September 23, 2002
The first two talks of the meeting had to do with the hormone leptin. This hormone has proven to be successful in the treatment of some congenital lipodystrophies, so there is strong interest in its potential for the treatment of HIV-associated lipodystrophy.
Leptin is a 16-kilodalton protein made by fat. The main known function of this hormone is to regulate the amount of fat in the body. A person with a low leptin level experiences an increase in appetite and a slower metabolism. The overall result tends to be an increase in total fat mass in the body. There is a lot of evidence that leptin acts directly on the brain. For instance, some neurons express leptin receptors that "receive" the leptin signal. Mutations in these receptors explain severe mendelian obesity forms in humans. Leptin may also have a direct effect on peripheral tissues (T cells, pancreatic beta cells and skeletal muscle), but it seems that its most important metabolic effects are mediated through the brain.
When leptin was first discovered, the immediate thought was that it could be used as an anti-obesity drug because high levels of leptin decreased appetites and total fat. However, it was soon clear that that was too simplistic. Obese individuals have higher leptin levels than non-obese subjects, suggesting that there is some sort of insensitivity (known as "leptin resistance") to the hormone, not a lack of production of it (similar in a way to what happens with adult-onset diabetes). However, there are some lipodystrophic syndromes associated with low leptin levels in which the use of leptin has been very successful.
One of the interesting things about leptin is that it improves insulin action. Ob/ob mice, which are mice that do not make leptin, tend to normalize their insulin resistance and their diabetes once leptin is administered to them. Also, these mice experience improvements to their fatty livers when they get this drug. How leptin does this is not very clear and there are different possibilities, which are not necessarily mutually exclusive. Leptin reduces body weight, and this effect is much greater if leptin is administered directly to the brain (without changing serum leptin levels). Leptin also reduces lipid content in peripheral tissues, and by doing that leptin reduces insulin resistance. Also, again through unclear mechanisms, leptin administered to mice peripherally improves insulin sensitivity at a level that does not affect serum lipid levels or levels of hepatic fat.
Dr. Friedman presented some data about how leptin reduces fat content and which genes are involved in this process. His group used Afimetrix technology to look for genes regulated by leptin that would explain how its effects are mediated. Leptin regulates Stearoyl CoA desaturase (SCD-1), which is the rate-limiting enzyme in the biosynthesis of monosaturated fats and reduces the fat in peripheral tissues.
There are mice lacking in SCD-1 that, when crossed with the mice that do not produce leptin, give a phenotype that will correct several of the abnormalities seen in the mice that lack leptin (obesity and hyperlipidemia). Drugs that target SCD-1 might be useful in the future for the treatment of obesity and lipodystrophy.
Dr. Friedman's talk was a basic, but very good talk that was a perfect preamble to Dr. Gorden's discussion concerning the treatment of congenital lipodystrophic syndromes with leptin.
Congenital lipodystrophies are rare genetic diseases whose phenotype reminds all of us of HIV patients with lipodystrophy. The rationale to use leptin in this setting is clear: Some of these patients have extremely low levels of leptin.
Leptin treatment of patients with congenital lipodystrophies improved those metabolic abnormalities associated with their disease: triglycerides, markers of insulin resistance and diabetes and fat infiltration of the liver. These results were published this year in the New England Journal of Medicine.
So, the million dollar question is: can we use leptin to treat lipodystrophy associated with HIV or its treatment? The answer is: we still do not know. Studies using leptin for the treatment of lipodystrophy associated with HIV or its treatment have just begun. The main problem is that many HIV-infected patients with lipodystrophy have normal leptin levels, and leptin might not help a lot in that setting.
We will definitely hear more about this hormone and HIV in the near future when these studies are completed.
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