Sunday, May 15, 2011

LIRKO mice (2)

This post is a bit rushed so apologies for typos/grammar, but there is a just usable swell and low tide in First Bay is in just over an hour's time so the 'yak is on the car... Just need the Baba to wake up and we're off.

Here are the facts and figures for LIRKO mice from this paper:

OK, they really are slim, they have about 10% less bodyfat than control mice. Here are some of the biochemical details:

The LIRKO mouse has a leptin level which is 10 times that of a control mouse, despite having 10% less bodyfat, that's graph A. Does this mean it's fooling its brain in to thinking it is obese? Probably not, Graph B shows that LIRKO mice have almost infinitely more sOb-R in their blood. This is a binding protein for leptin, bound leptin is biologically inactive. In graph C we can see that free leptin per unit fat mass is actually very low.

Graphs D, E and F show hat happens when you infuse leptin or saline intravenously for 30 minutes. Note the log scales. Graph D shows it is possible to get leptin to equally astronomical levels in LIRKO or normal mice. Graph E shows that the leptin binding protein, sOb-R, doesn't change in the LIRKO mice but falls non significantly in normal mice on leptin infusion. Graph F shows that the free leptin index goes up significantly more for control mice than for LIRKO mice. ie the control mice should feel less hungry and so eat less

But that's not what happens. Four days of leptin injections drops appetite and weight more in LIRKO mice than in control mice. Despite the appetite suppressing free leptin index being higher in the controls.

This appears to happen because the brain of a LIRKO mouse is more leptin sensitive than that of a control mouse:

SOCS3 mRNA level is something I've not read about but I'm willing to accept that it is a marker of hypothalamic leptin resistance.

Does any of this mean anything? Yes.

The LIRKO mice have no hepatic insulin sensitivity because of a very specific genetic defect which deletes their liver insulin receptors.

The liver does not know this. As far as it is concerned the pancreas is simply not secreting any insulin, ie there is no food being eaten. There may be a ton of glucose floating past but, as far as the liver is concerned, there is none.

Are there any other conditions which mimic this and might also spike sOb-R? The paper cites three. Type 1 diabetes. Here there is a ton of glucose but zero insulin. Total insulin deficiency is "hepatically" indistinguishable from the LIRKO liver not seeing any of the insulin (or glucose) raging through the bloodstream. Low insulin in T1 diabetes. High sOb-R.

Anorexia nervosa produces a genuine combined insulin and caloric deficiency with a high level of sOb-R. Low insulin. High sOb-R.

Ditto a 72 hour fast in men. Low insulin. High sOb-R.

How about ketogenic dieting? Here too there is low insulin. Will blood leptin binding increase? Hypothalmic leptin sensitivity increase? Appetite be normal? While ketogenic dieted mice do not particularly drop their caloric intake they do, like type 1 diabetics, fail to increase their caloric intake to meet on going caloric output (they become warm rather than glycosuric as their caloric "sink")...

Now, where does the letpin binding sOb-R come from? The liver is the source in LIRKO mice. The LIRKO mice have liver cells which are in a starvation situation. They manipulate leptin binding and availability to keep appetite normal.

What controls sOb-R production in normal liver cells?


If you put normal liver cells in a petridish with insulin they reduce production of mRNA for the short leptin receptor gene which produces one of the sOb-Rs. Under zero insulin the mRNA level for the Ob-Ra gene is 5 times higher than under 0.1micromol of insulin. Leptin itself has some suppressive effect, but insulin is the dominant hormone.

This looks very much like the liver has a mechanism for controlling leptin sensitivity.

Insulin. Hmmmmmm

As a complete aside: The other potential mechanism for the decreased appetite is insulin per se. Now, we are all fully aware that insulin is anorexic agent. All you have to do is inject a little insulin in to your brain and you will decrease your appetite. This is logical, after a meal you have a high insulin level and shouldn't want to eat.

Under fasting conditions you have low insulin levels and should want to eat. It's likely to keep you alive. Simple.

So, to stop people being hungry, all we need is to inject insulin in to their brain. Overweight? There's the queue...

For those of us who wish to lose weight without that intra cerebral injection we could try mainlining insulin. This may or may not suppress appetite. I've never tried it. Certainly none of my hyperglycaemic patients seem hungry when I inject them with insulin by the subcutaneous route. Until their blood glucose level drops below about 6mmol/l that is.

