Obesity and diabetes (2) Basal lipolysis and weight gain

This is a paper at the "dislike" end of my bias spectrum:

In Vitro Lipolysis is Associated with Whole Body Lipid Oxidation and Weight Gain in Humans

which can be summed up by the first line of the introduction

"Positive energy balance results in greater triglyceride storage in adipose tissue and resultant accumulation of body fat."

which explicitly states that they have the arrow of causation at 180 degrees to the correct direction. So don't expect too much from the paper. I also hate that they omitted to mention in the title that the association with weight gain is negative.

Beyond that the methods are sketchy and the results are limited to a number of model derived correlations subjected, eventually, to multiple unspecified adjustments. So not a lot of hope for the group or for the largely Pima Indian population under their misguided care. But I digress.

Once again adipocyte size is quite tightly correlated with basal lipolysis, like this

which looks quite linear until we convert the log numbers to normal numbers like this

which shows us that basal lipolysis rises progressively sharply with adipocyte size. There is an upper limit to adipocyte size, and this will be set by rising basal lipolysis equaling the obesogenic effect of linoleic acid facilitating the over action of insulin.

They fed the subjects a fixed macro, calorically calculated diet for three days before a day in a metabolic chamber, where they ate three similarly fixed macro/calorie meals.

People turned out to have differing RQs (they use RQ, respiratory quotient, as their term rather than RER, respiratory exchange ratio. My brain works this way too, it's about the only bit of the paper I like, even though RER is probably the correct term) on a fixed macro diet. So clearly something is happening on a fuel partitioning basis.

People who oxidised the most fat in the metabolic chamber were the least likely to gain weight over the following eight or so years. Those oxidising the most carbohydrate were likely to gain the most weight.

Funny that.

I can't see any explanation in the discussion of why that might be.

From the ROS/Protons perspective it is quite clear that people with smaller adipocytes have not finished gaining weight. They are part way to becoming obese because they are consuming LA in combination with an insulogenic diet so are over-storing fat. When they eat a fixed macro/calorie diet they sequester lipid in to adipocytes, fail to retrieve it and run their metabolism on the more accessible carbohydrate. They're probably the most hungry, in my book.

Those with maximum sized adipocytes eat the same fixed macro diet, sequester the same lipids in to their large adipocytes via LA augmentation of insulin's fat storage signal but then go on to release much of that extra stored fat by the increase in basal lipolysis which is associated with trying to further stretch large adipocytes. This supplies continuously elevated FFAs, with subsequent fat oxidation, despite the presence of glucose and insulin at the same time. They should be the least hungry.

What can a cell do when presented with a ton of FFAs and a ton of glucose, both having their uptake facilitated by insulin?

That's right. Resisting insulin is the correct option. That's what the systemic cells do.

The cost shows as elevated glucose in combination with the elevated fat oxidation (eventually FFAs rise measurably but early on the fat oxidation increase precedes the rise in plasma FFAs).

It is metabolic inflexibility encapsulated.

Of course the obvious question is whether that increased fat oxidation, associated with reduced rate of weight gain, is positively associated with insulin resistance. Alongside the reduced weight gain.

From the same institution, back in 1991 and forgotten about during the last 30 years, we have this paper:

Insulin Resistance Associated with Lower Rates of Weight Gain in Pima Indians

Insulin resistance is, indeed, associated with limited weight gain. As you would expect.

Summary overall:

Fat oxidation a major mechanism of insulin resistance. Increased basal lipolysis is a mechanism of both increased fat oxidation and decreased weight gain. Linoleic acid is the mechanism of increased adipocyte size to drive increased basal lipolysis. Some degree of insulin signalling is essential for linoleic acid to drive adipocyte size increase.

Life is logical.

Peter

Extra thoughts: During weight gain, while calories are being lost in to adipocytes, the rest of the body is in caloric deficit. Calories lost to adipocytes must be replaced by extra food. This is the correct arrow of causation. There is insulin sensitivity.

Once adipocyte basal lipolysis equals or occasionally outstrips fat sequestration in to adipocytes, the rest of the body is being provided with supplementary FFAs. It is in caloric surplus. Insulin resistance is then physiologically appropriate.

There is a gradual transition between the two states.

