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The Body Covers: The 2nd International Workshop on Adverse Drug Reactions and Lipodystrophy Coverage
The 2nd International Workshop on Adverse Drug Reactions and Lipodystrophy

September 14, 2000

  • Physiology of Lipoatrophy
    Marc Reitman
  • Lessons from Lipodystrophic Mice: A Vicious Cycle
    Iichiro Shimomura
  • Inborn and Induced Defects of the Mitochondrial Respiratory Chain
    Anthony Schapira

Physiology of Lipoatrophy

The sessions today were about fat, mitochondria and body composition. In the best Steinbeck tradition, we started with tales of mice and men. Marc Reitman from the National Institutes of Health (NIH), reviewed lipoatrophy and the physiology of fat. He explained that there are two types of fat: brown fat, used in thermogenesis (to maintain our temperature) and white fat, fundamentally used as energy storage. Small children have lots of brown fat, which they loose as they grow up. We also learned that adipose tissue is much more than a storage area for energy; it also has multiple endocrine functions, and is involved in the regulation of glucose metabolism.

Then he described transgenic mice, completely lacking adipose tissue. These mice were hyperinsulinemic and diabetic, which shows the close connection between lipids and glucose. The abnormalities in glucose metabolism were corrected after transplanting fat to these mice. This suggests that the lack of fat is the cause of the metabolic abnormalities associated with lipoatrophy, and not the other way around. He then tried to extrapolate about the therapeutic implications of these findings.

Lessons from Lipodystrophic Mice: A Vicious Cycle

The second speaker was Dr. Shimomura, who presented different mice. These mice were transgenic, expressing a truncated version of a protein (nSREBP-1c). They are a good model for a rare congenital disease called generalized lipodystrophy. These mice are hyperinsulinemic and diabetic, like many patients with lipodystrophy syndrome. The problems of this mouse reversed, or resolved significantly, with the administration of leptin (an important protein in the regulation of appetite and fat tissue).

Although these topics could seem obscure for some people, and the relationship with what we see in clinical practice distant (patients with lipodystrophy do have fat, the problem is that this fat is not in the right place), we can learn a great deal from mouse models like the ones above, teaching us about metabolic pathways and potential intervention sites so that we can improve the lipoatrophy and fat accumulation associated with chronic use of antiretroviral therapy. A clear understanding of the metabolic pathways involved is a sine qua non condition to develop useful interventions.

Inborn and Induced Defects of the Mitochondrial Respiratory Chain

The second session was about mitochondria. Dr. Shapira from the University College of London described the central role mitochondria play in the generation of ATP (the main source of energy of the cells). Mitochondria have their own DNA (which, curiously enough, comes only from the mother's side -- males do not "transmit" mitochondrial DNA to their children). Mitochondrial DNA is replicated by an enzyme called DNA polymerase gamma that can be inhibited by nucleoside analogs. Some research has suggested, without a lot of objective data to support it, that alterations of the mitochondrial DNA are responsible for some of the metabolic abnormalities associated with HAART, mainly the lipoatrophy we see so frequently.

There are some congenital diseases associated with mitochondrial mutations. Some of the clinical characteristics of these congenital disorders are similar to what we see in some patients treated chronically with antiretrovirals. Learning from these abnormalities might help us better understand what is happening in lipodystrophy.

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