Lipodystrophy could be caused by the effects of antiretroviral drugs on specific brain regions, according to a hypothesis presented by Dutch researchers in the November 22nd edition of The Lancet.
The group of doctors from Amsterdam and Leiden suggest that redistribution of body fat could be caused by the effects of antiretroviral drugs on the autonomic nervous system, the subconscious network of neurones that controls the activity of the organs and tissues.
They propose that HAART affects the brain regions controlling the amount of subcutaneous fat in opposite ways to the regions controlling the fat tissue around the internal organs.
Their hypothesis states that the drugs cause the ‘sympathetic’ component of the autonomic regions controlling the subcutaneous fat tissue to become more active than the ‘parasympathetic’ component. This leads to a loss of fat from beneath the skin. Conversely, the build-up of fat around the internal organs is a result of a greater increase in the activity of the ‘parasympathetic’ component of the regions controlling the visceral adipose tissue.
“We propose that HIV-1-associated adipose redistribution syndrome is mediated by the effects of antiretroviral treatment on the central nervous system” state the researchers, adding that it “could indicate a change in autonomic balance resulting in redistribution of adipose tissue.”
They argue that existing theories on lipodystrophy, such as disruption of fat cell differentiation and mitochondrial toxicity, do not account for the different ways in which the subcutaneous and visceral fat stores are affected. Their hypothesis, which remains to be tested, may offer an explanation.
The sympathetic and parasympathetic systems act in opposite directions to one another, and processes including heart rate, blood pressure and the rate of digestion are regulated by a balance between the two systems. The two systems are connected to different ‘autonomic nuclei’ in the brainstem: the neurones that form the parasympathetic system are controlled by the ‘dorsal motor nucleus of the vagal nerve’, whereas the sympathetic nervous system is under the control of a variety of areas including the ‘A1 region’.
The researchers have previously demonstrated that selective destruction of the dorsal motor nucleus of the vagal nerve in rats causes increases in insulin resistance, reductions in glucose and fatty acid uptake and an enhancement of the activity of fat-digesting enzymes. This suggests that activation of the parasympathetic nervous system stimulates fat accumulation. Conversely, activation of the sympathetic nervous system induces the breakdown of fat and the mobilisation of free fatty acids.
By tracing the pathway of the nerves from the adipose tissue to the brainstem, the authors have recently demonstrated that there is a clear anatomical separation between the brain cells that control the subcutaneous and visceral adipose tissues within the autonomic nuclei. This leads them to suggest that antiretroviral drugs may affect the activity of nerve connections to the subcutaneous and visceral fat stores differently and that this may account for the loss of fat from beneath the skin and its accumulation around the organs.
In addition to their animal studies, the group support their proposal with some circumstantial clinical evidence. Patients with lipodystrophy tend to have higher plasma levels of noradrenaline, the major neurotransmitter in the sympathetic nervous system, suggesting that alterations in this system may be involved in the redistribution of fat. Patients with HIV and AIDS also tend to exhibit general alterations in the activity of the autonomic nervous system, which may be due to the effects of antiretroviral treatment.
A problem for this hypothesis is how antiretroviral drugs access the brain regions comprising the autonomic nervous system, since most drugs and hormones are prevented from reaching the brain tissue by the blood-brain barrier. The researchers suggest that these drugs could enter at specific sites where this barrier is permeable to certain compounds. These include two regions (the ‘area postrema’ and the ‘arcuate nucleus of the hypothalamus’) that are connected to the parasympathetic regions of the brainstem. Damage to these areas by HAART may affect the activity of the autonomic nervous system, leading to changes in fat build-up or metabolism.
To support this, the researchers point out that detectable levels of amprenavir, saquinavir and ritonavir have been observed in the cerebrospinal fluid of patients. Furthermore, destruction of the arcuate nucleus of rats shortly after birth leads to obesity in adulthood, suggesting a link between damage to this brain region and abnormal fat accumulation.
To test their hypothesis, the researchers suggest that the penetration of antiretroviral drugs into the brain tissue must be confirmed in animal studies, particularly into the regions that control the sympathetic or parasympathetic nervous systems. Subsequently, they propose testing whether localised injections of antiretroviral drugs into these brain regions brings about body fat changes and increases in insulin resistance similar to those observed lipodystrophy. Discovery of this effect would suggest that antiretroviral drugs are likely to act on these brain regions to cause body-fat redistribution in man.
A major question surrounding the theory is whether the proposed effects on the autonomic nervous system are due to reversible changes in the activity of brain cells, or the irreversible death of these neurones. The researchers suggest that this could be addressed by analysing the brains of rats following antiretroviral treatment. By observing the anatomy of these regions under the microscope or by measuring their electrical and biochemical activity, they hope to assess the degree of loss of brain cells or alterations in their function following drug treatment. These findings could be complemented by nerve-tracing techniques to investigate how the connections between the adipose tissue and the brainstem change during antiretroviral therapy.
The investigators state that their hypothesis could eventually be tested in HIV-infected patients with lipodystrophy. One way in which they plan to do this is to sample the levels of neurotransmitters in the subcutaneous and visceral adipose tissue of patients. They point out, however, that sampling of neurotransmitter levels in the fat tissue surrounding the gut may be restricted on ethical grounds.
Fliers E et al. HIV-associated adipose redistribution syndrome as a selective autonomic neuropathy. The Lancet 362: 1758 – 1760, 2003.