Neurogenesis can accelerate obesity

B9_Duy bylineIf you haven’t noticed it already, a popular theme in The Brain Wave is adult neurogenesis, the production of newborn neurons in the mature, adult brain. This process has been shown to occur in two well-known regions: the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus. It is believed the neural stem cells in the SVZ give rise to neurons that participate in olfactory processing (at least in rodent models), whereas stem cells in the SGZ produce neurons that are important for certain aspects of learning and memory.

Much of recent research into adult neural stem cells has heavily focused on these two brain regions, as it is believed that these are the only places where stem cells exist in the adult mammalian brain. As a result, one of the goals of neural stem cell research is to develop strategies to promote neural regeneration across the brain in the context of neurodegeneration, even in places that do not have stem cells. Indeed, several works have shown that following neuronal damage, these stem cells may be able to migrate from the SVZ toward the injury site in other areas, potentially giving rise to new neurons that replace lost neural tissue or provide support to neurons that are still functional.

While the SGZ and SVZ have classically been thought to be the brain’s primary neurogenic niches, recent works have pointed to the existence of adult neural stem cells outside of these areas. Unexpectedly, one of these areas has been suggested to be the hypothalamus, which plays a role in mediating the body’s overall homeostasis, including its metabolism and circadian rhythms.

Researchers began to suspect that adult neural stem cells might exist in the hypothalamus when they observed that certain hypothalamic cells, called tanycytes, express the same genes as neural stem cells in the SGZ and SVZ. They later went on to show that tanycytes are directly able to give rise to newborn neurons in the hypothalamus, albeit at pretty low rates. Based on the evidence that tanycytes can produce adult newborn neurons in the hypothalamus, we then turn to a more interesting question: What is the function of hypothalamic adult neurogenesis?

Given that the hypothalamus participates in controlling metabolism, it has been hypothesized that hypothalamic adult neurogenesis could play a role in weight regulation. To test this hypothesis, mice were subjected to a high-fat diet (colloquially termed the “McDonald’s diet”), which has previously been shown to increase weight gain in mice.

Interestingly, the mice that were on the McDonald’s diet showed significant increases in hypothalamic neurogenesis, approximately four times as much as the rate of neurogenesis in mice on a normal diet. Moreover, ablating neural stem cells by radiation methods prevented weight gain caused by the McDonald’s diet. In other words, this means that a high-fat diet might underlie the recent rise in obesity by dysregulating the normal function of neural stem cells in the hypothalamus, leading to uncontrollable weight gain.

Altogether, these research findings show that a population of neural stem cells exists in the adult hypothalamus, and that they seem to play a role in an organism’s weight regulation. In particular, it seems that too much neurogenesis could mess up the pre-existing neural circuitries in the hypothalamus and cause uncontrollable weight gain.

I propose two explanations as to how a high-fat diet might perturb neurogenesis to cause weight gain. First, a high-fat diet may lead to extensive hormonal changes that then perturb the regulatory pathways underpinning the regulation of hypothalamic neurogenesis. Without the regulatory networks that keep cell growth in check, neural stem cells may spiral out of control and give rise to excessive neurons.

Alternatively, a high-fat diet might also cause neuronal damage or stress, and the increase in neurogenesis might simply be the brain’s endogenous response to damaging conditions. Indeed, high-fat diets have been shown to induce oxidative stress and inflammation in the rat brain.

The discovery of neural stem cells in the hypothalamus have several important implications in stem cell biology and obesity. For a long time, it was widely believed that the adult, mature brain is not capable of producing new neurons. Therefore, neuronal loss from injury or neurodegenerative conditions is permanent.

The existence of adult neural stem cells and their ability to produce new neurons provides the hope that we may be able to develop stem cell-based strategies to promote functional recovery and regeneration in the brain following injury or in diseased states. In the context of the global obesity epidemic, targeting neural stem cells could be a novel therapeutic avenue for the prevention of weight gain.

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