Sixteen post bumps for 2016 ... No. 4
While I'm way beyond behind in my post bumping for the new year, I still plan to finish out a total of sixteen at some point.
This one doesn't need much in the way of summary, but quick points:
- In terms of energy homeostasis, the main role of insulin in the body is as a signaling molecule in the regulation of the circulating levels of energy substrate, the two primary ones being glucose and free fatty acids.
- This post models this for just the fatty acids using a room temperature/thermostat feedback analogy.
- In the case of fatty acids, circulating levels are controlled mainly at the release point from the fat tissue.
- The role of insulin is to keep total amount of circulating free fatty acids at appropriate levels, and not to regulate the amount of fatty acids stored in the fat cells, and thus overall fat tissue mass.
Original post date: 12/13/14
Insulin signals fat cell functions that regulate circulating NEFA.
Insulin doesn't regulate fat mass. This is a bold statement. My wording is specific. Hear me out.
A little over three years ago, I wrote: What Does Insulin Regulate Anyway? Yesterday a blast from that past showed up in comments on the "new" Gary Taubes YouTube video. I use the quotation marks around new, because Taubes has been delivering some version of this talk for seven years now, and the most significant changes have been to delete (and delete and delete some more) the most blatantly erroneous parts (some of which yours truly has had a hand in exposing). It's amazing, really, that he still manages to fill an hour with the pared down version. It's even more amazing that there's anyone left buying his schtick, but ... well ... I'll just leave it at that.
Since circa 2010, this slide has become a part of Gary Taubes' lectures. It's all resting on the triglyceride/fatty acid cycle now (, which is a tenuous resting place at best. Ahhh how I imagine he must long for the good old days of the hypothesis, back before it was pointed out that his own references didn't support his lynchpin notion that you can't store fat without dietary carbohydrate-derived alpha glycerol phosphate (aka glycerol 3 phosphate).
In newer lectures, Taubes has swapped out his version of the TAG/FA cycle, from the Newsholme and Start graphic of the 70's, to the 2010 version from Frayn. (You're welcome Gary /inside joke)
The slide on the right now has the First Law/Energy Balance equation superimposed on it. Which is odd, because fat cells are open systems and have no calorie receptors so that's all meaningless. Oh, and entropy. But I digress .... Taubes' point is that in order to understand how a human gets fat, we need to understand how a fat cell gets fat. The idea is to look at the balance of what puts fat into the fat cell, and what lets fat out of the fat cell. There can be no doubt that insulin acts to store fat. It stimulates esterification, it limits lipolysis. Thus insulin regulates fat accumulation. High insulin = more fat will accumulate. Right?
What is Regulation?
But in that previous post, I talked about what regulating something means. Insulin is the signalling molecule in a negative feedback loop like the one shown at right. In such a scenario, a stimulus acts on a sensor which sends a signal to the controller. The controller processes the signal and sends out a signal to the effector which then does something to "effect" a reduction in the stimulus. There are other types of regulatory loops, but this is the one that is relevant to insulin. Insulin is the purple downward arrow from the controller to the effector.
It's Analogy Time!
You didn't think I'd make it through this without one, did you? Behold the crude drawing of a room in a house in a warm environment. This room is equipped with an air conditioner (blue) that "vents" into an insulated compartment rather than the outside. Even those portable air conditioners require using a hose to vent the heat that is removed from the room by the unit. (If interested: how air conditioners work.) Since the compartment is insulated, the heat is not dissipated and the temperature will continue to rise as the air conditioner is used. There is also a locking vent in the wall to allow heat out of the compartment and back into the room if warming the room is desired.
If you just turned the air conditioner on and let it run, the room would get colder and colder. No regulation. But this one is controlled by the thermostat on the wall. This device contains both the sensor and controller components in the negative feedback loop. The controller ultimately answers to the occupant of the room who sets it. When the room gets too warm (stimulus) this is sensed at the thermostat and if the temperature exceeds the set point, the thermostat (sensor & controller) sends an electrical signal to turn the air conditioner (effector 1) on and lock the vent (effector 2). The air conditioner essentially removes heat from the room and transfers it to the insulated compartment. It is acting to reduce the stimulus. If at some point during the night the temperature gets below the set point, this thermostat could also be wired to the vent to open it. (This would effectively be a different feedback loop)
QUESTION: What is the thermostat regulating?
