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Reactive oxygen species: role in obesity and mitochondrial energy efficiency

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Changes correlating with increasing obesity include insulin resistance, hyperlipidaemia, hyperinsulinaemia, highly processed food and environmental toxins including plastics and air pollution. The relationship between the appearance of each of these potential causes and the onset of obesity is unknown. Barbara Corkey discusses.

Image courtesy of interviewee. May 22, 2024

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This video video discusses the factors influencing fat storage and metabolism in the context of the obesity epidemic, particularly focusing on how changes in the food supply have introduced substances referred to as "obesogens," which can lead to inflammation and alter metabolic signaling in cells. The speaker explains the role of reactive oxygen species (ROS) in metabolic processes, highlighting their function as signals for the body to store excess fuel when needed. This video video process can become dysfunctional, leading to excess insulin production and promoting further weight gain.

The speaker outlines a hypothesis that inappropriate ROS signaling, often triggered by harmful food compounds, confuses the body’s mechanisms for managing fuel, resulting in increased eating to counteract drops in blood glucose. The discussion emphasizes the urgent need for research into the numerous new substances in food that may contribute to these effects. The speaker advocates for reducing processed food intake as a means of mitigating these issues, while also recognizing that individual actions alone won't resolve the broader obesity crisis.

Furthermore, the speaker critiques the perception of obesity as a personal failing rather than a disease linked to environmental factors, arguing for greater funding and research focused on understanding obesity as a complex health issue impacted by food technology and societal changes. The call to action highlights the need to identify harmful food additives and promote healthier dietary options to better address the obesity epidemic.

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00:00.425 --> 00:04.125
The issue was what kinds of things can happen

00:04.945 --> 00:07.605
to alter the way in which fats are stored

00:07.665 --> 00:10.045
and which signals are generated in cells?

00:10.825 --> 00:13.005
And it kind of stems back to the things

00:13.005 --> 00:16.045
that have changed in our environment since this

00:16.045 --> 00:17.685
obesity epidemic began.

00:18.305 --> 00:20.805
And the most notable and largest

00:21.225 --> 00:22.925
and dramatic change

00:23.955 --> 00:26.525
changes have happened in our food supply.

00:27.185 --> 00:29.605
And many, many of those things

00:29.995 --> 00:32.645
that are now labeled obesogens

00:32.645 --> 00:36.605
because of their association with obesity, generate,

00:37.705 --> 00:39.285
inflammation.

00:40.385 --> 00:43.485
And people, when they say they don't quite def define it,

00:43.585 --> 00:48.005
but inflammation is effectively Ross production,

00:48.645 --> 00:50.325
reactive oxygen species.

00:51.225 --> 00:52.725
And it's the normal way.

00:52.745 --> 00:55.805
For example, the body has a fighting off infection

00:56.785 --> 00:59.725
by generating reactive oxygen, oxygen

00:59.825 --> 01:02.685
and killing off the offending bacteria.

01:03.745 --> 01:08.525
So the focus on Ross came because of that connection.

01:09.025 --> 01:10.525
It is a redox issue.

01:11.105 --> 01:14.485
And redox is the ratio of a reduced

01:14.745 --> 01:16.965
to an oxidized moiety.

01:17.785 --> 01:21.845
And one of the main redox,

01:22.775 --> 01:27.405
teams in metabolism is the NADH to NAD ratio.

01:27.995 --> 01:30.525
That changes when fuel is metabolized.

01:31.145 --> 01:34.645
It changes when there's insufficient fuel.

01:35.075 --> 01:37.405
It's different when there's excess fuel.

01:38.225 --> 01:41.885
And this change in the NADH

01:41.945 --> 01:45.485
to NAD ratio is also mirrored

01:46.265 --> 01:50.085
by a mechanism that we understand quite well in the amount

01:50.185 --> 01:52.725
of reactive oxygen that's produced

01:52.865 --> 01:56.525
or the reactive to non-reactive oxygen, if you will.

01:57.145 --> 01:59.085
So the hypothesis was

01:59.235 --> 02:02.245
that changes in the redox state

02:02.625 --> 02:07.285
and in Ross levels would reflect changes

02:07.905 --> 02:10.725
in fuel storage and fuel handling.

02:11.585 --> 02:14.405
And in the course of this work, we determined that

02:15.355 --> 02:19.005
this Ross, which is a normal constituent produced in

02:19.145 --> 02:21.325
by the mitochondria in every single cell,

02:22.035 --> 02:23.245
it's normally a signal.

