Being fat suppresses brain cell formation

A new study from Harvard Medical School provides more evidence that diet-induced obesity hurts the hypothalamus, the brain region that drives your body’s energy usage and eating behavior.

As discussed here previously, a December 2011 University of Washington study showed that the hypothalamus in fat people is harmed by gliosis, a process leading to scarring.

This damage is possibly due to inflammation caused by eating a diet containing excess fat and/or energy (calories).  Rodents develop this brain damage after being fed a high-fat diet, so causation by diet appears certain, at least for mice and rats, if not humans.

The Harvard researchers found that obesity in mice, whether due to a high-fat diet or leptin deficiency, also reduces neurogenesis (formation of new neurons) in the hypothalamus.

Ordinarily in adult mice, and perhaps humans, there is turnover of neurons (nerve cells) in the hypothalamus: new cells form, and old cells die.  This keeps the hypothalamus “young,” working well in controlling body weight.

How do new neurons arise? Stem cells in the hypothalamus differentiate into progenitor cells, which, through cell division, become more mature, eventually producing new neurons.

A simplified view of the multistep process leading to generation of neurons is that slowly proliferating multipotent stem cells give rise to highly proliferative progenitor cells that have limited capacity for self-renewal (neuroblasts) and ultimately give rise to neurons.

Study findings

1) Compared with chow-fed (control) mice, the mice fed a high-fat diet showed less neurogenesis in the hypothalamus, making fewer new neurons and retaining more old ones.

DIO [diet-induced obesity] leads to an expansion of the pool of hypothalamic neural stem-like cells while leading to a depletion of the pool of highly proliferative progenitor-like cells. This suggests that DIO inhibits the differentiation of stem-like cells into more proliferative progenitor-like cells and/or impairs the survival of these progenitor-like cells.

2) Leptin-deficient mice, which become fat because there’s not enough leptin around to tell their brains to stop eating after a meal, “also generated fewer new neurons, an observation that was explained in part by a loss of hypothalamic neural stem cells,” said the study’s authors.

Rescue by food restriction

The good news is that short-term calorie restriction rescues the neurogenesis that has been impaired by diet-induced obesity.

When the diet-induced obese mice were calorie restricted for four weeks to 70% of the intake of control mice, their body weight fell to similar levels as those of the control mice.

More importantly, calorie restriction restored the mice’s ability to grow form new hypothalamic neurons.

[T]he number of hypothalamic … neural stem-like cells [] was similar to that obtained with DIO control mice. In contrast, the number of actively proliferating progenitor-like cells was increased by 69% after calorie restriction ….

This may bode well for fat people who restrict calories.

It would be interesting to see what the effect of calorie restriction is, if any, on the degree of hypothalamic MRI abnormalities seen in humans in the University of Washington study.

In obese mice, the UW researchers found clear evidence of neuron loss and irreversible gliosis, i.e., scarring, in the hypothalamus. This damage was seen under the microscope and by immunohistochemistry.

In obese humans, the UW researchers found that part of the hypothalamus exhibited a mildly hyperintense T2-weighted signal, which indicates gliosis in these patients.  But in theory, this finding could also represent at least a component of reversible edema (increased water content) due to inflammation.

If there is a reversible component to this hypothalamic damage in humans, we can hope that some treatment, such as calorie restriction, may partially reverse the damage.

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