At that point they will eat ANYTHING. And lick the bowl. I'm not sure if they feel guilty afterwards. None of them seem to go and make themselves vomit in private to stay slim. Difficult to hide the evidence in a ward cage!

But the LIRKO mouse, with insulin levels 8-20 times those of a control mouse, never becomes hypoglycaemic. It's ONLY hyperinsulinaemic BECAUSE it can't mop up dietary glucose.

So perhaps we are actually seeing the anorexic effect of insulin in this mouse model. The levels might be high enough. The paper wasn't set up to look at this, but it's an interesting afterthought. Back to leptin.

Finally, how does the hepatic insulin resistance of a LIRKO mouse compare to the hepatic insulin resistance of a sucrose fed mouse?

The sucrose mouse hepatocytes have insulin receptors. They can be made to respond. They prefer not to only because these hepatocytes are utterly stuffed with diet derived calories which they are converting to fat as fast as they can but can't export until insulin levels drop low enough to allow VLDL output. Which doesn't happen. Mmmm, Pâté de foie gras...

They are in a state of hypercaloric stuffedness, they see blood insulin and glucose and just don't want anything to do with either. Do they make a ton soluble of leptin binding receptor, sOb-R? No. In human obesity leptin is high, sOb-R is LOW and hypothalamic leptin resistance high.

Now, really finally, how does the LIRKO mouse type of liver insulin resistance compare to the hepatic insulin resistance of an extreme ketogenic fed mouse? It's exactly the same. Low insulin. So if you fed a LIRKO mouse an extreme ketogenic diet, would you "cure" its diabetes?

Probably yes.

If you based the ketogenic diet around butter rather than the almost pure PUFA in Mouse Diet 9F, would you prevent its cirrhosis? The liver is only getting its calories primarily from dietary fat after all.

Probably yes.

If you gave some LIRKO mice free choice of macronutrients ratio, would they put themselves on an extreme ketogenic diet to treat their diabetes? Of course they would. They're mice, they're not stupid.

Do I like the LIRKO mouse? Absolutely.

But the FIRKO mouse is even more interesting and paradoxical... Maybe another day.



bopes said...

So, are you agreeing, disagreeing, gently tweaking, trashing, or just acknowledging Stephan's latest?

gunther gatherer said...

Hi Peter, I'm interested in your answer to bopes' question too. Is it possible that insulin levels could be based on intensity of flavour, and therefore have a psychological basis as opposed to a physiological one?

I ask because after reading Stephan's posts, I began to look over my VLC diet, and even though it seems perfectly tasty to me, it is pretty bland when compared to most on a high-carb diet, and certainly much more boring to anyone used to SAD.

Not denying any of the other facets of the physiological side of what a high-carb diet does to you, but you can't deny that a VLC diet, especially based on half a potato or a teaspoon of glucose powder as your primary daily carb, really has a "low reward" impact on the brain, hence on hypothalamus, hence on leptin and insulin, etc.

STG said...

gunther gatherer:

What about butter? People on LC or MC generally eat it. It is not bland and is very satisfying. I notice that I taste natural sweetness more on a MC diet than I did on a HC diet.

Aravind said...


I know you have written (recently) that "the ultimate determinant of weight loss is fasting insulin". I asked Stephan what he thought of this in light of his recent post and his response was "I doubt fasting insulin plays much if any role in fat loss".

I will assume fat loss and weight loss can be taken as equivalent and not a technicality to get out of the discussion :-)

I certainly lack the biochemistry knowledge that the two of you have, so perhaps I am just too ignorant to understand, but it seems like a diametrically opposed position to me.

I don't think one point of disagreement throws the baby out with the bathwater. Having said this, for some unknown reason, after reading Stephan's post and then yours, this is what popped into me head.

I eagerly await your thoughts. May the force be with you!

Warm regards,

gunther gatherer said...

STG, I think the butter question depends on whether it is salted or not. Adding extra fat to foods can definitely make it blander; could this be a factor in why VLC works so well?

Aravind, maybe Peter's fasting insulin principle is more related to the Stephan's setpoint theory than we think. Perhaps the "setpoint" is just fasting insulin itself, and the "setting" is done through both external (dietary carbs and PUFAs) and internal (perception and psychological reaction) cues.

