Muscle fat oxidation : FAT people Vs LEAN People

I guess we've all seen the review article from gnolls.org  about impaired mitochondrial fat oxidation in obese people.   I ran over this interesting study today and wanted to post some tidbits! ( I hate going over the older literature sometimes because odds are someone else has already posted about it on another site )

 Despite significant weight loss, a lack of improvement in the ability to increase fat oxidation during β-adrenergic stimulation in obese subjects was observed (4), and under similar conditions the ability to increase fat oxidation during exercise in T2D individuals remained impaired (5)

What the above quote should tell you is that obesity is a disease, not simply a matter of "positive energy balance". The primary lesion of obesity ( whatever the hell it is )  is still THERE and causing impairment even after weight loss.

Anyway, this paper is about how serum FFA availability might influence the oxidation of intramyocellular fat. In both lean and obese people, higher levels of serum FFA reduce the oxidation of intramyocellular lipids, so basically, fat delivered to muscle cells from the blood seems to have a higher priority for oxidation than lipid already stored within the muscle cell.  This is NOT because of an effect of extracellular lipids on intramyocellular lipolysis.

I was thinking that the association between obesity, diabetes, and ectopic fat deposition might go like this...

fasting hyperinsulinemia -> elevated adipocyte insulin resistance, -> FFA leak -> elevated serum FFA -> reduced intramyocellular lipid oxidation -> increased ecoptic fat storage in muscle.

In the study, they took muscle biopsies from lean and obese T2DM people and cultered them in vitro. The interesting thing is that even in culture, the impaired muscle fat oxidation in the obese peoples cells remains. What this tells you is that it is unlikely ( but not impossible ) that a circulating factor present in obese people is causing the overall reduced fat oxidation, but it suggests the reduced fat oxidation is an intrinsic property of the cell.

As you can see, for each *gf* variation ( which refers to the different concentrations of glucose or fat in the culture ) obese people ALWAYS have reduced fat oxidation as compared to lean people The black bar is always smaller than the white bar.

An important observation is that when fatty acid availability is high, the oxidation of intracellular lipids is decreased. In general, most fatty acids that are taken up in skeletal muscle are shuttled toward oxidation (Fig. 8A). In subjects with a reduced capacity for lipid oxidation ( i.e. obese people ) , a larger part of the fatty acids taken up may be shuttled toward storage.

When comparing myotubes from obese T2D individuals to lean controls, the oxidation of both intracellular and extracellular lipids was reduced, and the T2D myotubes showed a lower ability to increase extracellular and total lipid oxidation upon increased fatty acid availability.

Anyway, im not a big fan of the mitochondrial disease theory of obesity/T2DM,  but the fact that the impaired fat oxidation is preserved when moving from in vivo to in vitro certainly argues for it.

Then again, maybe obesity is just a morale failing. Us fatties just eat too much. If only we had more willpower we could increase our muscle fat oxidation.

Fasting Hyperinsulinemia cause of Type 2 Diabetes?

The concept that fasting hyperinsulinemia causes insulin resistance and in turn causes T2D is not a new concept, peter mentioned this paper  before, with the basic idea that chronically elevated insulin down-regulates its own receptors in all cells, so that the widespread insulin resistance seen in T2D is a consequence of the elevated fasting insulin.

Of interest, there is a section in that paper talking about how hormones regulate their own tissue sensitivity in general, and its not just a feature of insulin. This makes me wonder about sleep and melatonin. Failure to properly suppress melatonin during the day from inadequate light exposure may leave melatonin chronically elevated and thus reduce cells sensitivity to melatonin. So that when night-time comes around and its time to sleep, your less sensitive to melatonin due to it being elevated all day, and thus dont get a good nights sleep.

Is that a possibility?

Anyway, back to T2D, a more recent paper suggests that further evidence of fasting hyperinulinemia causing insulin resistance and T2D comes from patients undergoing gastric bypass surgery. ( Roux-en-Y ).

They argue that, during the development from lean healthy to obese to obese diabetic,  there is a constant and consistent elevation in fasting insulin, indicated by the brown line in the graph below.

