Amber O'Hearn has a podcast conversation up on Spotify with LowCarbLogic here. Very early on in the discussion she mentions this particular study from Mark Friedman. He has championed the concept that obesity is a result of the sequestration of lipid in to adipocytes, fat trapping. This is mediated by insulin, hence the role of low carbohydrate diets, ie low insulin diets, in the management of obesity.
This idea, promoted by Gary Taubes, has profoundly shaped my thoughts on obesity, in common with those of Amber. It is difficult to over emphasise how important this is to any sort of understanding. It's that mind-bending concept that obesity is *causal* to over eating.
Your adipocytes steal your calories, so you have to eat extra calories to have adequate substrate for energy generation to run your metabolism.
Getting fat makes you hungry.
Of course there are a number of major problems with this simple but incomplete hypothesis. The two most spectacular of which are the observation that countries such as Japan and China, whose populations ate the vast majority of their caloric intake as rice, historically had no obesity and, conversely, that of rodents fed on an high fat, low carbohydrate diet become grossly, grossly obese. D12942 supplies only 20% of calories as carbohydrate but is the gold standard for generating diet induced obesity in rats and mice.
What separates fat trapping from obesity is the failure to limit insulin signalling to the appropriate physiological level. Correctly functioning insulin signalling does not cause obesity.
You cannot talk about what controls obesity without talking about what controls insulin signalling. Oddly enough there is more to insulin signalling than the level of insulin in the plasma.
Understanding insulin signalling is impossible without appreciating that the system is intrinsically related to the actions of reactive oxygen species, as elegantly demonstrated by Czech back in 1974. You can activate all of the functions of insulin on adipocytes in cell culture by exposure to hydrogen peroxide. Low concentrations activate the insulin signalling cascade, higher concentrations inhibit it.
Of course there is no point in talking about the generation of ROS without understanding the work of David Speijer. There is a comprehensive description of his ideas, from 2019, and his thinking goes back to 2011. Probably further. I would also say that Skulachev's work on ROS and membrane potential is fairly essential too.
All I have done in the Protons thread is to throw together the ideas from Czech and Speijer and spend nearly 14 years thinking about them. With a few other inputs from evolutionary biology and the origin of life, largely from Nick Lane. And especially thinking about the paradoxes.
Oh, the trigger for this post was that I have already written a separate post about that study published by Mark Friedman in his early days, back in 1984. It's the same study which Amber cited at the start of the podcast. Having her discuss the same study which I'd already written about but not quite published struck me as profound synchronicity. Got me thinking. Anyway, this post is too long and philosophical to go on to doodle lines all over graphs so I'll update the original post to include Amber's mention and get it published separately fairly soon.
Peter
Addendum. There has been some posting recently on X about the role of the Randle cycle by which the conversion of glucose to malonyl-CoA inhibits the uptake of long chain fatty acids in to mitochondria, leading to failure of fatty acid oxidation and preferential oxidation of glucose derivatives. This is absolutely correct. The massive hole in citing the "Randle cycle" to explain obesity is in failing to ask what limits this from happening. Obviously it is limited by limiting insulin signalling. What limits insulin signalling? Well duh, ROS limit insulin signalling. Presenting a cell with a mix of glucose and long chain saturated fats means that the oxidation of these fatty acids correctly limits insulin's ability to activate both the PDH complex and the ACC complex. So the concentration of malonyl-CoA is kept at a functional level.
Saturated fats limit insulin signalling to allow co-oxidation, in the same cell, of both glucose and lipid substrates. Hence the generation of whole organism respiratory exchange ratios that indicate both fatty acid and glucose oxidation are occurring concurrently. As they do.
Unless that fatty acid FAILS to generate adequate ROS to apply this essential limitation system.
Linoleic acid's low ROS signal (compared to stearate) allows excess insulin signalling to facilitate malonyl-CoA generation and the immediate inhibition of fat oxidation, even within the first hour of ingestion of D12451 (kid brother of D12942). I hope you have all read Matsui et al's paper where an oral dose of metformin 300mg/kg, 30 minutes before food access after an overnight fast, completely normalised caloric intake of D12451 when it is eventually re-supplied. And Chung et al's paper where they tracked the RER daily during the three day transition from low fat to D12451. This 45% fat diet *raises* the RER, despite increasing fat provision and decreasing carbohydrate provision. All just Protons.
It's quite straight forward.
Of course, without Protons, you're lost.
I'll stop now.
P.