Aravind said...

@GG - I tend to think that there will be a convergence of ideas and the science to tie it together, though that is rooted more in faith than evidence at this time.

Having said that, as I posted previously, the respective statements made by the two are at odds with one another, unless I am completely misreading the most basic of sentences, which are devoid of any recondite terminology.

I know Peter has posted many times "no gurus", but for me Peter and Stephan are my gurus (along with Kurt Harris). The gurus must agree dammit :-)

You really, however, should focus on the YouTube link I included, because that was the most significant contribution I could make. Geeks unite!


Peter said...

Hi all,

This is quite simple. I have a logical framework which seems to work quite well. Should all of the effects I note turn out to be secondary to food intake, which is being regulated by flavour effects on the brain, so be it. You work with the data you have. I have a very long way to go before I view hormonal changes as merely refections of behavior secondary to flavour effects, but I would never rule out the possibility that this may not change. It certainly doesn't feel likely, but you don't have to afraid of this possibility. If the data tell you something specific, better take note.

Never forget the sucrose addicted rodents having an acute withdrawal syndrome on naloxone... This is not a trivial effect.

But taste effects tell us very little about the LIRKO mouse physiology and trans fat margarine can be made to taste quite like butter with very differing metabolic effects.


bopes said...

' nuff said.

Stan Bleszynski said...

Hi Peter,

Different subject: Diet, vegetarianism, and cataract risk.

There has to be a catch, I suspect they screwed up something. Probably worth investigating if you can access the full text.


Peter said...

Hi Stan, EPIC shows all sorts of things. Some I like (HbA1c is positively associated with risk of death), some I don't (PUFA consumption is inversely associated with HbA1c!!!!).

Some EPIC papers allow you to see where their conclusions came from, others don't, but ultimately they are always observational. I'll see what I can do with this one.


Stipetic said...

Saying taste, palatability, satiety, call it what you will, could hold the answer seems like in the same league of statements as the one that says calories in/calories out is the cause of obesity. It is merely a statement. And basically stating the obvious--a tautology of sorts. There has to be a mechanism behind this--the answer has to be found at the cellular level. So, according to this tautology, it seems likely that some agents are causing insulin resistance centrally (in the food reward centers), which in turn could be affecting leptin (or vice versa), and therefore, both satiety and food intake (via set point or settling point) could be affected thereafter. So, it still could all come down to insulin resistance. Or not.

Anonymous said...

Peter, could you say how Cephalic Phase Insulin Response fits in? Some have an insulin response to thinking about food, or certain kinds of food, or to looking at photographs of food, or advertisements on the television, or to tasting sweet but not swallowing it (tests done with tasting and then spitting out the food).

Thanks very much.

blogblog said...

People who have lost their sense of taste and smell due to brain injuries don't stop eating. AFAIK they don't even change their eating habits to any great degree.

blogblog said...

most Westerners only eat lean muscle meat (steak, chops, chicken breasts etc). They also don't eat much in the way of animal fats such as butter. As a result they get few of the essential nutrients found in organs and fat eg vitamins A, B group and E as well as selenium, copper etc.

Paul said...

Can you give example of your daily diet.

blogblog said...

My typical diet (averaged over a week)

No fruit or vegetables of any kind except a smidgen of berries and some spices, chutney or mustard.

Breakfast: a cup of tea

Lunch; a cup of milky coffee

Mid afternoon: 300ml cream with grated dark chocolate

Dinner - 500-700g of meat. I like spicy foods such as chilli and curries.

Supper: 300ml cream with around 50g of berries.

Snacks: hard cheese or tuna about 100g/day

I usually eat about 200g per week of liverwurst.

2-5g fish oil
500mg vitamin C
Mega B group
400mg magnesium
Potassium around 3-4g/day (1 level teaspoon of potassium citrate dissolved in 1.25 litres of waters. This is consumed over the entire day)

Calorie intake - around 3500/day.

Age 48
Weight 85kg
height 182cm

Blood pressure 95/75
TC 7.7 HDL 5.5 LDL 2.2 Tri 20

No idea about any other tests because I've never had them.

Unknown said...

