Monday, November 11, 2019

Protons (51) From peripheral cells to the brain

Hunger and satiety. Can these be modelled from a very simple energy availability concept?

This post is a minimally referenced ramble through how I see satiety working.

At the peripheral cellular level energy influx is controlled, to a large extent, via reactive oxygen species. These regulate insulin signalling which controls the translocation of GLUT4 and CD36 proteins to the cell surface and so facilitates the diffusion in to the cell of glucose and fatty acids respectively.

When a single cell has adequate calories it generates ROS, largely from the electron transport chain, which disable insulin signalling. This insulin "resistance" is there to limit excessive ingress of calories. ROS are the signal that no further calories are needed. At the most basic level cellular energy ingress is regulated by the core energy utilising apparatus of the cell. Excess substrate means excess ROS means shut down caloric ingress.

This is a self-contained cellular satiety signal of the most basic type. When the cell has fully adequate supplies of ATP, a high mitochondrial membrane voltage and a deeply reduced CoQ couple then ROS generation becomes almost inevitable.

It is a core, deep level, simple system. How it works is the subject of the Protons thread of posts, as is how it malfunctions.

I find it very, very difficult to envisage that the control of ingress of calories on a whole body basis (hunger/satiety) is not similarly integrated around an ROS generating system within dedicated neurons of the brain, with the hypothalamus being the most likely location.

I've had this as a persistent suspicion for a very long time but you can't get around to reading about everything at the same time. And I have to admit that neurological thinking about hunger and satiety has always struck me as a highly disreputable field. Insulin and satiety smell like cholesterol and the lipid hypothesis.

So yesterday I finally went and had a look for a reasonably recent review of ROS within the hypothalamus and this one came up pretty high in the PubMed listing

Impact of hypothalamic reactive oxygen species in the regulation of energy metabolism and food intake

This gives a flavour:

"Thus, it appears that NPY/AgRP neurons activation is mediated by a decrease in ROS levels while POMC neurons activation is driven by ROS (Andrews et al., 2008). Indeed, icv administration of ROS scavengers induces significantly lower c-Fos expression in POMC neurons and increases food intake during light cycle, observed via an increase of c-Fos expression in AgRP/NPY neurons (Diano et al., 2011). Similarly, addition of H2O2 depolarizes POMC neurons, increases the firing rate, and an icv injection of H2O2 causes significantly less feeding of mice after an overnight fast".

A lot of the work cited is not terribly well performed and no one has the Protons framework to slot their findings in to, but it's a start. What I am looking for is that these cell types do express GLUT proteins and CD36 proteins. I would expect them to be sampling arterial blood or CSF and integrating NADH and FADH2 inputs to their mitochondrial electron transport chain to "decide" whether there are adequate calories to consider that satiety or hunger might be the preferred descriptor of the body's current state.

Whether these cells express insulin receptors to facilitate ingress of substrate is something to be picked at. As I am completely biased against the concept that insulin is a satiety hormone, I would prefer this not to be the case but may be wrong. Time will tell. It looks logical to me that the brain would look at the nutrient levels present in excess of those being disposed of by peripheral insulin in to peripheral cells. As large numbers of peripheral cells become "full" under the influence of insulin, the brain should pick up the rising level of excess nutrients as the signal to call a halt on hunger. Doing this within the brain shouldn't need insulin, merely a set of relatively low affinity transporters to allow glucose and lipid uptake as insulin completes its peripheral function. Satiety should be picked up when enough cells have enough calories, whole body, that they no longer behave as a calorie "sump". The job of the brain is to pick up evidence from the nutrient levels that the sump is full and satiety can be declared.

For hunger, high affinity transporters would allow ROS to be generated easily and falling ROS would signal that energy availability was low.

These signals will come from the neural mitochondrial ETC generating ROS. The best ROS generating nutrients will be the most satiating. Saturated fats spring to mind if you follow the Protons thread.

Obviously there are whole load more hormones which can influence the generation of ROS within neurons. Physiology has applied layers and layers of signalling to maximise reproductive fitness. I have minimal interest in these "higher level" signals. They are there, they will modulate the core process I've been talking about but I see no way that they will do anything fundamentally different from or in opposition to the ROS system.