02:24.145 --> 02:28.685
So for example, when fuel is needed,

02:29.225 --> 02:32.765
it is converted to NADH in the mitochondria

02:32.765 --> 02:34.605
where the NADH then

02:35.275 --> 02:38.685
donates its electrons becoming more oxidized

02:38.865 --> 02:40.485
to the electron transport chain.

02:40.705 --> 02:42.205
And a TP is produced.

02:43.105 --> 02:44.685
So if fuel is still present

02:45.185 --> 02:48.565
and NADH still keeps rising

02:49.625 --> 02:51.565
and no more a TP is needed

02:51.565 --> 02:55.005
because there's enough, Ross is produced.

02:55.665 --> 02:57.005
Now this is an important signal.

02:57.425 --> 03:00.885
So when Ross goes up, it signals the cell,

03:00.995 --> 03:02.285
it's time to store.

03:02.945 --> 03:04.725
We have more fuel than we need.

03:05.345 --> 03:08.405
And so for example, in our work, we discovered

03:08.675 --> 03:12.565
that increases in Ross stimulate insulin secretion.

03:12.835 --> 03:16.645
It's a good thing if you wanna store fuel increases in Ross

03:17.165 --> 03:19.525
stimulate lipid turnover in fat cells,

03:19.895 --> 03:22.205
which again is associated with fat storage.

03:22.825 --> 03:25.365
And in the liver it inhibits glucose production,

03:25.365 --> 03:28.685
which again, is an appropriate response to sufficient

03:28.685 --> 03:29.685
or excess fuel.

03:30.505 --> 03:34.085
So this is a nice simple, normal signal

03:34.675 --> 03:39.045
that rises in when we need to begin storing as opposed

03:39.145 --> 03:42.045
to begin using the fuel to make energy.

03:43.145 --> 03:46.785
And, but what happens when you get too much of it?

03:47.915 --> 03:50.285
Well, what happens, what we, what we'd known

03:50.345 --> 03:51.365
for quite a long while,

03:51.365 --> 03:55.525
but not had any explanation for, is that in obesity,

03:55.755 --> 03:58.965
most people have very high basal insulin,

03:59.395 --> 04:02.405
insulin levels when there's no need to store fuel.

04:03.785 --> 04:07.485
And, so what, what could be the reason for this?

04:08.505 --> 04:11.635
And and what would be the consequence?

04:12.545 --> 04:16.395
Well, a rise in insulin will stimulate fuel storage.

04:17.215 --> 04:19.955
And if you don't eat more glucose will drop

04:20.215 --> 04:22.235
and you'll become hypoglycemic.

04:22.855 --> 04:27.675
So in response to excess fuel, let's say in, in that case,

04:27.775 --> 04:32.355
you would, you, you, if that were happening in response

04:32.355 --> 04:34.035
to normal eating, you would keep eating

04:34.415 --> 04:35.475
and you'd become obese.

04:36.175 --> 04:39.595
But this didn't seem to be a reasonable explanation.

04:39.905 --> 04:41.755
However, if some of

04:41.755 --> 04:44.475
that junk in our food was generating raw,

04:44.655 --> 04:47.635
it would be generating a fake signal saying, well,

04:47.635 --> 04:48.875
now you have too much fuel

04:49.655 --> 04:52.755
and raw, you know, stimulate insulin secretion,

04:52.755 --> 04:56.235
which it does, and now you have to eat in order

04:56.255 --> 04:57.635
to maintain blood glucose.

04:58.615 --> 05:01.515
So I think that this is the sort

05:01.515 --> 05:03.595
of the sequence that we came.

05:03.655 --> 05:06.155
So if, if something generates Ross

05:06.335 --> 05:10.965
or inflammation inappropriately appropriately, that will

05:11.475 --> 05:12.525
confuse the cells

05:12.985 --> 05:16.765
and put them in a storage mode when stores are not needed,

05:17.625 --> 05:20.645
and that will lower the fuel supply in the blood

05:20.905 --> 05:24.925
and stimulate eating behavior in order to restore that.

05:25.585 --> 05:28.965
So that's the, that's the, the model in a nutshell.

05:29.255 --> 05:32.805
There are like 4,000 new things in our food supply.

05:33.465 --> 05:36.685
And I was running one single small lab,

05:37.305 --> 05:38.925
but I decided to tackle it.

05:38.925 --> 05:42.405
And we, we set up a high throughput screening, core

05:43.235 --> 05:45.245
measuring the effect

05:45.245 --> 05:48.445
of different things on basal insulin secretion.

05:49.305 --> 05:52.485
And the first 50 thing of the first 50 things

05:52.485 --> 05:55.445
that we tested, five of them had this effect.