Peter there are four specific parts of the leptin receptor and SOCS3 is but one. The mice knock out studies done at Michigan by Dr Murphy are classic papers already in leptin receptor functioning. This is white hot in my specialty of medicine. We know from his seminal work and the work of Lecea group at Stanford that leptin receptors can be modulated by neuropeptides and the hypocretin system. Moreover, leptin receptor affinity is tightly found in the lateral hypothalamus and projects directly to the dopaminergic median forebrain bundle(ventral Tegmental area) that controls rewards for drugs and food seeking and projects to the CART enzyme system. The hypocretins modulate the pathway and the leptin receptor but it is now clear scientifically that leptin control fertility and hormonal response for all energy production. The hypocretins actually can acutely stop cocaine and heroin addiction immediately based upon Lecea work. It is now the biggest target in addiction biology. And in obesity research. Dr. K

Bill said...

Hi Peter, great post. What’s up with this free leptin index “normalized for body fat?” If we are considering the free leptin index to represent satiety, should we also consider food intake “normalized for body fat?” Judging from the graph above, this would make actual food intake higher than it appears (body fat is reduced to a greater extent than food intake). So food intake (“normalized for body fat”) in LIRKO might even be greater than WT, which would make reduced ‘free leptin index’ alone in LIRKO indicative of normal leptin sensitivity. What do you think about differences “normalized for body fat” with respect to absolute changes in, for example, food intake?
Thanks, Bill

Peter said...

Hi john,

Yes, I don't doubt for a moment that leptin, like insulin, does many things in the body, thought I have not read a huge amount about leptin. Targeting the system will undoubtedly produce a sting of potentially catastrophic drugs. What fascinates me is that you can eat a Western diet and progressively gain both body fat and leptin resistance but if you slap a Western steak (and no fries) on your plate for 6 meals in a row the leptin resistance apparently disappears and your appetite normalises. From the LIRKO mouse my basic question is whether the brain monitors energy status directly or via the liver (probably both), and when the information it is processing is in conflict, which does it listen to? The LIRKO mouse has a very interesting liver. And, of course, how does the liver monitor nutrient status?

Of course there may well be other tools available, you have to wonder about 100% potato diet here, though the logic is not obvious to me...

The addiction question is interesting too. Reading Tom Naughton on alcohol and various "quacks" on opiate addiction makes slapping sequential steaks on your plate a potential route in to these problems.

Hi Bill, these mice are eating CIAB, my guess is that the WT mice will be partially leptin resistant.


Paul said...


Thanks blogblog for detailed information. So you are eating about 80% kcal from fat.
Any reason for taking potassium daily? I know Phinney used potassium and sodium in his keto study but I thought after somebody is adapted to keto diet it shouldn’t be necessary?
Are you drinking more water or just what you stated?


Pekka Pessi said...

Wow, these lirko mices are a real demonstration that the diabetes is really a disease of liver.

I wonder what causes the apparent insulin resistance in the adipocytes. At the tender age of 2 months the LIRKO liver is churning out glucose at full speed (fasting glucose at 132 mg/dl) and spewing all the extra acetyl-CoA as ketone bodies. However, after 4 more months on the CIAB diet the malnourished liver cannot anymore keep the fasting glucose up and the level of ketone bodies is probably pretty low, too. The FFA and triglys are significantly lower than in the normal mice.

Pekka Pessi said...
This comment has been removed by the author.
Beth@WeightMaven said...

I think Stephan and Peter are both right (in the spirit of the six blind men & the elephant).

I could imagine putting this together as follows:

1) eating a standard Western diet (high in sugar, veggie oils, refined grains, salt) wreaks havoc with food reward systems (not necessarily just via "flavor" but through other food reward/palatability mechanisms)

2) in those susceptible, appetite dysregulation leads to overeating of these foodstuffs, which leads to liver injury/insulin resistance via unrelenting overeating; high fasting insulin contributes to overeating behavior, fat storage

3) repeat 1 & 2 week after week, month after month, etc, get really sick/fat

Re the potato diet, I'm curious that Stephan was as impressed with that as he was given the short duration of the experiment, especially as the guy was relatively healthy going in. But it's also possible that even someone IR like me would do okay because an all potato diet would likely be a calorie restrictive diet (as it was in the test).

