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
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.
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
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
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.
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
My name is NORA VELLI, i am a RN from BAYONNE NJ. I posted under the moniker ITSTHEWOO, twitter handles itsthewoo and its_tew. You can review for yourself, years of communication between myself and these individuals.
ReplyDeleteI was targeted by EMILY DEANS MD, of evolutionary psychiatry, using the twitter moniker evolutionarypsy, back in 2010-2011. She arranged for me to be followed by hackers, and sold to a gang.
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https://youtu.be/mqEDQugmvzs
Please watch my video telling my story. It is too late for me, but i want people to know the truth.
http://evilandlies.blogspot.com/
ReplyDeletePlease also read my story. Bill Lagakos, Dr "Tro" Kalayjian , Ted Naiman and MANY MORE are all involved in this plot. They are fake influencers, established by a criminal group, particularly Dr Tro who established a CASH ONLY MD CONCEIRGE service that is actually a criminal money laundering front. I do believe EMILY DEANS is the original who unleashed this on me in REVENGE for posting rudely to her friends. Melissa McEwen detailed and hinted of it, on her blog paleo drama. She posted the ominous comment to jimmy "cute is a word used for toddlers". They framed him to go down as a pedophile 10 years later, like they set me up to be kidnapped by a gang.
This is all real, and Emily Deans MD is the mastermind i am pretty sure. She's a complete psychopath, EVEN MANIPULATING Melissa McEwen and Evelyn Kocur to seem like the "suspects" in the future. She knew a hacker, and arranged these elaborate future plots against us.
It is too late for me, but i will do my best to share our stories, her victims.
It was EMILY DEANS MD who posted under the moniker "SIDEREAL" some of you might remember. That was her. She was fanatically preoccupied with these elaborate life theft plots, even going so far as to PERSONALLY involve herself and infiltrate from 2012-2014 as this "sidereal" character. It is for this reason, I do believe she is the mastermind, as well as the fact the "main" hacker who hinted he is af riend, is about her age. I believe her REAL MOTIVE was bored in house with small children, feeling a way about being "robbed" of professional greatness. She repurposed ALL HER FREE TIME and personal angsts, into plotting against me and adding Jimmy Moore. An ironic, slow theft of 2 lives, to compensate for having to be forced to invest, in her two children, cheated out of "her right" to greatness in the real world.
ReplyDeleteSHE MANIPULATED McEwen to seem like the source, even Kocur. It was her. She's a psychopath, will never face justice, but I will TALK as long as i can. I am not OFFICIALLY kidnapped yet, just virtual kidnap, sold and raped every day.
https://evilandlies.blogspot.com/2023/04/fake-lawsuit.html
ReplyDeleteOH, AND ONE MORE THING. For MONTHS they have been threatening to frame me in a lawsuit. I am pretty sure this will happen mid April. This group can make anything not real, real AND anything real, not real. They have hackers, that can hack WEBCAM DATA to make fake videos, fake audio, AI photos you name it. By the same TOKEN, they can hack databases, to set people up that they never held licenses, or never went to school.
I am not sure what their angle is, but i suspect it will be either manipulating evidence AFTER infiltrating legitimate cases I may have been involved in... or they will frankly WIPE all data that EVER held a RN license, that I went to school and was valedictorian of my class.
The truth is, I have held an active unblemished license in the state of NJ since 2008. FOR NOW this is public free available information. I put a screen shot on my blog.
I will not be able to stop OR defend myself against what they will do. But I can talk now, before it happens... while her WHITE MD ELITIST friend, mocks it will happen.
Peter, interesting connection. I'm wondering if PM2.5 act as scavengers of pure H2O2, similar to how NO acts as scavenger of pure ozone (https://mct4health.blogspot.com/2022/11/ozone-o3-has-antioxidant-effects-are-we.html). If H2O2 is disposed of prematurely due to pollution, it is not available for proper regulation and activation of the antioxidant chain (like H2O2-NNT-NAD+). Just an idea.
ReplyDeleteJaromir
1) "these are very deep insights. You don't see that nowadays"
ReplyDeletei feel that's accurate, sadly
2) "But under everything is the ROS system"
my 2 favorite filters: natural selection and the ROS system
So the flux of fatty acids going in and out of adipose tissue is controlled by insulin x insulin sensitivity.
ReplyDeleteWe know that:
LPL move fat in to fat cells. HSL moves fat out of fat cells.
insulin is known to activate LPL in adipocytes
HSL is inhibited by insulin.
