Immunology and... obesity?

Here at ERV, Ive talked about all kinds of pathogens and all kinds of vaccination strategies against those pathogens and cancers how our immune systems respond to these pathogens and vaccines and cancers and blah blah blah.

When you think 'immunology' you think 'your body protecting itself', or if you watch 'House', you think of an autoimmune diseases like lupus.

You dont think "I feel fine, and Im not infected with anything, and I dont have an autoimmune disease... but my immune system is still FREAKING OUT."

But you should be. Because that is obesity, and how/why people develop Type II Diabetes. The field is absolutely exploding, as more and more pro-inflammatory cytokines, and ways they are induced, and what they are doing, and what cells (especially immune cells) are releasing them is being discovered every day.

As it has nothing to do with a virus, its not something I usually think about either. But I realized how epic this field is while reading up on immunology/obesity in response to some big breakthroughs recently reported in Nature:

The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance
Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes
(review) Type 2 diabetes as an inflammatory disease

I am just going to touch on one issue in this post. Like I said, this field has gotten epic, and this is just *one* aspect of how obesity screws around with your immune system and causes damage.

An inflammasome is a multiprotein structure in all of your cells (innate immunity), on the lookout for trouble. Like all forms of innate immunity, it looking for patterns-- patterns that are not supposed to be there. Patterns pathogens or messed up cells make, not 'normal healthy me'. There are lots of variants, but if an inflammasome is just hanging out, floating around the cytoplasm of a cell, and it comes up upon some double stranded DNA, it sounds the alarm that SOMETHING IS WRONG! SOMETHING IS WROOOOOONG AAAAAAAHHHHH!!! DOUBLE-STRANDED DNA FOOOK!

Double stranded DNA is fine-- thats what our genome is made of. But our dsDNA should be in the nucleus, not hanging out in the cytoplasm. dsDNA in the cytoplasm could be virus, or an aborted intracellular bacteria, or a sign of a messed up cell, but it means something is not right.

When an inflammasome is activated, it starts the caspase-1 cascade, which initiates cell death.

Now sometimes when cells notice something is wrong, they kill themselves in a nice, civil, dignified manner: apoptosis. Its a neat, clean death.

But in the case of activated inflammasomes, the cell kills itself in a less dignified but still tightly controlled manner: pyroptosis. Pyroptosis is kinda like necrosis (where cells are just blowing up from damage) except still tightly controlled and on purpose. As opposed to apoptosis, which is an non-inflammatory cell death, pryoptosis is a pro-inflammatory cell death. Its a way for the dead cell to tell your immune system that shit has hit the fan, and backup is needed ASAP.

In the case of obesity, its free fatty-acids (oxidized LDL) and islet amyloid polypeptides (maybe more stuff) that are triggering NLRP3 inflammasome. This leads to cells dumping out pro-inflammatory cytokines. This freaks out the beta-islet cells, which freak out the immune cells in adipose and the pancreas (macrophages and mast cells and T-cells luvs adipose), which freak out the beta-islet cells, which freak out the immune cells in adipose and the pancreas, which freak out the beta-islet cells... pyroptosis all over the place.

A snow-ball effect of inflammatory cytokines/proteins leading to dead beta-islet cells (no more insulin, aka Type II Diabetes).

Which leads to an interesting idea for therapies for Type II Diabetes... What if you could stop the snow-ball effect? Interrupt the self-perpetuating pro-inflammatory cycle? Apparently there are current therapies for Type II Diabetes in trials right now, using stuff like antibodies which inhibit some of the inflammatory cytokines (IL-1B), or molecules that inhibit the IL-1B receptor. Keep the pro-inflammatory molecules from delivering their message, all the cells can simmer down and relax, so more damage isnt done.

My initial concern when seeing this, was that pro-inflammatory cytokines are a normal part of your immune system. Whats the good in treating people for Type II Diabetes just to have them fall over dead from a cold or the flu? These therapies should be pretty specific-- they dont tell the immune system as a whole to 'shut up' (like the drugs you put transplant recipients on)-- just a little branch of it. And theoretically this kind of treatment wouldnt have to be long-term, assuming people were altering their diet/activity levels (this would just prevent more damage from being done in the mean time). We will just have to see what happens in clinical trials.

But I think its neat and weird that immunologists have a place in addressing the obesity epidemic, and had to share :P

More like this

The most recent issue of Nature Reviews Immunology is all about the metabolism : immunology interaction. I've been thinking about doing a series of posts on it, but as you say, theres so... much.


*two years ago - our fifth day in hospital*

Doctor: The results of our most recent batch of tests were also inconclusive. It wasn't what we thought it was. [something generically comforting].

*doctor leaves*

Daniel: I can't believe they still don't know what's wrong with you.
Partner: Yeah. I know I should be scared, but really I'm just bored.
Daniel: I know what you mean. It's like we're in a really dull episode of House.
Partner: *giggles*
Daniel: Only the tests take more than five minutes and none of our doctors are good-looking.
Partner: Yeah. They'll be telling me I have lupus next. *laughs*

*next day*

Doctor: Our most recent tests came back - you've tested positive for lupus.
Dan and Partner: *jaws drop*
Doctor: We'll need to do a kidney biopsy to be sure, but at this stage we're pretty confident that's what we're dealing with. [Something comforting]

*doctor leaves*

Daniel: What the fuck?
Partner: I know, right? Fuck. What the hell is 'lupus' anyway?