No, that's not a trick question, and yes I'm asking seriously.
ANSWER: The temperature of the room (a measure of the thermal energy it contains).
QUESTION: Does the temperature in the insulated compartment matter in this regulatory scheme?
ANSWER: No. The thermostat is in the room.
The air conditioner removes excess heat energy from the room and stores it in the insulated compartment. The thermostat is only able to sense and control the temperature of the room it is in, it doesn't care about the temperature in the insulated compartment. It engages the effectors -- AC on/vent closed -- to remove or add heat as needed to the room. It really doesn't care what's going on in that insulated compartment. I hope you get where I'm going here!
Your pancreas, more specifically the beta cells in your pancreas contain both the sensor and controller aspects of the regulation of NEFA (non-esterified, aka free, fatty acids) levels in circulation. The setting on the NEFAstat can be influenced by glucose levels, so it's a bit more complicated, but nonetheless, its not a bad analogy at all. Indeed I think it's one of the better ones that I've made. When NEFA levels rise above the set point, the pancreas secretes insulin which is akin to the signal sent from the thermostat to the air conditioner. Only this signal is molecular in nature. Insulin stimulates the rate-limiting step in esterification of triglycerides, an enzyme that goes by DGAT (or sometimes DAGAT, diacylglycerol acyltransferase) which helps draw the NEFA into the fat cell. (Note that I didn't include lipoprotein lipase, LPL, that breaks down triglycerides from VLDL or chylomicrons, NEFA are already ready for transport into the fat cell.) Insulin also inhibits HSL (hormone sensitive lipase) limiting release of NEFA from fat tissue. Just as Gary Taubes tells us it does. These two enzymes in the fat cells are the effectors in our feedback loops. When NEFA fall back to normal, they no longer stimulate the NEFAstat to secrete insulin. Pretty simple.
QUESTION: What is the NEFAstat regulating?
ANSWER: The concentration of NEFA in the bloodstream
QUESTION: Does the NEFAstat regulate how much fatty acid is in the fat tissue?
ANSWER: No. The NEFAstat senses NEFA in the blood.
Insulin, as the molecular signal from the controller, regulates the circulating NEFA by acting on the fat tissue. The fat tissue is not controlling anything on its own, it is being directed to do certain things. The internal status -- in terms of how much fat is stored -- of the fat tissue is NOT being regulated here.
INSULIN DOESN'T REGULATE FAT MASS
Insulin signals fat cell functions that regulate circulating NEFA.
What Does Regulate Fat Mass?
If one is interested in what regulates the fat mass of an organism, they need to go looking for the feedback loop(s). You need something to stimulate a sensor ... to elicit a response from the controller ... to activate the effector ... to do something about the stimulus. That initial something needs to come from within the fat cell itself. Hmmm ... whatever could that be? Bottom line: You cannot regulate something without a means to sense it.
Some Final Thoughts On My Analogy:
I'm not sure if any of you thought about my air conditioner scenario and thought, gee, why don't they do this to save energy? The reason is that air would be a very poor means of storing energy. If some of the heat could be converted into another form of energy, there might be something to that.
But that compartment is going to get awfully hot pretty fast. What happens to a gas when you heat it? It wants to expand. So pressure will build up in the compartment, and there is no way to get rid of it other than to release the air which will release the heat. So what's going to happen is that the air conditioner is going to have a harder time of working (if it even works at all after a while ... see previous link) and transferring heat to the hot compartment. That vent is also going to be more difficult to keep shut and will likely leak hot air into the room.
Does this sound familiar? It should. I don't know if we'll ever isolate *the* first thing that goes wrong in glucose and fat metabolism, but the fat cell is almost certainly the site where this occurs. When fat mass expands it does so by generating new cells and enlarging the ones that exist. When fat cells get too large they tend to become sick. For the same reasons as just described. It becomes more difficult to put the excess fatty acids into the cells and the cells "leak". The fat cell ceases to be a good effector -- it becomes an air conditioner that's low on coolant coupled with a leaky vent. The impaired fat cell means the metabolic feedback loop is no longer working properly. In this case, insulin fails to bring down the elevated circulating NEFA levels. This leads to both compensation and dysregulation of other pathways.
Sick fat. Adiposopathy. NOT rogue fat cells stricken with lipophilia.