Whether or not fasting insulin plays a role in fat loss or not, it certainly plays a role in health. Stephan has gone on record suggesting that a healthy fasting insulin is probably a lot lower than 7 (I think he suggested 3.5 or 4).

Unknown said...

Peter we know in neurosurgery circles that leptin clearly is the master switch here. The liver is the engine of metabolism but the hypothalmus (lateral) is clearly the microchip that controls it. How does it work.....obesity is pleotrophic. There a several causes. snp's deletions, inflammation altering the 4 recptor ligands epigenetically and by six signaling via the receptor, formation of palmitic acid via fructose hepatic metabolism is key in high fructose diets. The liver is merely a player......leptin is the the conductor. I strongly suggest you delve into this.....once I release my blog I think you may get more interested. in my treatise leptin holds position two. The final obesity pathway is quite bizarre but ties in the orexins and cataplexy. The intellectual ride will rock your face.

blogblog said...

unless you eat fruit and vegetables you get very little potassium and some very painful cramps. You will probably adapt eventually but I prefer cheap insurance.

Fluid intake ~3L/day in cool season and ~5L/day in hot season (I live in the subtropics).

blogblog said...

Maybe it's time to hire some chemists and physicists who actually understand the scientific method to get involved in medical research. You know people who know that you can have only one variable in an experiment, that a dozen subjects isn't statistically meaningful, that quality is more important than quantity in research and that rats aren't miniature people.

Yes the underlying biological mechanisms may be the same in all mammals but you could say the about a Ferrari and lawn mower. However no sane person would let a lawn mower mechanic service their Ferrari. Likewise no sane person would apply the results of murine models to human health.

blogblog said...

Egyptian princess shows heart disease is an ancient problem

THE oldest case of human heart disease has been discovered in an Egyptian princess - contradicting the theory that clogged arteries are the result of a modern lifestyle.

Researchers from the University of California, presenting their findings at a conference in Amsterdam yesterday, worked out that 3500-year-old Princess Ahmose-Meryet-Amon, who died in her forties, had suffered from diseased arteries.

The princess lived in Thebes [now Luxor] between 1580BC and 1550BC and was the daughter of Seqenenre Tao II, the last pharaoh of the 17th dynasty.

Egyptians living in this period are widely believed to have lived on a diet of vegetables, fruit, small amounts of lean meat and barley, but royals were likely to have access to red meats such as beef, pork, antelope and duck.

"Today she would have needed bypass surgery," said lead author Dr Gregory Thomas, speaking at the International Conference of Non-Invasive Cardiovascular Imaging.

Using computerised tomography scans, the researchers found that around 20 other mummies from the period also had calcification [or atherosclerosis] in their arteries.

"It was striking how much atherosclerosis we found," said Dr Thomas.

"We think of atherosclerosis as a disease of modern lifestyle, but it's clear that it also existed 3,500 years ago."

Note that the small amount of red meat is blamed for the atherosclerosis - not the huge amounts of sugar and highly refined grains they ate.

gunther gatherer said...

Hi Peter, just wondering if you could comment about something. In his newest post, Stephan has stated his opinion that fasting insuin is actually an EFFECT of weight loss instead of the cause. In other words, it has nothing to do with why we gain or lose weight.

I don't know how or if this reconciles with VLC or why it works, but he gives some compelling reasons why food reward is at the bottom of bodyfat loss as opposed to dietary carb content. Food reward could explain why many dieters plateau on just about all diets (eliminating either carbs or fat would make any diet much more boring).

In any case, I'd love your opinion on this. VLC has worked for me so I don't have to worry about weight loss, but lots of people could seize upon this idea (if it works) to eat flavourless industrial foods and wreck their health even while losing weight.

CarbSane said...

Peter: Just wanted to alert you that your content is being ripped off.

Google Gourmand Rats

gunther gatherer said...

Hi again, and sorry for the annoyance but this question gets to the very bottom of, well, everything and it needs to be settled so we aren't all barking up the wrong tree.

This is Stephan's reply to my query as to why fasting insulin would have nothing to do with lipolysis. If it is true, he is very modestly and nicely destroying the Insulin Approach to fat loss. I'm not trying to pit you against him or start any kind of ideological war, only trying to get to the Truth, so I'd love your take on it:

"Think about it this way. Insulin signaling depends both on the amount of insulin and the degree of sensitivity of cells to the insulin. In insulin resistance, you simultaneously have higher insulin but lower sensitivity, so why would you expect insulin to suppress lipolysis (fat exiting fat tissue)?