The remission of T2D and elevated glucose levels after surgery is shockingly rapid, and is accompanied by fasting insulin that is comparable to lean healthy controls within only 1 week post surgery. They argue that the changes in fasting insulin are independent of changes in either blood glucose, serum FFA, or insulin resistance, and therefore it is the reduction in fasting insulin which is primarily responsible for the remission of T2D.

I think this totally obliterates the idea that fatness causes insulin resistance and causes T2D, because glucose and insulin homeostasis is achieved without significant weight loss post surgery.

They also argue that, the elevated glucose levels seen in T2D is due to elevated gluconeogenic substrates like lactate and alanine driving elevated hepatic glucose production. Lowering fasting insulin improves insulin sensitivity and thus lowers lactate in the blood, which in turn lowers fasting glucose. ( the mechanism for this is fuzzy however ).

To me, it seems almost too obvious that fasting hyperinsulinemia would be the cause of T2D once your told that chronically elevated insulin levels causes severe insulin resistance. Some questions remain however.

1) How exactly does gastric bypass almost immediately cure fasting hyperinsulinemia? ( glp-1 hyper-secretion?  )
2) What role, if any, does increased beta-cell mass have in this cure by gastric bypass? Does the beta-cell mass rapidly shrink after surgery? ( seems unlikely ).

Hyperinsulinemia or Insulin Resistance, Which comes first?

Some of you may have seen this study before, but *I* havent, which is why im making a post on it.

This study  is one of the references in B.Corkeys paper very interesting paper in which she lays out the framework supporting the hypothesis that hyperinsulinemia is a likely cause of diabetes and obesity. In it, she says.....

Hyperinsulinemia also can cause insulin resistance through insulin-induced receptor down-regulation both in the periphery and in the brain where hyperinsulinemia-induced insulin resistance may abrogate insulin's role as a satiety signal.

If we now turn to the 1974 study linked above we see that chronic ( 5-16hr ) insulin exposure produces a decrease in insulin receptor concentrations. Meanwhile, acute exposure ( 0-2 hr ) was without affect. This seems to indicate that it is the fasting hyperinsulinemia causing the problems,  and possibly not the acute insulin spikes in the postprandial state. Infact this is exactly what JJ talks about in his recent paper.

In JJ papers there is an emphasis on the basal hyperinsulinemia, that seems to be caused by beta cell growth. Thats probably exactly where elevated fasting insulin levels comes from, the beta cell proliferation and increase in beta cell mass.

But wait a minute, the acute postprandial insulin spikes aint off the hook yet. The burning question from JJ's paper is, what causes the increase in beta cell mass to begin with? What gets the ball rolling? Remember that we learnt from JJ's paper that insulin positively regulates the growth of its own secretory cells. Is it the acute postprandial insulin spikes then that sets us up for beta cell growth? Which in turn sets us up for fasting hyperinsulinemia?

One of Jane's comments in response to JJ's paper was that it seems to indicate that it is the absence of low insulin which is the problem. Looking at the data from the 1974 paper, Jane may have been more right than anyone would give her credit for.

Absence of low insulin  ( i.e. chronic exposure ) keeps insulin receptors down-regulated, so when meal-time does eventually come around and you eat your potatoes, what do you think is gonna happen? Blood sugar spikes, insulin spikes, and suddenly we have all this glucose and insulin in our blood but we have less insulin receptors because of our chronic fasting insulin exposure, so the blood glucose takes longer to clear and we end up secreting even more insulin because our pancreas is panicking trying to keep our blood sugar under control. If you plot these events on a graph, youd be labelled as "glucose intolerant"

We may even experience decreased satiation because of down-regulation of the insulin receptors in the brain. Maybe!

I have another post coming up which further supports the idea that hyperinsulinemia comes before insulin resistance and that hyperinsulinemia may be the initial cause in type 2 diabetes.

P.S.

In corkeys paper there is another passage worth mentioning, she says...

An elegant study by Sims et al in the 1970's found that experimentally overfed volunteers required nearly 6000 calories per day to maintain a 20% increase in bodyweight and most of these subjects rapidly returned to their normal weight at the end of the study when overfeeding ceased.

So to all those people out there who think over-eating causes obesity. The question is why didnt it more reliably cause obesity in the Sims et al study? If over-eating is such a strong cause of obesity, if over-eating is *sufficient* to produce obesity, then why does it not produce obesity in experimental over-feeding with a success rate of near 100%?

