Researchers from the Medical College of Georgia have demonstrated in a new study that visceral fat is harmful to the brain because it allows the inflammatory cytokine interleukin-1 beta to heavily infiltrate the brain .
It is well established that excessive amounts of visceral fat tissue is detrimental to health in the long term. Excessive weight causes the microglia, immune cells that reside in the brain, to become dysfunctional and turn against us, unleashing a wave of inflammation that harms cognitive ability.
Cytokines are a large and loosely defined collection of small proteins that are critical in cell signalling, allowing cells to communicate and interact with each other. The interleukin-1 beta cytokine is produced by visceral fat, which then travels through the bloodstream, passes through the blood-brain barrier, and enters the brain, where it causes microglia to become dysfunctional and harms cognition.
Normally, the brain is not exposed to high levels of interleukin-1 beta, but the researchers found that visceral fat produces a chronically high level of this particular cytokine. Essentially, the more visceral fat present, the higher the production of interleukin-1 beta, so it is not hard to see why excessive visceral fat is harmful to health.
The chronic inflammation produced by visceral fat creates the formation of inflammasome complexes that aggravate the inflammation and escalate the immune response. The protein known as NLRP3 is a critical component of the inflammasome complex in visceral fat, and its presence causes the creation and release of interleukin-1 beta by fat cells.
The researchers already knew that the presence of excessive interleukin-1 beta is harmful in the body and suspected that it is also detrimental to the brain. In order to investigate its effect on the brain, the research team studied mice engineered to lack the NLRP3-producing gene and found that these NLRP3 knockout mice were resistant to obesity-induced inflammation of the brain and the resulting cognitive problems.
As a next step, they transplanted visceral fat tissue from obese mice and obese NLRP3 knockout mice into lean mice. The transplanted tissues from NLRP3 knockout mice had no significant effect at all. However, the transplanted tissue from normal obese mice elevated the presence of interleukin-1 beta in the brains of the lean mice and resulted in impaired cognition. These results show that transplanting visceral fat between mice causes the same harm as obesity.
Next, the researchers knocked out the receptor for interleukin-1 beta on microglia cells to confirm what was going on between the immune and visceral fat cells. Microglia have a surface receptor that reacts to the presence of interleukin-1 beta, and it is likely that their behavior is either helpful or harmful, depending on the signals they recieve.
Normally, microglia protect the brain by patrolling for pathogens and clearing out waste and dead cells. In addition to their role as soldiers and garbage gobblers, microglia also support brain health by forming and pruning the connections between neurons. However, under certain conditions, microglia can become dysfunctional and start attacking the brain, producing more inflammatory signals.
The researchers observed that the presence of interleukin-1 beta encouraged the microglia to wrap themselves around synapses, possibly harming them through gripping them too tight or potentially releasing molecules that disrupt the interactions between neurons. Macrophages can also wrap around synapses even when there is no interleukin-1 beta; however, in these cases they are known to secrete brain-derived neurotrophic factor, a secretion that is known to stimulate the synapses and strengthen connections.
Finally, the researchers found that the microglia were different between mice fed a high-fat diet compared to NLRP3 knockout mice. NLRP3 knockout mice microglia are more complex and capable of performing longer strings of actions compared to the microglia in mice on a high-fat diet, which are less complex and have a significant reduction in the amount of actions that they can perform in a series.
In order to determine influence on cognitive ability, the mice were assessed for their ability to navigate a water maze following a 12-week high- or low-fat diet. The researchers found that regular mice given a high-fat diet and the visceral fat transplant recipients with working NLRP3 both took longer to negotiate the maze. These mice also struggled to locate platforms under the water surface to walk upon as they traveled the maze; the mice with the interleukin-1 receptor knocked out in their macrophages had no issues finding the submerged platforms and were able to navigate the maze faster.
The mice that were fed a high-fat diet and had received visceral fat transplants were also noted to have weaker synapses between their neurons, which impaired their learning and memory processes. Mice that were given a high-fat diet but had NLRP3 knocked out did not suffer the same issues as mice eating a low-fat diet.
The researchers’ next step is to try to understand why the location of visceral fat causes such excessive inflammation compared to fat stored in other areas of the body. Their next aim is to study subcutaneous fat, which is deposited under the skin and does not appear to elicit the same highly inflammatory response that fat in the abdominal area does.
Induction of the inflammasome protein cryopyrin (NLRP3) in visceral adipose tissue (VAT) promotes release of the proinflammatory cytokine IL-1β in obesity. Although this mechanism contributes to peripheral metabolic dysfunction, effects on the brain remain unexplored. We investigated whether visceral adipose NLRP3 impairs cognition by activating microglial IL-1 receptor 1 (IL-1R1). After observing protection against obesity-induced neuroinflammation and cognitive impairment in NLRP3-KO mice, we transplanted VAT from obese WT or NLRP3-KO donors into lean recipient mice. Transplantation of VAT from a WT donor (TRANSWT) increased hippocampal IL-1β and impaired cognition, but VAT transplants from comparably obese NLRP3-KO donors (TRANSKO) had no effect. Visceral adipose NLRP3 was required for deficits in long-term potentiation (LTP) in transplant recipients, and LTP impairment in TRANSWT mice was IL-1 dependent. Flow cytometric and gene expression analyses revealed that VAT transplantation recapitulated the effects of obesity on microglial activation and IL-1β gene expression, and visualization of hippocampal microglia revealed similar effects in vivo. Inducible ablation of IL-1R1 in CX3CR1-expressing cells eliminated cognitive impairment in mice with dietary obesity and in transplant recipients and restored immunoquiescence in hippocampal microglia. These results indicate that visceral adipose NLRP3 impairs memory via IL-1–mediated microglial activation and suggest that NLRP3/IL-1β signaling may underlie correlations between visceral adiposity and cognitive impairment in humans.
Recently, we wrote about how our immune cells damage our brains during aging due to receiving too many inflammatory signals, and this new study is further confirmation of this. Once again, the microglia, which normally help to keep our brain healthy, become harmful and damage the very tissues that they are designed to protect due to the negative signaling of inflammation.
Given that chronic inflammation is a well-known driver of aging and the decline of health and that excessive visceral fat appears to aggravate the problem greatly, it makes sense to avoid excessive weight gain.
As humans, we evolved to walk, run, climb, and move, and we should listen to our evolutionary past to inform our present health measures. In a world where sitting and sedentary lifestyles are becoming more prevalent, it is more important than ever to take the time to be active and engage in physical activity to support continued health. With an effective price point of zero, exercise is pretty much the best thing you can do right now to combat the effects of aging and avoid the harmful effects of excessive visceral fat.
 Guo, D. H., Yamamoto, M., Hernandez, C. M., Khodadadi, H., Baban, B., & Stranahan, A. M. (2020). Visceral adipose NLRP3 impairs cognition in obesity via IL1R1 on Cx3cr1+ cells. The Journal of Clinical Investigation.