Obesity and diabetes (1)

There is absolutely no doubt in my mind that adipocytes can become insulin resistant. The most convincing paper I've come across is this one

Basal lipolysis, not the degree of insulin resistance, differentiates large from small isolated adipocytes in high-fat fed mice

They took adipose tissue from a group of mice which had been made insulin resistant, and obese, by feeding a high coconut fat/sucrose (ie Surwit-like) diet and extracted a supply of adipocytes. Whether these cells were large or small, provided they had been exposed to Surwit-derived conditions for eight weeks, they were all equally insulin resistant. Big ones and little ones. Size made no difference. Insulin resistance is real but not associated with adipocyte distention.

What they also found was that size of adipocytes was very closely and positively associated with basal lipolysis, that is with the rate of lipolysis in the absence of insulin or sympathomimetic agents.

This is not a new finding. From 1972:

Effect of cell size on lipolysis and antilipolytic action of insulin in human fat cells

I like this paper. I have certain biases, one of the strongest of which is that I like papers in which you are given the concentration of glucose which is used in their cell culture medium. Here they happen to have used 1mmol/l, which might rightly be considered a little low, but at least they tell you. Unlike many papers.

Basal lipolysis correlated well with cell diameter. If basal lipolysis is related to the function of lipid droplet surface proteins this is completely plausible and almost predictable. Here's their graph:

The ability to suppress basal lipolysis using insulin appears to be completely determined by the conditions you use to incubate your cells, higher glucose appears to make insulin more effective on suppressing basal lipolysis, but that's an aside. This current study used a glucose concentration of 1mmol/l and showed absolutely no effect of insulin on basal lipolysis. In fact, as you increase the concentration of insulin from zero through high physiological to gross pharmacological the rate of basal lipolysis actually increases. Like this:

If anyone thinks this might represent insulin induced insulin resistance I might be tempted to agree, though the significance to anything physiological of exposure to 100,000microU/ml of insulin seems somewhat dubious.

They did find that physiological insulin exposure suppressed sympathomimetic induced lipolysis, an effect blunted by a grossly pharmacological overdose of insulin. Again, something confirmatory to my biases:

The take home message is that insulin is not particularly effective at suppressing basal lipolysis and that basal lipolysis increases with adipocyte cell size.

We have certain inter related processes here. Insulin facilitates lipid storage in adipocytes and we know that this function is both normally self limiting via ROS generation and is augmented pathologically by the oxidation of polyunsaturated fatty acids, leading to increased adipocyte size.

As adipocyte size increases the separate process facilitating basal lipolysis progressively increases, which cannot be suppressed by hyperinsulinaemia, certainly not completely.

Above a certain size it becomes almost impossible to suppress free fatty acid release from adipocytes using insulin. Under these circumstances there is a continuous supply of free fatty acids, despite the presence of insulin and a copious supply of post prandial glucose.

At a certain point the processes of augmented lipid storage and increasing basal lipolysis will come in to something approaching equilibrium.

The size of adipocytes at this point will be determined by the level of insulin being generated by the diet, the degree of augmentation of that insulin signalling by linoleic acid and whatever factors influence the rate of rise of basal lipolysis with increasing adipocyte size (currently unclear).

That's assuming a pancreas of steel which can crank out insulin at adequate levels to control glycaemia to non diabetic levels despite an increasingly un-suppressible fatty acid supply.

This will be relatively easy, provided adipocytes remain insulin sensitive. We know from 

Diet fat composition alters membrane phospholipid composition, insulin binding, and glucose metabolism in adipocytes from control and diabetic animals

that it is perfectly possible to have insulin sensitive adipocytes, adipocyte distention and systemic insulin resistance without those adipocytes becoming insulin resistant themselves. Under these circumstances the is ample scope for further weight gain. Provided the pancreas can hypersecrete insulin, glycaemia can stay fairly well controlled as weight increases.

Whatever causes adipocytes to change from insulin sensitive, as in this last paper, to insulin resistant, as in the first paper, will markedly increase the demand for insulin to maintain normoglycaemia. If the pancreas cannot meet this demand or beta cells start to undergo apoptosis secondary to exposure to elevated glucose and free fatty acids in combination, progression to DMT2 occurs where insulin secretion can no longer control glycaemia, let alone FFAs.

With the onset of DMT2 weight gain will stall. It is perfectly possible to facilitate the process of further weight gain (and associated increased basal lipolysis) by continuing to squeeze more insulin out of the pancreas using a sulphonyl urea drug or by the injection of exogenous insulin. Both approaches appear to be favourites with diabetologists once they've started with metformin.

