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.
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.
Hi Kindke,
ReplyDeleteInteresting that obese myotubes (in vitro) still had lower FA ox even when mitochondrial mass was the same - suggesting poor mitochondria "quality."
or an intracellular FFA trafficking defect?
best, Bill
Yes I should of mentioned the mitochondrial mass part, the researchers say
ReplyDelete"In the present study, mitochondrial mass was not related to ICLOX in the myotubes established from obese T2D individuals. "
"These findings support a reduced mitochondrial capacity in primary cultured myotubes. This is in line with a previous report where we showed reduced activities of citrate synthase (−14%) and TCA cycle in myotubes from diabetic individuals compared with lean, whereas the mitochondrial mass was not different "
Anyway, im not a big fan of the mitochondrial disease theory of obesity/T2DM,
ReplyDeleteWhat? How? Explain!
omg!
DeleteMy very sci-ency answer is that it just doesnt "feel" right. :D
I have this analogy, where I work we have thousands upon thousands of network cables ( RJ45, fibre etc) in place and working continuously 24/7. Every so often we get network outages and the first thing we are always asked to check is the physical cabling, which NEVER turns out to be a problem. Once a cable is working it tends to work forever, for if it did not, we would get constant alarms because surely 1 of those thousands of cables would fail on a daily basis.
Im viewing mitochondria in the same fashion, and we have billions working in us 24/7, if they were so prone to failure or malfunction, surely disease due to their failure would be more rampant?
/end mumbling :)
I think this is one of those things where it is sometimes true and sometimes not true.
DeleteResearch regarding clear cut mitochondrial diseases shows these individuals tend to have specific symptoms that cluster, not surprisingly involving the energy hungry body organs mainly the brain -they develop seizures, they develop mood/personality disorders. They also develop diabetes and abnormal blood glucose regulation. Sometimes they develop more nebulous issues which is specific to the mitochondrial disorder, like lactic acidosis, and degeneration of nerves and muscles.
http://en.wikipedia.org/wiki/Mitochondrial_disease
Many metabolic disorders can be controlled by ketogenic diets. Some are not.
I believe petro discussed this recently; most metabolic disorders seem to affect mitochondria in a way that is responsive to fat based/ketogenic diet (defect in complex 1).
But, lets assume a condition which is not as severe as a frank mitochondrial disorder... perhaps instead what we have is merely a state where mitochondria are rather poor at oxidizing glucose for energy due to low numbers and high degree of damaged. The mitochondria you *do* have are mostly normal, with the exception of the ones that are dying / dead... but you merely have very few "normal" mitochondria compared to your thin crossfit attending 25 year old neighbor who thinks you need to exert some self control, lazy fat ass.
In this instance I would not necessarily expect optic nerve degeneration, seizures, encephalopathy, myopathy... but instead perhaps we merely observe that the blood glucose tends to linger abut in the blood excessively, necessitating postprandial hyperinsulinemia (because these weak mitochondrai do not produce a lot of energy, cannot respond to sugar bolus normally). This hyperinsulinemia promotes hypertension, and there is also dyslipidemia as excessive glucose is partitioned to the liver for conversion to fats and storage (again, body is not normally oxidizing glucose at meals, liver must convert it to fat for storage relatively more, with increased triglycerides and lipid abnormalities resulting).
Body fat gain occurs as energy production is diminished, people feel fatigued and appetite increases as teh hyperinsulinemia required to process postprandial glucose also suppresses fat oxidation abnormally greatly. Thus food intake makes these individuals hungrier due to greater insulinemia and suppression of fat oxidation, with relatively poor energy output from glucose and a poor ability to shift back to fat oxidation due to supraphysiological insulin to process glucose.
I don't see this as necessarily unreasonable, I think it is very reasonable.
I would expect this to be the etiology of obesity that occurs later in life and with severe insulin resistance/diabetes. Studies support that people who develop diabetes have abnormal mitochondria even before obesity and diabetes onset; it runs in families. It occurs later in life usually so there is a period of being "thin" before exploding into frank hyperglycemic fatness.
Earlier onset obesity I think is more likely to relate to genetic or acquired defects in nervous or endocrine system vs a mitochondrial origin... e.g. praeder willis with early onset severe obesity is obviously a defect in brain leptin signalling, with hallmark signs like infertility and unsuppressed ghrelin and suppression of the thyroid axis, indicating non-detection of leptin, radically different from "normal" obesity. Obesity that occurs with mental retardation is usually related to receptor/structural defects in hypothalamus.
As a network engineer, I agree - layer 1 is rarely a de novo problem. *But* - this is biology, not electronics. Mitochondria turn over periodically, and the (local) population evolves. Peter has mentioned a time or two - do you have any *good* mitochondria left to be favored? Might depend on how badly you're broken -- and for how long.
ReplyDeletehaha yes not a great analogy, but it still doesnt feel right to me. I have a case report of a women ( n=1 ) who was cured of type 2 diabetes immediately after duodenal bypass. Examples like this is why I dont feel the mitochondrial disease theory is exactly right.
DeleteWhat I mean is, while I think the mitochondria can go "off-course", its not because they are diseased, its because they are getting incorrect feedback from hormonal signals from the host.
It feels for me that my body just doesn't want to get close to 25 BMI and sending hormonal signals to keep me plump. Well ,I am 52, at that age one suppose to be realistic. I even can't starve myself - my blood sugar then goes to 125 and stays there.
DeleteNice Post!
ReplyDeleteCarole AKA Carbsaner
Hi.
ReplyDeletehttp://www.ncbi.nlm.nih.gov/pubmed/10998055
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leptin increased acetate degradation by 69% and the maximal activity of citrate synthase by 50% in isolated adipocytes.
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I'm thinking citrate synthase activity might be increased by a decrease in gluconeogenesis (and so also glyceroneogenesis, since this is in fat cells in this study). Leptin decreases fat accumulation in liver and muscle. In liver it reduces gluconeogenesis. Maybe reducing the suction of oxaloacetate out of the Kreb's cycle facilitates formation of citric acid, increasing oxidation of fat?