If you look at actual lypolysis rates in the obese (who are typically insulin resistant), you find that they're actually higher than normal, although lower per unit fat mass. CarbSane has commented on that in the past. So in an absolute sense, there's actually more fat exiting their fat depots than a lean person.

The problem is, it mostly gets re-incorporated into fat tissue after it leaves rather than getting burned. That's also modulated by insulin. My point is that if you want to say anything about how insulin's effect on lipolysis influences fat gain/loss, you would have to show that the net flux of fat into/out of fat tissue is altered in people who are insulin resistant. But an easier way to do that is to just see if people who have high fasting insulin are resistant to losing weight. It appears they are not, so I don't understand the rationale for thinking insulin resistance prevents fat loss.

I think the reason very low-carb ketogenic diets cause fat loss is the same reason extreme low-fat diets cause it: they have a greatly reduced reward value. Both diets also introduce some degree of metabolic inefficiency (e.g., making ketones from fatty acids), so that may help as well by effectively increasing energy expenditure."

Chris said...

"In insulin resistance, you simultaneously have higher insulin but lower sensitivity, so why would you expect insulin to suppress lipolysis (fat exiting fat tissue)?"

Reminds me of explaining relative rates while tutoring chemistry. If the water flows into the bath tub faster than it drains, the tub will eventually over flow, etc.

Maybe I missed it but one issue I don't seem to see addressed in the rewards model is the idea of an acquired taste. For example, to a lot of people the first drink of alcohol tastes vile but, or so one explanation goes, the body eventually recognizes that drinking it feels good and includes calories that aren't immediately lethal so it starts to taste good. If it's purely a rewards system, why wouldn't the body simply adapt to the "unrewarding" diet to encourage the body to survive and return to the earlier state commensurate with the broken rewards system?

Peter said...


Plotting graphs, no rush...


Aravind said...

@Gunther - based on our questions to Stephan and Peter, we seem to be vexed by the same thing!

Peter said...

Hi H, sorry I missed your comment, I doubt the cephalic phase is a problem at all if you are eating food. Might be tricksie after sucralose...

Pekka, the liver has essentially nothing to work with other than PUFA and these are prime drivers of cirrhosis in rodent models. This looks like more of the same to me...

Beth, I don't doubt that Stephan is looking at a very important aspect. I doubt it is the whole story, any more than the trunk I am feeling is. I too am curious what would happen on long term spuds. Interestingly Stephan mentioned Barnard's catastrophic vegan diabetes study, a piece of writing I have been intending to address for some time. Might get around to it now.

john, I will read.

Ah, blogblog, the perils of even looking at an ancient Egyptian steak!

Thanks CarbSane, it's being going on for a while. Must get off my *rse and complain to Wordpress.

Chris, I'm expecting Stephan to clarify many things as the weeks progress.


Geoff said...

Hey Peter,

Stephan has said in a number of different places that leptin, "and to a lesser extent insulin," acts as a signal in the hypothalamus as to fat mass size. If insulin has a proportionally smaller, but still significant effect on the brain's interpretation of the negative feedback loop, I think that his explains why the mice with extremely high insulin would have lower fat mass than the control mice.

Does this sound plausible?

Peter said...

Hi Geoff,

Yes, I'd view it as an aspect of the "anorexic" effect of insulin... I think these are essentially saying the same thing.


Geoff said...

Hey Peter,

So I guess I'm a little confused as to what the LIRKO mice models are telling us that is inconsistent with the hypothesis that Stephan has put forward i.e. leptin is the driver of decreasing fasting insulin, and lipolysis is not inhibited with elevated insulin. If anything it would seem to support this idea.

Under the carbohydrate insulin hypothesis, at least as I understand it, these mice should be like the Zucker rats as a result of their elevated fasting insulin. Massive fat tissue, very little muscle mass, potentially cannibalizing organ muscle at the expense of fat tissue. Just trying to wrap my head around these ideas myself.

Peter said...

Hi Geoff,

Fasting FFAs are depressed but not to zero in the LIRKO mice. You should, theoretically, be able to suppress FFAs to just above zero with insulin, but it doesn't happen in these mice.