To summarise: Excess insulin sensitivity from linoleic acid, combined with elevated insulin secretion, expands adipocytes. Expanded adipocytes increase basal lipolysis, which is difficult to suppress. With increased basal lipolysis fat oxidation, whole body, increases and induces the normal physiological insulin resistance which occurs via ROS/Protons mechanism. Eventually reduced pancreatic function leads to diabetes primarily via the inability to secrete enough insulin to normalise glucose levels while FFAs are elevated.

There's more to this.

Peter

Metformin (12) You don't need to be SHORT

Metformin is a drug which blunts the action of insulin.

Metformin is the most widely prescribed insulin sensitising agent in the world.

Discuss.

It is quite core to any logical self consistent view of the world that metformin is an agent which blunts insulin signalling, as per the ROS/Protons hypothesis via inhibition of mitochondrial glycerophosphate dehydrogenase.

The first clinical hint that this might be correct was from this study

Metformin paradoxically worsens insulin resistance in SHORT syndrome

discussed in this post.

If you are unlucky enough to be born with with SHORT Syndrome, a genetic defect in the insulin signalling pathway, you need to be hyperinsulinaemic to maintain normoglycaemia, especially during an OGTT. If some joker puts you on to metformin for 4 days then repeats the OGTT the level of insulin needed to maintain normoglycaemia goes from extremely high (690microU/ml, pax the typo on the graph) up to way too high to measure (well over 1000microU/ml for over an hour), like this:

Note, apart from the typo for insulin units, that the colours were switched between the graphs. Oops.

SHORT Syndrome is rare. Finding studies of the effect of acute metformin administration on the results of an OGTT in normal people is quite difficult. The closest I have is looking at the effect of metformin on an OGTT in obese people who still have a normal OGTT result. This is the paper

Effects of short-term metformin treatment on insulin sensitivity of blood glucose and free fatty acids

and here are the results for the obese normal OGTT people. Dashed line is under metformin after a ten day course, solid line before metformin:

The increased level of insulin secreted is not quite enough to effectively control blood glucose. As I might have mentioned, metformin blunts insulin signalling. No surprises there then. 

However, if you give the metformin to someone who is already insulin resistant or has type 2 diabetes, the opposite happens, same study:

This has a lot of bearing on what we mean by diabetes but might be better left for a few posts while I run though the transition form health through obesity to impaired glucose tolerance to frank DMT2.

Peter

Ossabaw pigs

I notice that Brad Marshall has a great post out on PUFA/insulin sensitivity and especially ALA. Brad is seriously thinking along ROS/Protons lines. He looks at ideas I've toyed with over the years but never found the papers to follow through on, finds the papers and follows through. Enjoy.

Obesity prone pigs go from Normal to Pathological Insulin Sensitivity to Torpor when given enough PUFA

Peter

Random musings on uncoupling (7) DNP and metformin

NAFLD, NASH, ALD and alcoholic steatohepatitis (ASH?) are all associated with the accumulation of lipid within liver cells. The two primary culprits are fructose and alcohol. Both undergo rapid metabolism to acetyl CoA (+/- lactate) with the potential to generate lipid within hepatocytes as a result.

Sadly life is never quite that simple. Certainly some of the liver lipid does indeed come from the metabolism of fructose or ethanol, but back in this post there are the papers which suggest fructose acts systemically to induce acute insulin resistance in adipocytes and so releases fatty acids which transfer to the liver (and visceral fat) stores:

Fructose and lipolysis

and this post points out the same about ethanol:

Alcohol and weight loss

Hepatic lipid delivery should trigger hepatic insulin resistance and the resultant persistence of metabolic substrate in the blood should signal to the hypothalamus that there are plenty of calories available, ie it's not time to eat yet. You have only to look at the hepatic response of FGF21 production, which increases thermogenesis, in response to both alcohol or fructose to see this in action. FGF21, when not produced in response to starvation (which it is), signifies that the liver sees enough calories to stimulate thermogenesis in excess of obligate needs.

So what goes wrong in fatty liver disease?

The action of insulin on hepatocytes is to suppress glucose release, facilitate lipogenesis and facilitate triglyceride formation. You just have to ask yourself, is there any dietary component which facilitates the excessive action of insulin? Which might make a perfectly reasonable process into a lipid-storage overload pathology?

Could that be linoleic acid? Which induces a failure to resist caloric ingress at times when that would be appropriate.

Fatty liver disease, from fructose or ethanol, looks to me very much like the result of excess insulin action on hepatocytes. The same linoleic acid which produces this accumulation of lipid in adipocytes  will also facilitate accumulation in hepatocytes and facilitate the conversion of benign fatty liver into inflamed hepatitis though its lipoxide derivatives.

