I’m a country boy and I grew up around woodstoves. If you want the fire to last all night – if you want the fuel to burn slowly – what you do is you close the damper to almost nothing. If you do that there will still be a half or three-quarter of the way burned log when you wake up. If your firebox was quite large and you did this continuously you could imagine that the pile of fuel would build up.
Metabolism is a tricky thing. The mitochondria is going to mitochondria given enough fuel which in most cases is just floating there in the bloodstream. If it was the biological imperative of the organism to fatten up for winter a trick it might use is to limit oxygen flow into cells. This works in copepods!
Copepods Fatten At The Oxygen Minimum Zone
Copepods are interesting because their clade is 400M years old, they exist at the base of the marine ecosystem and they primarily eat algae, which is full of PUFA. Like grass, algae is swamp food although its a bit more literal in this case depending on the context. The copepods eat the algae and the fish eat the copepods. Copepods have neither gills nor a circulatory system. Oxygen simply diffuses through them. Copepods are not strong enough swimmers to swim against the current but they can migrate vertically into shallower or deeper water.
What do they do when they need to fatten so that they can repoduce?
In summer the C. euxinus population in deep layers of the Black Sea … small sexually undifferentiated
gonads and mean lipid content of 14.1% of body volume. At the same time, intermoult and premoult CV with enlarged gonads and low lipid content (7.7% of body volume) were found at shallow stations. … vertical migrations to the oxygen
minimum zone (OMZ) are necessary for formation of large lipid reserves providing high reproductive potential of this species. On
the basis of an energy balance model it was shown that under low phytoplankton concentration … preadults and
adults migrating to the OMZ could accumulate lipids (up to 5% of body energy content daily), in contrast to copepods constrained
to shallow oxic water columns of the Black Sea and from the Marmara Sea.— Svetlichny et al
When copepods want to fatten they swim to the area with less food because there is less oxygen there. When they are confined to “oxic” water they cannot fatten. They have to close the damper to retain the fuel. That’s how fire works.
Obese Humans Have Limited Oxygen Flow Into Fat Cells
The situation in human adipose tissue is a bit nuanced. Po2 is the partial pressue of oxygen. It simply means oxygen concentration.
Ingestion of a glucose drink increased adipose tissue blood flow and adipose tissue Po2Â in lean subjects, but these responses were blunted in obese individuals. However, adipose tissue Po2Â was higher (hyperoxia) in obese subjects despite lower adipose tissue blood flow which appears to be explained by lower adipose tissue oxygen consumption. This was accompanied by insulin resistance, lower adipose tissue capillarization, lower adipose tissue expression of genes encoding proteins involved in mitochondrial biogenesis and function, and higher adipose tissue gene expression of macrophage infiltration and inflammatory markers.
Goosseens, et al
Blood flow to the adipose tissue in the obese humans is limited and does not respond to glucose ingestion. The adipose cells couldn’t get the oxygen they need to burn the fuel even if they wanted it. But they don’t want it. The fat cells are not using the oxygen.
Why does this happen? The following paper gives some insight. They looked at glucose uptake and lactate production of human adipose cells grown in cell culture as the oxygen levels were lowered.
When cells are doing “oxidative phosphorylation”, they use their mitochondria as little woodstoves, combining the fuel with oxygen while extracting ATP and heat. Fire In A Bottle.
The other way to obtain energy is glycolysis. The cells take in glucose, extract a small bit of ATP and then eject lactate. This is what bacteria – who do not HAVE mitochondria – do. It’s also cancer cells and stem cells do.
Glycolysis does not require oxygen. So when oxygen is limiting, cells switch to glycolysis. This is what happened in the adipose cells in response to lowered oxygen:
glucose uptake and lactate release showed progressive increases as O2Â concentration fell, being significantly raised at 10% and 5% O2
—- Wood, et al
As oxygen supply to the adipose cells became limiting, they switched to glycolysis.
Chicken And Egg
This leaves us with a bit of a chicken and egg. Did the adipose cells become glycolytic because the blood supply to them was limited or did the vessels to them decline because the cells weren’t using oxygen? How do cells become glycolytic? What is the switch?
Next time we’ll talk about a model for the glycolytic switch: the activation of macrophages. Macrophages are immune cells who rely on oxidative phosphorylation until they become activated by some type of immune insult. Then they very rapidly turn on glycolysis and turn off oxidative phosphorylation.
If you are the nerdy type who wants to cheat ahead, the hint is: HIF-1a, NF-kB, Nrf2.
Goossens, Gijs H., et al. “Increased Adipose Tissue Oxygen Tension in Obese Compared With Lean Men Is Accompanied by Insulin Resistance, Impaired Adipose Tissue Capillarization, and Inflammation.” Circulation, vol. 124, no. 1, July 2011, pp. 67–76, https://doi.org/10.1161/CIRCULATIONAHA.111.027813.
Vidhya, V., et al. “Oxygen Minimum Zone Copepods in the Arabian Sea and the Bay of Bengal: Their Adaptations and Status.” Progress in Oceanography, vol. 206, 2022, p. 102839, https://doi.org/10.1016/j.pocean.2022.102839.
Wood, I. Stuart, et al. “Modulation of Adipokine Production, Glucose Uptake and Lactate Release in Human Adipocytes by Small Changes in Oxygen Tension.” PflĂĽgers Archiv – European Journal of Physiology, vol. 462, no. 3, 2011, pp. 469–77, https://doi.org/10.1007/s00424-011-0985-7.
So, by that rational, we should see that people living at higher altitudes (there is less oxygen in the air the higher you live) are more likely to be obese. But that is not what we see, it is the other way around. In fact, a study found that for every 200-meter increase in altitude, there was a decrease in the odds of obesity, so less oxygen=lower odds of obesity.