Either over-feeding is a cause, or, its not a cause. If its a cause, the success rate should be very high.

over-feeding, while it can cause *weight gain* ( which appears to be only temporary in most cases ), it does not reliably produce obesity. Remember obesity is not just defined as having a BMI > 30. Obesity is DEFINED by having a homeostatically defended elevated fat mass, and accompanying resistance to weight loss.

Gallstones in the Antarctic

 The effect of the isolated Antarctic environment on biliary disease has not been reported previously

Ok, so there could potentially be something about going on an artic expedition that predisposes you to gallstone disease.  What on earth could that ever be??????

Indigenous inhabitants of the Arctic polar regions have been reported to have higher prevalence of obesity and gallstone disease

Dietary factors, physical activity and energy expenditure, obesity and dyslipidemia affect the hepatic secretion of cholesterol and saturation of bile leading to a lithogenic state. Thus, residence in the Antarctic environment and the consequent lifestyle changes predispose susceptible individuals to cholesterol GD. 

Now, here is the first line of the text about changes in dietary habits....

Total caloric and fat intake was found to be higher and dietary fiber lower when compared with the regular diet in India

 And then, a few lines later, we see this.....

 the high energy intake can be explained by consumption of calorie-dense precooked meals, instant noodles, biscuits and canned foods 

omg look at those high-fat foods, instant noodles and biscuits!!

Now here comes the graph of the macro-nutrient intake of the diet, lets see if anyone can spot the invisible elephant in the room, as the writers of this report clearly could not....

Anyone see it?????? Calories are high, especially in winter. Fat is also high in winter! Calories and fat. Everything else looks fine doesnt it?  Fiber could be higher. That might be it, gallstones = low fiber?!

 As a consequence of changed dietary habit and lifestyle, the subjects in this study developed a positive energy balance, weight gain and obesity, hypertriglyceridemia, low HDL cholesterol and a lithogenic biliary profile

We are into the discussion section now, but still no sign of the proverbial elephant in the room.  Next! they highlight the risk factors for gallstone disease, these include ,   obesity, dyslipidemia, and .......

Diet:  The dietary assessment revealed calorie consumption and total fat intake far in excess of energy expenditure during summer. Increased consumption of energy-dense and processed foods was noted in summer when outdoor work was performed. During the lower activity period of winter, food intake including consumption of total fat and calories reduced significantly in many individuals as a result of a decreased requirement and increased awareness after diet counselling.

lol, the elephant is still invisible. Lets have a look at the conclusion.....

Obesity, dyslipidemia, impaired glucose tolerance ( hold breath in anticipation.... ) and high fat and caloric intake were found to increase the risk of developing cholesterol GD during the course of the year-long 30th Indian Antarctic expedition.

and.......breath out. No. no elephant is seen in the room according to these reporters. Better luck next time!

But me, yes ME, I think I see it ,     heres what I see........

OK look, im not gonna pretend I know exactly what causes gallstones. Does ANYONE have a definite answer? But what I do think is that there are some suspicious associations between gallstones, hepatic insulin resistance and high carbohydrate diets. First we have to remember that, yes, high CHO intake causes hepatic insulin resistance. And yes, 417 +/- 72g per day counts as "high" in my books.

Second, insulin regulates the enzyme that controls cholesterol to bile acid conversion.

And lastly, ( not a great example but what the hell ) the LIRKO mouse has a very high susceptibility to gallstone formation. Not a great example because LIRKO doesnt have "hepatic insulin resistance" per se, but rather it has complete hepatic insulin deficiency.

But the bottom line remains, dysregulated insulin signalling pathology in the liver allows the cholesterol->bile acid synthesis enzymes to go out of whack, the result of which seems to be gallstones.

Nuts!?

I like Nuts but they are not something I have really made an effort to have in my diet. However I think may have under-estimated the importance of nuts in lowcarb eating. Severely.

I ran an experiment today where I tried to eat 100g of plain unblanched almonds, which is only about 611 calories. Anyway, I got to 70g and , MY GOD, I was absolutely dying. I couldn't believe how satiating they were, I really had to force myself to eat more and it got actually a bit unpleasant.  I stopped at 80g.

