Obesogens

How might we define an obesogen?

If we go back to this paper from 1974

Evidence for Electron Transfer Reactions Involved in the Cu2+-dependent Thiol Activation of Fat Cell Glucose Utilization

we have this well worn graph:

We can clearly observe that if we expose adipocytes to any local ROS generation of the equivalent to around 0.3-1.0mM of hydrogen peroxide we can perform exactly the function of insulin on glucose uptake and oxidation in the complete absence of insulin itself.

The effect of ROS on glucose incorporation in to fatty acids was reported by the same group a couple of years previously.

Cu ++ -dependent thiol stimulation of glucose metabolism in white fat cells

At this point they had not realised that hydrogen peroxide (+/- superoxide I guess) was the essential insulin "mimetic" and were still interested in sulphydryl groups per se as the mediator of insulin signalling (understandably so, just look at the structure of insulin itself). Once they realised that the Cu2+ ion was essential in combination with a sulphydryl source I think the penny dropped that ROS were the active essential component, hence the 1974 paper. Given the tools they had in the 1970s these are very deep insights. You don't see that nowadays.

Anyway, if we combine the ideas from both papers we can ask very simple questions about exogenous obesogens.

Just consider Fine Particulate Matter (FPM), an absolute hot topic in 2023 (thanks to Gabor Erdosi for the link and the hints to go and Pubmed the other two)

Fine particulate matter induces adipose tissue expansion and weight gain: Pathophysiology

Thirty secomds on Pubmed produced this

Fine particulate matter (PM2.5) promotes IgE-mediated mast cell activation through ROS/Gadd45b/JNK axis

and FPM even phosphorylates AKT, just like insulin:

Urban particulate matter activates Akt in human lung cells

and, slightly less topical but still good, endocrine disruptors

Induction of oxidative stress by bisphenol A and its pleiotropic effects

or low dose TNFa

MiR-29c Inhibits TNF-α-Induced ROS Production and Apoptosis in Mouse Hippocampal HT22 Cell Line

I haven't read any of the above papers. The titles/abstracts tells you how essential ROS are for the the actions of these known obesogens.

My view: compounds generating ROS "equivalent" to 0.3-1.0mM of exogenously applied H2O2 will mimic insulin, continuously, and promote adipogensis without exposure to insulin or to food intake. The "uncontrolled" loss of calories in to adipocytes will make you hungry. You could include very low dose (<1μM) 4-HNE with these.

Between 1.0 and 5.0mM "equivalents" of H2O2 exposure will generate insulin resistance. This will limit fat gain at the cost of hyperglycaemia and/or hyperinsulinaemia.

With H2O2 at as low as around 5mM then all function as an insulin replacement is lost and we are getting beyond insulin resistance and in to cell dysfunction, ie the region of ROS -> apoptosis, given enough ATP or ROS -> necrosis with inadequate ATP for apoptosis. And all shades of grey between the two. Very high H2O2 is lethal.

Neutrophils do not throw H2O2 (and superoxide) at invading pathogens to make them grow and/or reproduce. ROS from a respiratory burst are at usefully lethal levels.

These features of the ROS signalling system are quite distinct from the action of linoleic acid and metformin, which tweak the ROS system in their own distinctive ways. But under everything is the ROS system.

I may have mentioned that before.

Okay, hopefully back to metformin soon.

Peter