We've known for years that a high saturated fat diet protects against NASH: 

Long term highly saturated fat diet does not induce NASH in Wistar rats

provided it is very low in PUFA. In fact the low PUFA is probably more important than the high saturated fat content.

If we accept this chain of thought, fatty liver represents an accumulation of lipid in response to linoleic acid facilitated excessive action of insulin. It happens because while the oxidation of linoleic acid generates enough ROS to allow insulin signalling to occur, it does not allow the generation of enough ROS to limit insulin's actions when the hepatocytes are full. Exactly as for adipocytes.

So hepatic lipid accumulation is a consequence of excess insulin signalling, and only once the ability to accumulate any more intrahepatic lipid has been exceeded does the generation of ROS become adequate to resist insulin's caloric ingress/retain signal. After that, hepatic insulin resistance will occur, glucose will no longer be retained and the liver will no longer be a sump for absorbing FFAs.

Systemic levels of FFAs and glucose will rise and the rest of the body will have to go in to anti-oxidant defence mode, AKA whole body insulin resistance. Hunger will plateau and weight will stabilise.

So. The primary problem is the excess storage of (largely adipocyte derived) FFAs as intra hepatocellular triglyceride, beyond the point where this is adaptive.

It cannot happen without the LA facilitated augmentation of insulin signalling. This does not happen if the lipids being oxidised within the liver are predominantly saturated, as in the NASH prevention paper above.

Looking at hepatic lipid accumulation in these terms suggests that blunting insulin signalling might he a simple solution. Hence the efficacy of 2,4-dinitrophenol. You could view DNP as acting as a caloric sump for hepatocytes, burning off the fat and introducing a caloric deficit. Or you could speculate that all that is needed is a small drop in mitochondrial membrane potential, to produce a reduction of insulin signalling to approximately offset the augmentation induced by LA, and the problem would self correct.

I tend to favour the latter option. But then I would.

My personal view is that this is what low dose DNP does. It blunts insulin signalling in hepatocytes. Blunted insulin signalling blunts lipid accumulation and the liver never accumulates enough lipid intermediates to generate insulin resistance. Without the enhanced insulin signalling sequestering calories into lipid stores the liver will allow more glucose and FFAs in the systemic circulation which will reduce hunger. This might not be enough to generate detectable weight loss in a few weeks of a rodent study but it just might over a few years.

The parallel with metformin is that I consider metformin's core action at therapeutic dose rates is the inhibition of the mitochondrial component of the glycerophosphate shuttle, limiting FADH2 input to the CoQ couple and so limiting the ROS generation which is needed to maintain insulin signalling (and to markedly reduce insulin-induced insulin resistance, but that's another story). It does this at micromolar concentrations in the cytoplasm, where it can easily access mtG3Pdh.

Metformin and DNP both reduce the generation of ROS needed to maintain insulin signalling, all be it by different mechanism. Insulin signalling is blunted. Excess lipid (and glucose) storage is inhibited. There might be a trivial loss of weight due to reduced hunger.

ASIDE Obviously as metformin/DNP reduce ROS and insulin signalling they allow increased fat oxidation, largely via AMPK, and some "new" ROS will be generated to replace those suppressed by metformin/DNP. But the "cost" of these "new" ROS is fat loss. Which is a win overall for metformin/DNP/obesity END ASIDE.

Interestingly both metformin and vintage DNP increase lactate formation systemically, presumably because glycolysis is still on going, especially when glucose levels are raised post prandially, and the activation of the pyruvate dehydrogenase complex is blunted in proportion to the blunting of insulin signalling. Hence pyruvate to lactate becomes the preferred route to continue glycolysis.

Also both are longevity drugs, even using old fashioned plain DNP in rodent drinking water

Mild mitochondrial uncoupling in mice affects energy metabolism, redox balance and longevity

Blunting insulin signalling certainly does interesting things.

I have tried to resist insulin for decades. So far, so good...

Peter

Random musings on uncoupling (6) Nouveaux DNP

 I started here with with DNP

2,4 Dinitrophenol as Medicine

Several links came out of the paper. First was this one from Shulman's group

Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats

The paper contains a great deal of information about the development of the sustained release DNP formulation, which sounds good. All we know about the rats and diets are that they were Sprague Dawley rats or Zucker Diabetic Fatty rats and the diets are minimally described as safflower oil 60% fat for NAFLD or methionine/choline deficient for NASH.