It appears that ROS is what controls insulin sensitivity.
There is also this:
Obesity is associated with macrophage accumulation in adipose tissue
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC296995/
My hunch is that ROS is also part of some immune signaling pathway - triggering macropahage.
(I think of metal exposure being a big cause of increased ROS).
The bit about fine particles - where the material is not well defined - might be misleading a bit.
The finer the particles the higher the surface area to volume. This really matters - I could swallow a couple of grams of lead - no ill effects - but if I swallow a gram of nano particles of lead - I would die. When we get to close to nano particle size - the area - and thus the likelihood of biological interaction goes very high.
The surface area of a sphere is:
A = 4πr^2
The Volume of a sphere is :
V = 4/3πr^3
So the ratio of A/V is
3/r
As r becomes very small the area is greatly increased. Take particles of sand - say 1mm grind it down to 100nm and for the same volume, you have 10,000 times more surface area.
The effective dose of particulate matter that doesn't dissolve is a direct function of the surface area. Things that are GRAS may be no longer be safe as a fine powder.
Anyway - the hypernovalty of what now passes for food and even the air we breath has risks that are not quantifiable for the complex systems that make up life. Not sure how we fix this on a population level.
,.,. Wandering Wondering OT:
Vit-D - I'm drawn to the appealing narrative that cats get vit-D from the oils they consume from grooming fur that has had sunshine exposure. I've started wondering if their grooming behavior has been selected for just this purpose? What happens to cats that only get sun through the filtered light of a gas filled window? Or a cat that can't groom for some reason?
Some young student that wants to publish an interesting paper could control the UV exposure of cats for a time and measure the vit-D levels.
Or is there a difference with vit-D and humans? There seems to be a relationship with brain development and vit-D - did we evolutionary loose our fur to improve our brains? Did we loose skin pigment as peoples migrated to the north for the same reason?
"Interestingly,lung-specific overexpression of the antioxidant enzyme extracellular superoxide dismutase (ecSOD-Tg) protects against PM2.5-induced pulmonary oxidative stress, preserves vascular VEGF and insulin sensitivity, and prevents vascular inflammation (20, 23), suggesting that pulmonary oxidative stress is a key mediator of PM2.5-induced vascular pathologies."
ReplyDeletehttps://pubmed.ncbi.nlm.nih.gov/33666505/
Is it an effect of eliminating O2- or increasing H2O2?
Peter, this looks like newer version of "A" shape insulin sensitivity curve.
ReplyDeletehttps://www.researchgate.net/publication/51811134_Concentration-dependent_Dual_Effects_of_Hydrogen_Peroxide_on_Insulin_Signal_Transduction_in_H4IIEC_Hepatocytes
karl, ROS seem to underly pretty well everything. It's amazing how the various overlay systems (opioid, angiotensin, GH etc etc) keep their signals separated! Presumably that's what the overlay proteins are doing. Re particle size, I guess you could consider this in studies where pelleted food is non obesogenic and the same food as a fine powder -> obesity.
ReplyDeletePlus re vit D, I see a preprint is out that it, like HCQ, appears to work against covid. The Vit D preprint particularly surprises me as the previous D studies have been very random in their outcomes in other infections. When people have to
argue that a study used the wrong form, the wrong dose or the wrong duration I wonder if the intervention works at all. I recall curcumin. It probably only works if harvested with a golden sickle at midnight by a naked virgin who has two children. Under a full moon.
So D seems to work re covid, but you can only get published once the vaccs have made enough $$$$.
Jaromin, nice find. Sadly a missed chance for insight that ROS underly insulin signalling, but clearly describing reality.
Re FPM. It looks like it's a localised false signal acting on part of a generalised control system. I wonder how much of a problem it would cause if it was dropping on to a system already attuned to high ROS (ie ketogenic diet) with high compensatory antioxidant systems and a deficit in substrate for long distance signalling molecules such as 4-HNE and family?
Peter
Oh, forgot. If you limit the players in diabesity to LPL and HSL you will end up lost. You need ATGL and basal lipolysis to make sense of the system.
ReplyDeleteP
Peter, What goes 'round comes around. Thoughts?...https://mistermedic.substack.com/p/how-to-cure-post-covid-syndrome-permanently?utm_source=post-email-title&publication_id=849551&post_id=113367440&isFreemail=true&utm_medium=email
ReplyDeleteNice adipocyte graphic in this paper:
ReplyDeletehttps://www.cell.com/fulltext/S1550-4131%2806%2900120-3