I couldnt make it to 100g. -> EPIC FAIL. ( well in my defense I had already had my main meal of the day just before of sausages and eggs, but since I only eat once per day I still had room for plenty more calories )

My Motivation for Nuts!? was recently spurred after reading a paper about how a low-calorie diet ( not something I recommend btw ) that consisted of almonds instead of complex carbs produced significantly better weight  loss.

In this study humans were assigned a 1000 calorie diet per day for 24 weeks of which either 513 calories came from either almonds, or self-selected complex carbs  (peas, corn, potato, pasta, rice, etc). Here is a table of the macro-nutrient breakdown...

Right ok, so remember what you learnt at the paleo guru website? a calorie is a calorie right? You know the score, all that counts is calories, so the subjects should lose the same amount of weight. Here is the graph showing weight loss....

So as you can see, the subjects on both diets lost the same amount of  weig....... er okay nevermind about that bit. Onwards!

Heres what the researchers say........

The CHO-LCD group reached a plateau at week 16, similar to the onset of plateaus shown while using intermittent and continuous sibutramine therapy. Meanwhile, the almond-LCD group experienced a sustained and greater weight reduction for the duration of the 24-week intervention.

Infact the almond group finished with a 62% greater reduction in BMI at the end of the study, including a 50% greater reduction in waist circumference. Now the researchers have to figure out what happened. heres what they think...

higher fat diets may be more satiating than lower fat diets containing high glycemic index foods. Others have noted that unanticipated weight loss occurs in controlled feeding trials featuring the inclusion of nuts under isocaloric conditions.

The fiber matrix of the nut may have compromised the absorption of the fat from the almonds yielding an imbalance of energy sources between the groups. These data suggest that the greater weight loss observed in almond consumers may have been secondary to greater satiety and the lower bioavailability of calories from nuts 

Above all, the almond group experienced a significant reduction in fasting insulin compared to the complex carb group ( 54% greater reduction ) which was probably the true cause of the weight loss. What I personally find so astonishing is the weight loss plaeteu did not occur in the almond group, only in the complex-carb group, Infact if you look at the weight loss graph, it appears the almond group where still losing weight at the end of the study.

So anyway, if youve recently signed up to Dan's Plan, you might want to consider plain unblanched almonds instead of plain boiled potatoes. You might also want to consider cancelling your subscription because this almond study is available at Nature's obesity journal full text for free.

high-Nuts!?  bitcheez!    

thats where its at.

Or maybe,        just maybe,        low-insulin is where its at.

On a more serious note, I found some other interesting spin-offs from the almond paper.

• Replacing 500 calories of your diet with peanuts increases resting energy expenditure by 11% ( link )
• 10-15% of the energy in nuts is wasted due to processing and/or poor bio-availability ( link )

Another study published recently actually showed very slightly better weight loss in a dieting group that did NOT consume nuts compared to the group that were given 56g almonds per day. So as always in obesity research, its not too hard to find conflicting data. However I think this study has limitations, because the participants were given less strict advice about what their diet should be, where-as in the study in the top of this post, participants were given a specific diet formula, meaning they did not have to think about what to eat and probably resulted in higher compliance. Also the Almond consumption was higher in the first study, 84g per day vs 54g per day here.

Either way, I like nuts. And will start eating more of them. they are very low in the glycemic and insulin index even if some varieties contain some carbs/starch. Personally I cant stand macadamia nuts I hate the taste, but I will include almonds, brazil nuts, and cashews.

I cant believe it, 10 years after discovering atkins I am only now discovering the brilliance of nuts. duh!

High glycemic index starch promotes hypersecretion of insulin

High glycemic index starch promotes hypersecretion of insulin and higher body fat in rats without affecting insulin sensitivity.

I think im approaching a pretty convincing model for diabesity. Some additional clues come from this paper. 

The major finding here is that 7 weeks of a high GI diet in rats leads to increased insulin secretion in response to an intravenous-glucose tolerance test. Importantly this increased insulin secretion is NOT a response to insulin resistance because glucose tolerance was not impaired.

So the insulin-hypersecretion is primary.

