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.

Peter