Bottom line is that a sustained release hepatic targeted DNP preparation is enormously safe and produces marked amelioration of liver disease in all of the models tested.

Using Bl/6 mice they also show that the degree of hepatocyte mitochondrial uncoupling was so minor as to be undetectable in a CLAMS apparatus.

Next is this one, again from Shulman's lab, where the hydrogen of the DNP hydroxyl group was replaced with a methyl moiety, rendering this DNP derivative inactive. This was then converted to active DNP primarily in the liver by cytochrome P450, with no detectable toxicity and no detectable increase in oxygen consumption on a whole body basis:

Reversal of Hypertriglyceridemia, Fatty Liver Disease and Insulin Resistance by a Liver-Targeted Mitochondrial Uncoupler

There is pretty convincing evidence that both of the above modified DNP delivery systems were fairly tightly targeted to the liver. Relatively little appeared to act on other organs and there is no information about the action on adipose tissue, but then these experiments were not looking for weight loss, merely controlling the liver damage/dysfunction of metabolic syndrome.

And the drugs do control metabolic syndrome. Here are the intraperitoneal glucose tolerance test results for the high fat fed Sprague Dawley rats, red being the treatment groups throughout:

and the insulin levels at the same times:

and the results for the Zucker Diabetic Fatty rats are even more impressive:

and insulin levels:

All of this is merely by limiting lipid accumulation within hepatocytes.

And the rats stayed fat.

You have to look at this and wonder: Here we have an intervention which primarily blunts insulin signalling originating from the mitochondria of hepatocytes. A drug which reduces insulin signalling and yet leads to a dramatic improvement of of whole body insulin sensitivity.

The parallels with metformin are striking

Peter

Random musings on uncoupling (5) Vintage 2,4-dinitrophenol

Thinking about uncoupling leads to the idea that it is wasteful if it occurs in excess of that needed for useful thermogenesis. Being energetically wasteful on a fixed calorie input means you do not have adequate calories left for your metabolism (though you might cut a few metabolic corners) so you should be hungry in proportion to the extra calories-out as heat. On a non restricted diet you should just eat more.

When I started thinking about the activation of uncoupling proteins by linoleic acid and its derivatives it seemed logical to have a look at the metabolic effects of other mechanisms of uncoupling, the best known of which is 2,4-dinitrophenol (DNT). It is, at first glance, a much simpler situation than that of LA because there is no feature of its metabolic effects which might promote excess caloric storage.
All it does is uncouple respiration and turn food, mostly fat, in to heat.

A more nuanced reflection would be that such a huge calories-out might be the equivalent to climbing Ben Nevis several times a day. Which ought to make you hungry.

While high dose DNP undoubtedly does make you hungry, the increase in hunger can be relatively easily offset by mild stimulators of lipolysis such as caffeine and/or sympathomimetics.

It would take more than a couple of cups of coffee to get you up and down Ben Nevis four times in a day.

So DNP not only increases calories-out, it must also be increasing access to calories-stored, allowing them to become calories-in so as to convert them to calories-out without excessive hunger.

Reverse electron transport, needed to generate the ROS which are essential to maintain insulin signalling, is highly dependent on the mitochondrial membrane potential. The core function of DNP is to lower that membrane potential and it should lower ROS generation and so blunt insulin signalling.

The effect is non specific, it doesn't matter where the FADH2 and NADH inputs are coming from, if membrane potential is artificially lowered, all of insulin's signalling will be reduced.

Not eliminated, but enough to access adipose tissue's stored fat in proportion to the blunting of insulin's action. Clearly there is no obvious need for the decrease in insulin signalling to exactly offset the increased heat generation. It happens to be close and a bit of caffeine appears to match things up nicely.

This is how I view the high dose rate fat loss facilitating effect of DNP. It still seems to be used as such in cultures where rapid loss of residual fat is required to get the perfect physique for a competitive edge in physical culture circles. Risk of death is of little concern, after all, exogenous insulin is used to bulk up muscle before cutting fat with DNP, if you are dedicated enough.

There are currently attempts to rehabilitate low dose/sustained release DNP as a useful drug. This review was written by a researcher heavily committed to such a drug development project. He's biased, of course, but that doesn't stop him being correct:

2,4 Dinitrophenol as Medicine

In some ways I approve, getting rid of people's fatty liver for them, or even correcting full blown NASH, is a Good Thing. Except I'm uncomfortable with the concept of applying a sticking plaster to metabolic syndrome and then waiting to see what other catastrophes turn up further down the road. After all, you only have metabolic syndrome because you have chronic linoleic acid intoxication.

