Can Hypothalamic Inflammation and Leptin Resistance be Reversed?

A new study by yours truly begins to address the key question: can hypothalamic inflammation and leptin resistance be reversed?

Leptin is the primary hormonal regulator of body fatness in the human body (1).  Secreted by fat tissue, it acts in many places in the body, but its most important effects on body weight occur via the brain, and particularly a brain region called the hypothalamus.  The hypothalamus is responsible for keeping certain physiological variables within the optimal range, including blood pressure, body temperature, and body fatness.

In obesity, the brain loses its sensitivity to leptin, and this causes the body to begin 'defending' a higher level of body fatness, analogous to how a person with a fever 'defends' a higher body temperature (1).  Once a person has become obese, it's difficult to return to true leanness because this system vigorously opposes major fat loss.  Leptin resistance makes fat loss more difficult.

In rodent models, leptin resistance is caused at least in part by inflammatory signaling in the hypothalamus.  We can observe this in multiple ways, but one common way is to look at the appearance of specific cells in the brain that change number, size, and shape when inflammation is present (2).  These cells are called microglia and astrocytes.  In addition to the work in rodents, we've published preliminary evidence that these same inflammatory changes occur in the hypothalamus of obese humans (2).

A key question is whether or not these inflammatory changes can be reversed.  Is a person with leptin resistance doomed to have it forever, undermining fat loss efforts for the rest of his or her life?  Or can it be corrected, possibly allowing easier and more sustainable fat loss?  We just published a study in Endocrinology that begins to answer this question, using a mouse model of dietary obesity (3).  I'm co-first author of this study along with my colleague Kathryn Berkseth, MD.  My former mentor Mike Schwartz, MD is senior author.

The Study


We divided the mice into three groups:

1. CHOW.  This group received standard unrefined rodent food for 5 months.  This is a diet composed primarily of unrefined corn and soybeans, with a little bit of added fat, meat, and micronutrients.  Rodents do well on this diet, particularly if they're encouraged to exercise (which they weren't in our study).
2. HFD.  This group received a refined high-fat diet for 5 months.  This is the same diet many research groups use to produce dietary obesity.  Most of its calories come from lard.
3. HFD-CHOW.  This group received the refined high-fat diet for 4 months, then was switched to unrefined chow for an additional month.

Each mouse had unlimited access to its assigned diet at all times.  We periodically weighed each mouse and measured its fat mass and lean mass.  At the end of the 5-month period, we collected brains and looked for evidence of the cellular changes that indicate inflammation.  We also used MRI to attempt to measure signs of brain inflammation non-invasively.

Results

What we found is quite remarkable.  The HFD group rapidly became obese, achieving a five-fold higher fat mass than the CHOW group.  However, when we switched the HFD-CHOW group back to the unrefined chow diet for one month, the mice lost nearly all of their excess fat mass!  It was a remarkable physical transformation in just four short weeks.  We were expecting fat loss, but not to that extent.

When we examined their brains, we found that the inflammatory changes in the hypothalamus were essentially gone in the HFD-CHOW group.  Microglia and astrocytes had returned to their resting state.  Although we didn't directly test leptin sensitivity (for practical reasons), it was likely restored since body fatness normalized and hypothalamic inflammation disappeared.

Unfortunately, the MRI arm of the study didn't work out as well as we had hoped.  MRI was able to detect an increase in inflammatory changes in the HFD group, as previously published, but not reversal in the HFD-CHOW group.  The sensitivity of this technique is currently much lower than looking at the hypothalamus under a microscope.  Our collaborators Ellen Schur, MD, and Joshua Thaler, MD, PhD, are continuing to work on improving it.

Interpretation

Our study shows it's possible to reverse hypothalamic inflammation in mice and cause a nearly complete reversal of obesity, using diet alone and without imposing calorie restriction*.  This raises the possibility that the same could be true in humans.  Since our study was conducted in mice, and under highly controlled conditions, it remains unclear how relevant our findings will be to humans.  However, it provides a rationale for further study.

Dietary fat loss strategies typically have limited effectiveness in humans.  We think this is due primarily to two factors: 1) limited adherence to the weight loss diet, and 2) opposition to fat loss by the brain/body, particularly the leptin system.

The cool thing about rodent studies is that we can exert complete control over what the animals eat.  This is a major difference between animal weight loss studies and most human weight loss studies.  Humans like the food we like, and it's tough to change habits.  In our experiment, we were able to completely restrict the HFD-CHOW group to an unrefined healthy diet for the last month of the experiment.  This is impossible in free-living human studies, and difficult to achieve under tightly controlled conditions due to high costs and the difficulty of recruiting volunteers.  It allowed us to eliminate the diet adherence factor, focusing on the diet's effects on the system that opposes fat loss.

Our findings raise the possibility that leptin resistance could be reversible by diet in humans, under the right conditions.  I hope future research will pursue this important possibility.


* To clarify, calorie intake did decrease temporarily, but not because we restricted the amount of food available to the mice.  They chose to eat less.