That's partly why the FIRKO mouse is so interesting. It has complete adipocyte insulin resistance and is slim and relatively long lived (about 20%>controls).

So you have to look at the effects of adipocyte insulin resistance and why the FIRKO mouse is slim and non diabetic.

This leads to very interesting questions about GLUT4s on adipocytes and the role of glycogen in adipocytes during feeding, starvation and refeeding. It's an interesting subject

The second aspect is that the liver of a LIRKO mouse has no access to glucose. The only way it can get bulk calories is from the fat content of the diet. This is quite low but will be taken by the liver for it's caloric needs. The role of insulin is the storage of dietary fat. There's not a lot to store if it's all that keeps your liver functional.

Third is that there is no source of saturated fat in this mouse. You can't make normal adipocytes with soya oil, it's liquid. There is no de novo lipogenesis in the liver (no access to glucose) and, if the adipocytes (like the rest of the body) are insulin resistant, not a lot of adipocyte de novo lipogenesis going on.

The real question is why the FIRKO mice do so well. I'll get the full text sometime to look at this.


Geoff said...

Let us speculate for a second that the adipocyte insulin resistance as well as the slimness of the mice is an effect of the hypothalamus telling the body not to store fat as a result of the elevated blood insulin signaling that the fat mass is of sufficient size.

So the lack of hepatic insulin sensitivity as a result of the knocked out receptors causes the insulin build up once all muscular glycogen stores are full. The insulin build up causes the hypothalamus to cut off hunger and make the adipocyes insulin resistant. Since the liver is performing very little de novo lipogenesis and not doing any regulation of blood glucose, the liver has very little to do in this system so doesn't particularly need much energy to get by. All muscles and the brain have adequate glucose as needed sitting around in the blood stream.

To my mind everything seems to be working as it should, which is why these mice live longer than you'd expect. I'd be interested to see things like thermogenesis and activity levels measured, as I suspect that these mice would be operating as if they have energy generally in balance if not slightly net positive, requiring the body to burn some of the excess off.

Melodie said...

Forgive my ignorance, but I am quite confused about this matter.

So the LIRKO mouse are running on 'no insulin' due to their liver insulin resistance, but don't feel hungry (due to leptin injections?) and are not overweight? (As well as having high s0b-R).

The sucrose fed mouse has high insulin, and their appetite is suppresed, but they can't get into lipolysis? (As well as having low s0b-R). This is similar to obese humans too?

Here's how I see it: Someone with type I diabetes does not feel full due to absence of insulin with a result in extreme weight loss (and other things). Once they are given insulin, their appetite is suppressed, however they begin to gain weight. (They would then go from having high s0b-R to low s0b-R). Are type I's very leptin sensitive? Do they produce a lot of leptin before diagnosis, or after?

With obese humans, it seems that they are 'never full' but yet their insulin and/or fasting insulin is high. (Due to insulin resistance? or leptin resistance?) If their insulin is high (which is presumably true), this inhibits liplysis. Why do they not get the appetite supression that non-obese people get from high insulin? Is it because of the adipocytes being insulin sensitive for the longest? (Their liver and muscle cells rejecting insulin at this point). So I guess the difference between obese people and these LIRKO mice is that the LIRKO mice are whole-body insulin resistant, not just the liver? Even if the obese person is mostly insulin resistant except for the adipocytes, then their bodies should respond as if there's less amount of insulin than a normal insulin sensitive person...and therefore should have higher levels of s0b-R than a normal insulin sensitive person, but maybe not as much as the LIRKO mouse (or type I)?

Also, let's look at someone who starts off slim, but then gains excess weight: They eat, they get insulin spike (normal response people, let's not get so afraid of insulin). Then once insulin drops and glucagon is secreted, then appetite is increased again. But what is it that causes that person to not feel full after the meal? Is it a slow response of insulin? Is it insulin resistance? (But how can they be resistant while still slim?) I suppose I'm excluding the role of leptin too much here, of which I know little of. (I am talking of a scenario independent of any other endocrine malfunctions etc.) So can one have normal insulin function, high resistance, be slim, yet never feel full?

I hope someone can answer my non-directional question(s). I reckon studies like these make Gary Taubes' explanations too simplistic at times. Not wrong, but not enough to explain the whole picture.