In the discussion the researchers are not sure why a high GI diet leads to insulin hyper-secretion and speculate that it may have to do with triglyceride accumulation in the beta cells. But from JJ's paper we learned that there is positive feedback mechanism between the pancreas and insulin secretion. More insulin can easily lead to MORE insulin during future hyperglycemic challenges from your plain boiled potatoes.

Oh, and the insulin hyper-secreting rats on the high GI diet also had increased fat mass. But im sure thats just coincidence. ( feeding regime was isocaloric, just before you CICO nutters try to jump in. )

The high GI diet promoted a high insulin response during an intravenous glucose tolerance test (IVGTT) (14), which increased with the duration of feeding (15) and eventually led to fasting hyperinsulinemia

So if the results of JJ's study says that hyperinsulinemia drives obesity, we have a connection, for the above quote says that consumption of a high GI diet leads to hyperinsulinemia.

Which, according to JJ's paper says, drives obesity.

I.E. spiking your blood sugar makes you fat. 

But, most of us ( educated ) fatties already know this. So lets move on...........

It has been reported that the mRNA expression and activity of fatty acid synthase, a key lipogenic enzyme, increase in adipose tissue after only 3 wk of wheat starch feeding

hhhhhmmmm, what about 3 weeks of plain boiled potato feeding?

We speculate that this hypersecretion of insulin in response to a glucose challenge after only 7 wk of feeding may alter fuel utilization and patterns of energy disposition, irrespective of changes in insulin sensitivity.

Indeed, this study  says that  "fatty acid oxidation was significantly blunted as early as 3 wk after beginning of the high-GI intervention" and occurred before any significant increase in fat mass, indicating a possible causal role. ( only "possible"?! lol )

Bottom line, I think the idea that insulin feeds back positively to increase beta cell mass and insulin secretion is a missing part of the "Insulin Hypothesis".

Calorie restriction for weight loss?

I am strongly against calorie restriction. All the evidence I have seen indicates that, even if weight loss does occur, it changes your physiology and sets you up for future weight gain. Heres an introduction to "wet your appetite".

If an animal is in energy balance, its body mass and body composition generally remain stable. Although animals can adjust for subtle alterations in energy budget over the short term, prolonged imbalances can cause weight gain or loss. Dietary restriction has been advocated as a treatment for obesity for over 2500 years (Hippocrates, 5th century B.C.). Yet, despite the fact that caloric restriction is the oldest, most frequently prescribed and self-prescribed treatment for overweight and obesity, the strategy is seldom successful. Rates of weight loss under restriction are rarely sustained for any protracted period. Moreover, the lost weight is frequently regained when the period of restriction ends. ( link )

This paper does a good job of laying out what happens with calorie restriction, here are the best bits.....

• There are 3 primary mechanisms how organisms cope with reduced calorie intake, increased digestive efficiency, reduced basal metabolic rate, and third, reduced activity.
• There are 2 phases to calorie restriction, first, an adaption phase, where energy parameters are adjusting ( reducing ) to match the new energy availability of the diet. And second, a maintenance phase where the adjustments are now complete and energy balance is established. ( i.e. weight loss has finished, you are now weight stable at a reduced calorie intake, welcome to hypo-metabolism )
• Body temperature declines during calorie restriction, shown for both rodents and monkeys.
• During calorie restriction, not all weight lost is fat mass, a significant amount is also fat-free mass.
• Different things happen depending on the severity of the calorie restriction. For example in rats, 25% reduction allowed only temporary weight loss before compensatory mechanisms adapted and body mass increased again. Meanwhile 50% reduction wasn't able to be compensated for and body mass continued to decline.
• In Monkeys, After 30% calorie restriction for 5 years only fat-free mass showed reductions, fat mass was comparable to controls.

And lets not forget our 5% calorie restricted mice that straight out gain fat mass. In general it appears mild calorie restriction serves only to increase fat mass.

A recent study has examined the neuroendocrine changes that occur with diet-induced weight loss. ( Lets put aside the well known affect of leptin insufficiency for the moment ). One of the things that occurs in diet-induced obesity is ghrelin resistance in the AgRP neurons. Normally, ghrelin serves to increase AgRP.

So anyway, this study starts off with making some rodents fat, ( high-fat diet again ) then, after obesity is established, they switch the diet of the rodents back to chow, or chow with 40% calorie restriction. Heres a graph of the final body weights...

