eating. To prove this, he administered recombinant leptin and by the age of 6, the child had lost much of his weight and was no longer pre-diabetic.

Leptin levels tell the brain, specifically the neurons that control eating, when to stop caloric intake. The greater the fat mass, the more leptin produced and the greater the inhibitory signal to stop eating, unless there is a defect in either leptin production or leptin sensitivity in the brain. For example, patients with lipodystrophy have a congential loss of adipose tissue. As a result, leptin levels remain low and the patient continues to eat. In such patients, the ingested fat, while not stored as adipose tissue, is stored in other organs, namely the liver leading to hepatic steatosis. Such steatosis can be revered with the administration of recombinant leptin.

Dr. Friedman makes the case that adipose tissue is more than just fat — it is an endocrine organ that has a significant role in maintaining body weight.
Obesity is not a decreased leptin state. Obesity is more likely to be a condition in which there is a defect in leptin signaling, particularly in the brain. High doses of leptin (0.3 mg/kg weight/day) can result in greater than 5% weight reduction in about 35% of obese patients. Perhaps these high doses, which is difficult to administer pharmacologically, can overcome the signaling defect.

Finally, 80% of serum leptin is eliminated by the kidney. There is evidence that impaired kidney function prolongs the half-life of leptin. One wonders if this is an explanation for why ESRD patients, who have no renal function, becoming increasingly “malnourished” as they continue on renal replacement therapies.