Rethinking an inflammatory receptor's obesity connection

September 12, 2018, Agency for Science, Technology and Research (A*STAR), Singapore
Rethinking an inflammatory receptor’s obesity connection
A model of several TLR4 receptors within the mammalian plasma membrane. Credit: A*STAR Bioinformatics Institute

Toll-like receptor 4 (TLR4) is a protein that plays a vital role in the body's immune response by sensing the presence of infection. It has long been thought to also sense particular types of fats, which suggested a mechanism linking high-fat diets to the inflammation that is a feature of metabolic disease. However, new research by an international team has undermined that link by showing that dietary fatty acids cannot interact directly with TLR4.

Peter Bond's team, from the A*STAR Bioinformatics Institute, has been studying TLR4 for a long time, looking at how the receptor interacts with a lipid molecule found on the surface of bacteria, called a lipopolysaccharide, and how this can lead to sepsis; a potentially deadly immune over-reaction to infection.

It was believed that dietary fatty acids could also bind to TLR4, and that this was the mechanism underlying the increased associated with and . However, Bond was skeptical of this.

"It made no sense to me that this receptor would be activated by such , because they look very different from bacterial lipids," he says. He was also puzzled as to why such a major component of our diets would trigger this potentially dangerous inflammatory reaction.

He and colleagues hypothesized that TLR4 didn't interact with fatty acids directly, but instead indirectly influenced fat-induced inflammation. To prove this they first had to demonstrate that fatty acids couldn't bind and activate TLR4.

They did this by modelling the possible ways that fatty acids—in particular, palmitate—might bind to the receptor and activate it. The team found that no model allowed palmitate to bind to TLR4 in a stable fashion.

Meanwhile, collaborators Graeme Lancaster from the Baker Heart and Diabetes Institute, Mark Febbraio from the Garvan Institute, and colleagues in Australia were conducting wet laboratory experiments to explore possible interactions between palmitate and TLR4. As with the computer simulations, they found that palmitate was unable to activate TLR4. Subsequent research by the team confirmed the idea that TLR4 influenced fat-induced inflammation indirectly.

The team's theory is that a diet high in fats could change the bacterial populations in the gut, and that this would expose TLR4 to more bacterial components, such as lipopolysaccharides, which in turn could make cells overly sensitive to fatty acids in obese adipose tissue. "The exposure of TLR4 to bacterial components is priming the cells to alter their metabolism and be activated in other ways by these ," Bond says. "The bacteria themselves are over-activating the immune system and making it more sensitive to fats."

Explore further: An immune regulator of addiction

More information: Graeme I. Lancaster et al. Evidence that TLR4 Is Not a Receptor for Saturated Fatty Acids but Mediates Lipid-Induced Inflammation by Reprogramming Macrophage Metabolism, Cell Metabolism (2018). DOI: 10.1016/j.cmet.2018.03.014

Related Stories

An immune regulator of addiction

August 7, 2017
Drug addiction is often thought of as neuron-centric, but in a study published in the Proceedings of the National Academy of Sciences, M.D./Ph.D. student Daniel Kashima and his mentor, Brad Grueter, Ph.D., show that the immune ...

Mouse study adds to evidence linking gut bacteria and obesity

February 12, 2018
A new Johns Hopkins study of mice with the rodent equivalent of metabolic syndrome has added to evidence that the intestinal microbiome—a "garden" of bacterial, viral and fungal genes—plays a substantial role in the development ...

New research reveals how cat dander triggers allergic responses

July 25, 2013
New research reveals how the most common cause of severe allergic reactions to cats, the Fel d 1 protein which is found in cat dander, triggers an allergic response.

Drug that could aid in vaccines activates innate immune system in novel way

February 1, 2016
A new drug with the potential to aid in vaccine development has been identified by researchers at UT Southwestern Medical Center.

Restricting unwanted immune reactions

June 7, 2018
The immune system often initiates its response to pathogens by activating immune cells, so-called phagocytes, which migrate to sites of inflammation. There, the phagocytes release certain proteins, including the S100A8/S100A9 ...

High-fat meals a no-no for asthma patients

May 17, 2010
People with asthma may be well-advised to avoid heavy, high-fat meals, according to new research. Individuals with asthma who consumed a high-fat meal showed increased airway inflammation just hours after the binge, according ...

Recommended for you

Mothers more influential than fathers when it comes to children's weight

November 21, 2018
Overweight and obesity often continue for generations in families. The links can be genetic, but are also related to family relationships and lifestyle habits.

To resolve inflammation, location matters

November 19, 2018
Health conditions that involve inflammation run the gamut, from multiple sclerosis and lupus to arthritis, diabetes, and cancer. While inflammation can serve as a normal response to help the body deal with injury or infection, ...

Patchy distribution of joint inflammation resolved

November 16, 2018
Chronic inflammatory rheumatic diseases such as rheumatoid arthritis (RA) and spondylo-arthritis (SpA) are chronic, disabling diseases with a poor outcome for loco-motoric function if left untreated. RA and SpA each affect ...

Race plays role in regaining weight after gastric bypass surgery

November 15, 2018
African Americans and Hispanic Americans who have undergone Roux-en-Y gastric bypass (RYGB) are at greater risk to regain weight as compared to Caucasians. To date, no study has addressed the effect of race on weight regain ...

Discovery suggests new route to fight infection, disease

November 14, 2018
New research reveals how a single protein interferes with the immune system when exposed to the bacterium that causes Legionnaires' disease, findings that could have broad implications for development of medicines to fight ...

Can't exercise? A hot bath may help improve inflammation, metabolism, study suggests

November 14, 2018
Hot water treatment may help improve inflammation and blood sugar (glucose) levels in people who are unable to exercise, according to a new study. The findings are published ahead of print in the Journal of Applied Physiology.


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.