Both sets of rodents switched back to chow and chow with 40% calorie restriction lost weight. The calorie restriction group lost more weight than the Ad libitum chow group. Although this just barely made statistical significance. This is 40% calorie restriction btw, if you live on 2000 calories per day this is equivalent to putting you on a diet of 1200 calories per day, and you loosing only slightly more weight than someone eating 2000 calories per day.  Sounds fair right?

Now here is the really interesting part, despite both the chow and chow + 40% calorie restricted groups both losing weight, ONLY the 40% calorie restricted group experienced a ( very ) significant increase in hypothalamic AgRP expression. See next graph.....

Despite the 40% calorie restricted group weighing the same as never obese controls, they have marked increased AgRP. Hence, just because they weigh the same as controls, they are NOT metabolically the same as controls. The increased AgRP means their bodies perceive their current weight to be too low and in a state of starvation even though they are actually of normal weight.

But look at HF-C, this is the group that lost weight eating Ad Libitum. They had the same level of AgRP as controls, indicating that their bodies did not perceive their new reduced weight as a state of starvation. This result suggests that weight loss without enforced calorie restriction does not increase AgRP, and so should hopefully make you less vulnerable to weight regain. Indeed, the authors make the point that it is the detection of negative energy balance that leads to increased AgRP following weight loss, and not the actual weight loss itself. If you can lose weight without your body detecting the negative energy balance, without stimulating an increase in AgRP, your probably more likely to maintain the weight loss.

In short, this study says weight loss must be achieved without enforced calorie restriction to be sustainable. Weight loss with enforced calorie restriction increases AgRP, which is NOT sustainable unless you prefer to live in misery.

Infact we saw this same thing back in the ketogenic diet unique state study.  Mice subjected to 35% calorie restriction had a nasty increase in AgRP despite similar bodyweight compared to ketogenic fed mice eating Ad Lib. Although these mice did not start off from an obese state.

This increase in AgRP in response to calorie restriction is very prominent in the literature, and make no mistake, AgRP WILL make you gain weight.

Lets re-iterate how potent AgRP is, courtesy of this paper.

• Agouti-related protein acts as an inverse agonist for the melanocortin receptors, MC3R/MC4R
• The integral role of the melanocortin system in body weight homeostasis is supported by the fact that any mutation in the melanocortin signaling pathway including MC3R- or MC4R-null mutants and ectopic expression of MCR3/4 antagonist, AgRP, results in hyperphagia, hypometabolism, hyperinsulinemia, and hyperglycemia in both rodents and humans
• The release of α-MSH by POMC neurons and its binding to G-coupled MCR’s initiates the central anorexic signaling pathway that results in decreased food intake and increased energy expenditure while AgRP exerts its orexigenic action partly by blocking the binding of α-MSH to its receptor there by preventing the α-MSH-induced anorexic pathway
• Thyroid-releasing hormone (TRH)-, oxytocin (OT)-, and corticotropin-releasing hormone (CRH)-expressing neurons located in the PVN all express MC4R. The binding of α-MSH to MC4R on these neurons has a positive action onto the hypothalamic–pituitary–thyroid (HPT) axis and the hypothalamic–corticotropic axis (HPA). During fasting ( or calorie restriction as we learned in this post ), increased release of AgRP by AgRP neurons has been demonstrated to be a key mechanism for fasting-induced down regulation of the HPT axis and the consequent adaptation during negative energy balance
• AgRP neurons are necessary and sufficient to initiate the full feeding sequence.
• extinction of α-MSH signaling cascade was not necessary for AgRP neurons to initiate feeding. ( basically this is saying an increase in AgRP will always initiate feeding, regardless of what the POMC neurons are doing )
• Lack of AgRP neurons results in death from starvation because mice lose all interest in food and stop eating.
• AgRP decreases fertility ( link )
• AgRP increases respiratory quotient, making you oxidize carbohydrate and preserve fat. ( link ) 

"Starvation mode" is a mythical bro-science term that would commonly be stated to be a mode that you get into if you chronically restrict food intake. Well to me, it looks like "starvation mode" is actually a very real phenomenon and is mediated by AgRP.