New Evidence Strengthens the Link Between Hypothalamic Injury, Obesity, and Insulin Resistance

Obesity involves changes in the function of brain regions that regulate body fatness and blood glucose, particularly a region called the hypothalamus.  My colleagues and I previously showed that obesity is associated with inflammation and injury of the hypothalamus in rodent models, and we also presented preliminary evidence that the same might be true in humans.  In our latest paper, we confirm this association, and show that hypothalamic injury is also associated with a marker of insulin resistance, independently of BMI.

Introduction


A key reason why it's so hard to lose fat is that the brain defends against fat loss by ramping up hunger and the seductiveness of food, and shutting down calorie expenditure (1).  Essentially, the brain of a person with obesity "wants" him to to be obese, and if he tries to lose fat, it mounts a starvation response designed to undermine the effort.  This is primarily coordinated in a brain region called the hypothalamus.

Why does this happen?  If we can answer this question, we might be able to understand how to prevent and treat obesity more effectively.  Naturally, a number of researchers are working on the problem.

Our research team (led by Josh Thaler and Mike Schwartz) previously showed that diet-induced obesity in rodents causes changes in the hypothalamus that suggest inflammation and injury (2).  We saw increases in the expression of inflammation-related genes, and changes in the size, shape, and number of specific brain cells called microglia and astrocytes.  These cells protect the brain against threats by activating themselves through a process called gliosis, and the changes we observed in fat rodents suggested that they were doing exactly that.

Yet ultimately we're interested in human obesity, not rat obesity.  The problem is that it's a lot harder to study human brains than rat brains, because humans don't usually want to give them up.  So we developed a method to look for gliosis in the brains of living people.  This relies on a technique called magnetic resonance imaging (MRI), which is sort of like a fancy X-ray that's better at examining soft tissues like the brain.

Using MRI, my colleagues Ellen Schur and Ken Maravilla looked for signs of the same cellular changes in the hypothalamus that we had observed in rodents (increased T2 relaxation time, to be precise).  And we found them.  The higher a person's body mass index (BMI), the more we tended to see MRI evidence of gliosis in their hypothalamus.  This suggested that people with obesity might also have hypothalamic inflammation and injury that makes it harder for them to lose weight-- and may have also contributed to their obesity in the first place.

Yet this experiment was preliminary, because the MRI data weren't specifically collected to look for hypothalamic injury.  Also, we were operating under the assumption that the MRI signal we were detecting was related to actual gliosis-- which we hadn't directly tested yet.  In our new study in the journal Obesity, we sought to address these concerns, and look for a possible role of gliosis in insulin resistance as well.

The study

In our latest study led by Ellen Schur and Ken Maravilla, we recruited 70 male and female volunteers, 18-50 years old, of all body weights (3).  We then put them in the MRI scanner and looked for evidence of gliosis in the hypothalamus.  We divided the group into thirds based on the degree of suspected gliosis, and compared the top third to the bottom third to see if they differed in other respects, like body weight and insulin levels.

We also took blood samples to measure blood glucose and insulin, and calculate an estimate of insulin resistance called HOMA-IR.

In a second experiment, we analyzed post-mortem human brain tissue both by MRI and by tissue staining, and compared the MRI gliosis signal to a direct microscopic measure of gliosis.  This was to make sure that our MRI signal was actually a good measure of gliosis.

The results

In the overall cohort, we were able to confirm that people with higher BMI also tend to show MRI evidence of gliosis in the hypthalamus.  This replicates our preliminary finding from the previous paper.

When comparing the top third of our cohort to the bottom third, we saw striking differences in two areas.  First, people in the top third of gliosis were much more likely to be obese (64 vs. 39 percent).  Second, their insulin levels were nearly twice as high as people in the bottom third of gliosis.  Similarly, HOMA-IR, an estimate of insulin resistance, was almost twice as high.

Surprisingly, higher insulin and HOMA-IR levels in the third with more gliosis was partially independent of their body weight.  In other words, the association between gliosis and insulin resistance couldn't be fully explained by the fact that they carried more fat.

In the second experiment, we found that there was a strong correlation between MRI evidence of gliosis and direct evidence of gliosis, as seen in stained human brain sections.

Discussion

Our new paper strengthens the evidence that MRI can be used to detect hypothalamic gliosis in humans, and that it is associated with obesity.  It also confirms that our MRI signal actually measures gliosis, and not something else.  And lastly, it suggests that hypothalamic gliosis is also associated with insulin resistance, regardless of whether or not a person is obese.

These findings have several interesting implications.  First of all, they give researchers a powerful new tool for studying the role of the brain in obesity.  We believe that hypothalamic inflammation and injury play a role in obesity, and now we can measure it in living humans.  This means we might get a real-time glimpse at a process that may be a fundamental driver of fat gain-- and see what factors, dietary or otherwise, promote or suppress it.  Previously, I co-led a study showing that hypothalamic gliosis and obesity are reversible in mice when we put them back on a strict whole-food, low-fat diet (4).  Could the same be true in humans?  Or could we achieve the same outcome with a different diet?

That said, it's too early to know exactly how useful this tool will be for research, and it's much too early to know whether it will be useful to individuals.  There is a lot of variability in the data, and the associations aren't tight enough that we can reliably categorize someone as lean or obese based on gliosis alone (r = 0.31).

Another interesting implication is that hypothalamic gliosis could be related to blood glucose regulation in addition to body fat regulation.  The hypothalamus plays a key role in regulating blood sugar, and the neurons that do so are intertwined with those that regulate body fatness.  So gliosis could be directly relevant to diabetes as well-- even among people who aren't obese.