05:56.145 --> 05:58.725
So, my god, you know, a lab with three

05:58.725 --> 06:01.085
or four people, how are we gonna, you have

06:01.085 --> 06:03.005
to do dose responses, you have to know

06:03.005 --> 06:04.485
what the levels are in people.

06:05.355 --> 06:07.445
This seemed like an almost hopeless task.

06:07.585 --> 06:08.845
We started with three of them

06:09.835 --> 06:11.815
and all three of them generated Ross.

06:11.995 --> 06:14.815
And I thought, my God. And there were 4,000.

06:15.835 --> 06:18.535
So the answer is, as far as I know,

06:18.755 --> 06:20.255
it hasn't yet been looked at.

06:20.875 --> 06:25.255
And, it, it is not an e easy job

06:25.475 --> 06:28.015
for a single research lab to undertake.

06:28.195 --> 06:31.575
So what we need, you know, I, I've done high

06:31.575 --> 06:33.255
through throughput screening.

06:33.295 --> 06:35.015
I had a little company at one point.

06:36.085 --> 06:37.335
What we need is a library.

06:38.715 --> 06:39.895
And I've actually written

06:40.045 --> 06:44.695
that we need such a thing in my review articles so that

06:45.785 --> 06:47.705
I don't have, and, and I had to by each one of these.

06:47.765 --> 06:51.425
By the way, these five that I tested separately,

06:51.425 --> 06:54.105
from different companies, they were not available easily.

06:54.965 --> 06:58.425
And so, you know, to do so, you need

06:58.425 --> 07:00.225
to do high throughput screening, you need

07:00.225 --> 07:03.025
to have measure Ross production in some sort

07:03.025 --> 07:04.065
of a model cell system.

07:04.215 --> 07:06.345
It's an easy thing to do.

07:06.925 --> 07:10.785
But in order to do that, you need a library of these four

07:10.815 --> 07:13.505
that includes these 4,000 compounds.

07:14.085 --> 07:16.185
And we don't have that. So that's

07:16.185 --> 07:17.425
where we're stuck at the moment.

07:18.685 --> 07:19.785
And I'm retired still. Very,

07:20.755 --> 07:22.185
Still very intrepid though.

07:22.185 --> 07:24.265
Sounds fantastic. Okay, final two questions.

07:24.525 --> 07:27.385
How can we reverse the redox potential metabolize?

07:28.485 --> 07:31.305
So the easiest way is to remove the things

07:31.305 --> 07:34.465
that are giving false signal, which requires

07:34.465 --> 07:35.825
that we identify them first.

07:37.045 --> 07:38.865
The second easiest thing, and the,

07:38.885 --> 07:41.705
and the approach that I've taken, you know,

07:41.725 --> 07:44.625
in my little world of diabetics

07:44.625 --> 07:46.905
and metabolic disease is to eliminate

07:46.905 --> 07:50.105
as much processed food from my diet is possible.

07:51.365 --> 07:53.295
It's not going to do the whole job

07:53.995 --> 07:55.535
beyond any reasonable doubt,

07:55.535 --> 07:58.215
because so many things are different

07:59.015 --> 08:00.865
from whatever they used to be.

08:01.205 --> 08:05.335
And for example, milk that you buy lasts for weeks.

08:06.285 --> 08:09.415
When I was a child, the milkman delivered it every morning

08:10.315 --> 08:13.775
and the milk didn't last more than a, a couple of days.

08:14.475 --> 08:16.575
So something's different about that milk, right?

08:16.685 --> 08:17.815
It's not milk anymore.

08:18.355 --> 08:21.135
And if you look at the list of ingredients in the milk,

08:21.685 --> 08:24.415
it's really, I mean, one of the ones is the one I tested

08:24.525 --> 08:26.495
that causes hyper secretion.

08:27.175 --> 08:29.615
I don't know if it reaches that level

08:30.195 --> 08:32.735
and there's a lot more work to be done to prove it.

08:33.195 --> 08:36.535
But as I say, eliminating as much as possible

08:37.075 --> 08:40.735
and you can't do it all, has a beneficial effect.

08:40.735 --> 08:42.495
And we've, several people have tested that.

08:42.915 --> 08:45.895
And one of my colleagues has actually done a very nice

08:45.945 --> 08:50.455
experiment with humans in which he gave the same composition

08:50.475 --> 08:53.535
of diet, carbohydrate, protein and fat.

08:54.275 --> 08:56.745
Uh, in one case was from processed food

08:56.765 --> 08:59.865
and the other from as pure food as he could get,

09:00.525 --> 09:01.585
and the process.