(Yes, this is far enough in the past that I'm intending this to be a funny story. You're all allowed to chuckle - my girlfriend is doing really well.)

By Daniel Schealler (not verified) on 24 Feb 2011 #permalink

1) This stuff is so interesting. Poor little bloated adipose-tissue stuffed macrophages.
2) @Daniel HA!
3) I was entertained to see in a recent paper that the inflammasome is also linked to autophagy. (as in, activation of autophagy prevents activation of the inflammasome- no busted up mitochondria = harder to turn on caspase for inflammasome). Therefore, I can now tie diabetes to autophagy. EVERYTHING WILL RELATE BACK TO AUTOPHAGY! Victory will be mine!
Actually, I'm surprised such a recent paper as the one you cite didn't go to the trouble of linking up the NLRP3 connection to the damaged mitochondria and Beclin 1 et al. I mean, put calorie restriction in on one end, get reduced inflammation out the other... autophagy must be in the middle. Duh. Oh well. They'll get around to it, I'm sure.

Everytime I hear Adipose, I keep thinking of that Dr Who episode. Eww!

By Richard Hendricks (not verified) on 24 Feb 2011 #permalink

quick correction, it is diabetes type I in which the pancreatic islets have bitten the dust. In diabetes type II, the pancreas still produces insulin, there is just what is called "insulin resistance" which I think is actually a feature and not a bug.

Just for information: it appears the problem of type 11 is common in all mammals, at least cats and dogs and horses and humans have that, spanning a good range of the class.
Actually if you take an evolutionary view, what has happened is that we have put ourselves our companion animals and pleasure horses (i.e. those riden for pleasure that primarily just hang out) in a situation we did not evolve for, i.e. one with surplus food. Until 150 to 100 years ago famine was just around the corner, since transport was so expensive as well as agriculture not having made problems. Back then if you had excess food, since you did not know when the next meal might be. My niece has a cat that was ferral for a while, and you would expect this sort of behavior since the cat had a period where it was not clear where her next meal was coming from.

Of course this does present a chance to do more lateral research across species and look for the deeper issue.

Another paper came out this morning related to obesity and diabetes that points a finger at a gene humans lost over the course of our evolution. Good stuff =)

By Poodle Stomper (not verified) on 25 Feb 2011 #permalink

I was going to go with the "It's not lupus!" line, but apparently sometimes it actually is lupus.

Thanks for disproving the rule of House (TM), Daniel.

By Kemanorel (not verified) on 25 Feb 2011 #permalink

Good stuff! Thanks. Do you have a link to anything more on the concept of using stuff like antibodies which inhibit some of the inflammatory cytokines?

You've made a small error in your post. oxidized LDL is not the same as a free fatty acid, nor does oxLDL lead directly to obesity. oxLDL is cholesterol (a sterol, not fatty acid/lipid), packaged by a combination of phospholipids and proteins. When oxidised, LDL becomes oxLDL, which is a major driver of atherosclerosis. oxLDL is generally not stored by adipocytes; its major mechanism of removal appears to be the production of bile salts (and, unfortunately, the formation of foam cells in our hearts).

Obesity and diabetes are driven more by free fatty acids; basically a long saturated or partially unsaturated hydrocarbon chain, 8-24 carbons in length, with an acid (COOH) group at one end.

That said, people with high FFAs also tend to have high LDL/oxLDL, so its not like they are mutually exclusive.


Yes, type II starts with insulin resistance, but it does eventually progress to beta cell death.

Previously, I'd heard the hypothesis that beta cells ended up dead because of the strain imposed onto them by insulin resistance, but I've been hearing about fat as a promoter of pro-inflammatory cytokines for a while.

Nice to see someone over here at Science Blogs that can relate the "cutting edge". I agree there has been a veritable explosion in immunological reasearch and obesity, diabetes, mental disorders, etc.

It is great to see that something mainstream such as SB is picking up on this, Kudos ERV!

One particular interest of mine is the connection between the microflora of the human body (bacteria that inhabit the mucosal surfaces and skin) and there relation to the development of obesity, diabetes, and mental disorders.

If you think about the many trillion bacteria that inhabit each of us and the continual interactions with TLR's (the transmembrane PRR's) and NLR's(intracellular PRR's) it becomes clear that the composition of the microbial population has a dominant impact on the immunological state of the organism. In fact, the microflora may very well control the inflammatory state of the organism (the milieu of cytokines, both pro and anti inflammatory). The consequence of this is quite profound based on the emerging understanding that the innate immunity is fundamental to so many different processes in the body and brain.

The immune system needs to be viewed as a sense, just like vision, hearing, etc. It is responsible for sensing the microbial and metabolic state of the organism and feeding this info to the brain for appropriate action.

Couple this fundamental biological role of the microbiota with the change in environmental pressures which select this microbiota and you have a field ripe for research and therapeutic potential!

We have to think about the impact of our actions, such as antibiotic usage, diet change, chemical usage, vaccine uptake, bathing standards, etc. in terms of how this alters the composition of the microflora. Then how this composition change affects basic biological signaling that has evolved over millions of years and what this means for development and disease. Very interesting and epic indeed!!

By skeptiquette (not verified) on 28 Feb 2011 #permalink

One particular interest of mine is the connection between the microflora of the human body (bacteria that inhabit the mucosal surfaces and skin) and there relation to the development of obesity, diabetes, and mental disorders.

There were some good articles on Aetiology regarding this topic several years ago now. I haven't checked on Tara's blog in a while to see how current it is, but that might be a place to check if you haven't already.