I'll give the rest of the review a bit of a read and see if it's worth posting about.



raphi said...

"Obviously there are whole load more hormones which can influence the generation of ROS within neurons. Physiology has applied layers and layers of signalling to maximise reproductive fitness. I have minimal interest in these "higher level" signals. They are there, they will modulate the core process I've been talking about but I see no way that they will do anything fundamentally different from or in opposition to the ROS system"

higher level signalling as modulating the core process is pretty much where i've landed.

Would a prediction of the model you propose be that the hypothalamic derived ROS signal is equivalent/in agreement with the sum of peripheral ROS signals? It would be simpler if it were the case, otherwise we might have to call upon higher level signalling to smooth that discrepancy, presumably..

Peter said...

That sounds correct to me, we're not talking about the low grade ROS essential for facilitating insulin signalling, but the "I'm full" peripheral signal, summed up over the whole body of insulin sensitive cells. This should be replicated in the hypothalamus to signal that energy input is complete.

Of course the main system in competition with the ETC is the NOX complexes, especially NOX4. These do function in the hypothalamus as they do in the periphery and look almost as core as the ETC ROS generation. I've seen hints that the NOX systems may be controlled by the ETC but there's a lot more to search for on that...


Pernickety said...

Could the relatively high antioxidant content of nuts and dark chocolate contribute to the lack of satiety after eating a large quantity, as this presumably reduces ROS production and generation of satiety? In the paper it stated "This anorectic effect is directly attributable to hypothalamic ROS release since icv infusion of antioxidant drugs, such as glutathion and trolox (an analog of vitamin E), abolishes the decrease of food intake." -> the effect of the vitamin E analog led me to wonder if that, alongside the high polyunsaturated fat percentage, could explain why nuts in particular are so moreish...

Peter said...

It's an interesting idea but I doubt that the antioxidants ever achieve tissue levels to do anything much. The liver has their elimination as a major priority. Looking at the sat fats vs MUFA contents might tell us more, and lots of nuts are PUFA based...


karl said...

From what I've dug up - Most antiox never are absorbed - the apparently have their effect within the bowel flora. I have a hunch they do good by keeping us from absorbing toxic metals.


The ROS signaling is within the cell - it could differ in different parts of the body. So this hypothalamus bit seems like it could drive the higher system response - hormones etc. I think you are quite right to focus on the low level stuff - the higher level systems are much to complex for humans to understand. The signals often have non-linear feed back loops that are nested in other loops - much to easy to spin any narrative one is fond of.

OT: That being said - I read a bit by tucker (an observation n=1 we really need a study) about reducing sunburn by reducing LA exposure - sun almost has to influence the ROS of the cells exposed.

Even further OT:
There is another thread/narrative I picked up via Tucker about LA and 2-AG - there are now papers that suggest LA as a cause of ADD :

2-AG is produced from Linoleic acid - The theory is that it is what causes the attention deficit problem from high seed-oil diets. It effects a cannabinoid receptor.

This is also involved in another narrative that it induces over eating.

There was a saying in my time - that pot caused the 'munchies' - binge eating.

I have no idea how solid these papers are.. but ... interesting.

Peter said...

karl, the sunburn resistance thing seems quite common with LC eating, possibly people who go LC also ditch the lipid dogma? My wife still burns easily. I can't recall the last time I burned and I live pretty well outdoors most of the summer... No sunblock.

Ah, the munchies. I'm told that the biggest danger from cannabis is consuming the contents of the shelves of all night garages...


Boundless said...

@Karl (for ω6LA), & Peter (for protons)

Chris A. Knobbe - Omega-6 Apocalypse: From Heart Disease to Cancer and Macular Degeneration - AHS19

39 minute video. He drills down to mitochondrial dysfunction induced by excess Omega 6 linoleic acid. He reviews the history of the components that define junk food, and appears convinced that ω6LA is the ringleader, and therefore the main villain in all the diseases of civilization.

altavista said...


Peter said...

Alta, I particularly like this line:

“I do it because my curiosity motivates me to do so,” he says

Says it all really.

Boundless, thanks, he certainly makes some interesting points.