Lifestyle-induced metabolic inflexibility and accelerated ageing syndrome: insulin resistance, friend or foe?

Serendipity strikes again!

The tipping point and the metabolic syndrome.

The picture that I used for the last post came from Lifestyle-induced metabolic inflexibility and accelerated ageing syndrome: insulin resistance, friend or foe?

Fascinating stuff!

Metabolic flexibility - do you have it?

I'm not quite sure what the picture below means (I need to do a spot of reading!).

Metabolic flexibility "bowl" and "Adaptability envelope"

While replying to Kade Storm this morning, it suddenly occurred to me that the Eskimos have an unusual ability. RER (a.k.a. RQ) normally varies from 0.7 (100% fat-burning) to 1.0 (100% carb-burning aerobically) to >1.0 (100% carb-burning, some anaerobically). Eskimos manage to get an RER of 0.600 *Mind blown.*

One theory that comes to mind is BAT. As Eskimos live in a very cold environment, it's possible that this has resulted in them having a large amount of BAT. BAT is very metabolically-active and turns ATP into heat via UCPs.

Nowadays, first-world people don't live in a cold environment (unless they're old and/or poor), so we don't have much BAT after infancy. Naturally-skinny people may be that way due to having more BAT. They seem to be able to eat whatever and as much as they want without getting fat. I would like to scratch their eyes out!

Everyone is Different, Part 3.

Cont'd from Everyone is Different, Part 2.

Hat-tip to Bill Lagakos, whose article Missing: 300 kilocalories reminded me of the following graphic from Effects of Dietary Composition During Weight Loss Maintenance: A Controlled Feeding Study.

Lo and behold, even when subjects are bribed to stick to the diets that they are provided with, the effect of eating those diets varies hugely.

So, people like ItsTheWoo and Petro Dobromylskyj (yes, I have to copy and paste the name from his site every freakin' time!) rave about how awful carbs are, while people like Go Kaleo and Matt Stone rave about how awesome carbs are.

Everyone is different for a number of reasons, some of which are unchangeable and some of which are changeable. We can't change our birth weight, what our mums ate when we were in the womb or the chemicals that we were exposed to in the past. We can't change our genes, but we can change the expression of our genes by changing diet, activity and even supplementation. See Influence of Vitamin D Status and Vitamin D₃ Supplementation on Genome Wide Expression of White Blood Cells: A Randomized Double-Blind Clinical Trial.

Adipocyte Hyperplasia - Good or Bad?

First, a picture. Ignore B, C, D and E.

The above picture is Fig. 4 from Cytokine-mediated modulation of leptin and adiponectin secretion during in vitro adipogenesis: Evidence that tumor necrosis factor-α- and interleukin-1β-treated human preadipocytes are potent leptin producers.

I've posted the above picture to show that leptin secretion increases non-linearly with increasing culture period. As adipocyte content almost certainly increases non-linearly with increasing culture period (like THIS), leptin secretion almost certainly increases very non-linearly with increasing adipocyte content. As adipocyte content increases, there's no/minimal leptin secretion up to a certain level of fullness. Above this level of fullness, leptin secretion increases rapidly. What this means is that reducing adipocyte content by x% reduces leptin secretion by much more than x%.

If somebody's adipocytes become 100% full due to caloric excess, there are two extreme possibilities.

1a: If there is continued caloric excess, no preadipocytes are converted into adipocytes. There is no storage capacity available for excess nutrients, so they remain in circulation. T2DM has developed - BAD.

1b: If there is subsequent caloric deficit, adipocytes start to deplete, storage capacity becomes available and T2DM goes away (if beta cells haven't been completely destroyed in the meantime). The relatively full adipocytes secrete plenty of leptin, so metabolic rate is high and hunger is low - GOOD.

2a: If there is continued caloric excess, pre-adipocytes are converted into adipocytes. This is adipocyte hyperplasia. There is storage capacity available for excess nutrients, so T2DM doesn't develop - GOOD.

2b: If there is subsequent caloric deficit, adipocytes start to deplete. However, there are more adipocytes than in 1), so for a given fat mass, adipocytes are emptier than in 1). The greater number of emptier adipocytes secrete less leptin than in 1), so metabolic rate is lower and hunger is higher than in 1) - BAD.

Adipocyte hyperplasia is good for preventing T2DM as fat mass increases, but bad for metabolic rate and hunger after subsequent fat mass loss. I believe that growing children are much more likely to get adipocyte hyperplasia than adults. Therefore, childhood obesity is highly likely to result in misery after subsequent fat mass loss. This is why I believe that growing children should be protected from the evul greedy manufacturers of Crap-in-a-Bag/Box/Bottle (CIAB).

EDIT: Jane Karlsson just e-mailed me a link to the following study:- Adipocyte Turnover: Relevance to Human Adipose Tissue Morphology.
"Occurrence of hyperplasia (negative morphology value) or hypertrophy (positive morphology value) was independent of sex and body weight but correlated with fasting plasma insulin levels and insulin sensitivity, independent of adipocyte volume (β-coefficient = 0.3, P < 0.0001). Total adipocyte number and morphology were negatively related (r = −0.66); i.e., the total adipocyte number was greatest in pronounced hyperplasia and smallest in pronounced hypertrophy. The absolute number of new adipocytes generated each year was 70% lower (P < 0.001) in hypertrophy than in hyperplasia, and individual values for adipocyte generation and morphology were strongly related (r = 0.7, P < 0.001). The relative death rate (∼10% per year) or mean age of adipocytes (∼10 years) was not correlated with morphology."

So, if you want to remain slim, high fasting serum insulin (due to hepatic and/or muscular insulin resistance) is bad mmm-kay?

How stuff works.

My last post got a bit technical and delved into the finer points of cell biochemistry. For those who would like to learn more about how cells work, I thoroughly recommend the book Metabolism at a Glance (Paperback) by Jack G Salway, Sen. Lecturer in Medical Biochemistry, University of Surrey. It's crammed with diagrams of metabolic pathways.

I've also got Medical Biochemistry at a Glance (Paperback) by Jack G Salway. EDIT: I thoroughly recommend this book, too.

For more general information on nutrition and metabolism, I recommend the book Introduction to Nutrition and Metabolism (Paperback) by David A Bender, Sen. Lecturer in Biochemistry, UCL.

A good website for medical biochemistry information is MedBio.info by Prof. em. Robert S. Horn.

A good website for enzyme structures is Enzyme Structures Database.

Here's a searchable version of Biochemistry by L Stryer. It's a bit dry, but of interest is Food Intake and Starvation Induce Metabolic Changes and Phosphatidate Is a Common Intermediate in the Synthesis of Phospholipids and Triacylglycerols.

Here's NCBI Bookshelf where you can search many textbooks.

Here's an absolutely humongous diagram in .pdf format of Metabolic Pathways. You need a fast machine to view this.

Update: Here are some cool Animations and Computer-Generated Movies by Harvard University.

Here's a YouTube video of ATP Synthase, which takes a proton gradient and, using a molecular motor-generator, converts ADP + Phosphate into ATP, the energy source that cells use.

Happy reading and viewing!