However this might be quite a good sticking plaster, as sticking plasters go.

Peter

Random musings on uncoupling (4) coconut

Feeding mice on a high sucrose, low linoleic acid diet activates FGF21 production by the liver which stimulates heat generation in brown adipose tissue, leading to a lean phenotype, marked insulin sensitivity and poor glucose tolerance secondary to down regulated glucokinase in the liver. This latter is not surprising as fructokinase has a much higher rate constant for fructose phosphorylation than glucokinase does. Use it or lose it applies, even if only temporarily, so glucokinase down regulates. A bit like eating a low carb diet also down regulates glucokinase.

This is the post and this is the paper:

Chronic high-sucrose diet increases fibroblast growth factor 21 production and energy expenditure in mice

Edit, this one too

Ingestion of a moderate high-sucrose diet results in glucose intolerance with reduced liver glucokinase activity and impaired glucagon-like peptide-1 secretion

End edit

My basic feeling was that fructose generated a caloric overload in the liver. Rather than dealing with this issue using hepatocyte mitochondrial uncoupling the task of dealing with the excess was delegated to brown adipose tissue and FGF21 was the messenger. "Higher  level" signalling. BAT uncouples on behalf of the liver. 

Of course that immediately suggests that other caloric overloads, especially if uncontrolled, might do the same thing. George Henderson tweeted this paper, which I've known about for years but have never gone in to in great detail:

Long term highly saturated fat diet does not induce NASH in Wistar rats

I hadn't realised how much uncoupling these rats were doing. They all weighed pretty much the same but caloric intake was way higher in the butter fed rats and even higher still in the coconut fed rats. That's interesting compared to coconut oil used in the Surwit type diets but these current diets are low in PUFA and sucrose free. Here are the caloric intakes:

The coconut based diet was particularly interesting as the rats were consuming twice the calories of the chow fed rats and weighed exactly the same. You could argue that coconut just tastes better than chow and the rats over ate then uncoupled. Or, more interestingly, you could suggest that medium chain fatty acids enter liver mitochondria in an unregulated manner and generate large amounts of input to the electron transport chain. If hepatocytes are experiencing a caloric overload what else should they do other than generate FGF21 and sub contract a calorie disposal solution to the BAT?

This arrangement would benefit, as with fructose, from the hepatocytes being the primary cells targeted to receive the unregulated caloric supply and is a good reason for keeping MCTs out of chylomicrons and passing them directly to the liver via the portal vein. Which is what happens.

So we can look at this study (just ignore everything about stress response and how a few ketones will do horrendous things to you):

Dietary Manipulations That Induce Ketosis Activate the HPA Axis in Male Rats and Mice: A Potential Role for Fibroblast Growth Factor-21

Here is what gavaging a chow fed rat with MCT oil does to FGF21 an hour later

LCT stands for corn oil. The acute effect of a low dose is almost nothing. Corn oil enters the systemic circulation in chylomicrons via the thoracic duct. It will be obesogenic as per ROS/Protons and only very mildly stimulating of FGF21 generation. Long term at high dose rates it will, as we've noted, uncouple enough to offset the metabolic syndrome induced as per ROS/Protons and result in a slim rodent which needs to over eat mildly to compensate for the side effect of uncoupling.

After coconut oil the uncoupling effect via FGF21 is marked so the compensatory eating has also got to be marked because the primary source of calories floods liver mitochondria with medium chain fatty acids.

So......... Localised hepatic caloric overload is a stimulus for FGF21 production leading to BAT thermal caloric disposal. As far as the rest of the body is concerned there is just the BAT caloric loss induced deficit to be perceived. There is a hypercaloric state in hepatocytes and a hypocaloric state in other systems, hypothalmus included. Food intake rises to maintain a normal energy supply to avoid weight loss.

Note the arrow of causality. The rats/mice are not over eating and burning off the excess. They are eating extra using an appropriate appetite to cope with BAT calorie expenditure/loss. They might not want to be hot but they have no choice. They eat to make up for it.

Peter

BTW there is this:

FGF21 treatment ameliorates alcoholic fatty liver through activation of AMPK-SIRT1 pathway

with alcohol being another hepatocyte caloric overload source which also generates FGF21 to "dispose" of the excess hepatic calories via BAT.

Using AMPK.

Which is where things get complicated.