09:01.845 --> 09:02.865
And then he crossed over.

09:03.045 --> 09:05.825
So during the time of eating processed food,

09:06.745 --> 09:09.105
I think the people gained eight pounds on average.

09:09.805 --> 09:11.825
And during the time when they crossed over

09:11.925 --> 09:14.065
to non-processed food, they lost it.

09:15.675 --> 09:18.455
So it, it has some value whether it,

09:18.525 --> 09:20.855
it's not gonna cure the obesity epidemic,

09:20.995 --> 09:23.135
but it is beneficial

09:23.515 --> 09:27.095
and maybe it would encourage commercial enterprises

09:27.195 --> 09:32.125
to produce foods that are contain less

09:32.185 --> 09:36.405
or tested or proven safe, additives.

09:36.715 --> 09:39.085
Well, I think that it has to, the issue

09:39.085 --> 09:40.685
of obesity is a big problem

09:40.685 --> 09:45.245
because it's considered a, bad behavior as opposed

09:45.385 --> 09:49.445
to intoxication by, environmental agents.

09:49.825 --> 09:51.405
And because it's a bad behavior

09:51.745 --> 09:53.005
and everybody thinks

09:53.005 --> 09:55.525
that humans can control their own weight, even though

09:56.105 --> 09:59.405
the evidence from the entire animal world is that every,

09:59.495 --> 10:03.685
every other creature, including us prior to the 1970s,

10:04.085 --> 10:06.045
maintained weight without commenting any calories.

10:06.585 --> 10:09.605
But now it's our fault. And as a consequence,

10:09.945 --> 10:12.845
our governments do not support research in this area.

10:13.225 --> 10:15.285
So it's terribly underfunded

10:15.865 --> 10:19.725
and, you know, for example, cancer research gets

10:21.285 --> 10:24.685
thousands times more funding to understand

10:24.705 --> 10:27.285
and to find treatments than obesity research.

10:27.585 --> 10:32.405
So my, I think that, that my main bottom line is we need

10:32.405 --> 10:33.805
to study this area.

10:33.905 --> 10:37.605
We need to recognize that obesity is a disease caused

10:38.425 --> 10:41.205
by environmental, influences,

10:41.625 --> 10:45.325
and we need to, approach it in that manner

10:45.345 --> 10:46.645
and try to find solutions.

Understanding Obesity: Signals and Food Supply

00:00:00 - The issue was what kinds of things can happen to alter the way in which fats are stored and which signals are generated in cells? And it kind of stems back to the things that have changed in our environment since this obesity epidemic began. And the most notable and largest and dramatic change changes have happened in our food supply. And many, many of those things that are now labeled obesogens
00:00:37 - inflammation. And people, when they say they don't quite def define it, but inflammation is effectively Ross production, reactive oxygen species. And it's the normal way. For example, the body has a fighting off infection by generating reactive oxygen, oxygen and killing off the offending bacteria.
00:01:09 - It is a redox issue. And redox is the ratio of a reduced to an oxidized moiety. And one of the main redox, teams in metabolism is the NADH to NAD ratio. That changes when fuel is metabolized. It changes when there's insufficient fuel.
00:01:38 - And this change in the NADH to NAD ratio is also mirrored by a mechanism that we understand quite well in the amount of reactive oxygen that's produced or the reactive to non-reactive oxygen, if you will. So the hypothesis was that changes in the redox state and in Ross levels would reflect changes
00:02:11 - And in the course of this work, we determined that this Ross, which is a normal constituent produced in by the mitochondria in every single cell, it's normally a signal. So for example, when fuel is needed, it is converted to NADH in the mitochondria where the NADH then donates its electrons becoming more oxidized
00:02:40 - And a TP is produced. So if fuel is still present and NADH still keeps rising and no more a TP is needed because there's enough, Ross is produced. Now this is an important signal. So when Ross goes up, it signals the cell, it's time to store. We have more fuel than we need. And so for example, in our work, we discovered that increases in Ross stimulate insulin secretion.

Obesity, Insulin, and Fuel Storage Dynamics

00:03:17 - stimulate lipid turnover in fat cells, which again is associated with fat storage. And in the liver it inhibits glucose production, which again, is an appropriate response to sufficient or excess fuel. So this is a nice simple, normal signal that rises in when we need to begin storing as opposed to begin using the fuel to make energy.
00:03:47 - Well, what happens, what we, what we'd known for quite a long while, but not had any explanation for, is that in obesity, most people have very high basal insulin, insulin levels when there's no need to store fuel. And, so what, what could be the reason for this? And and what would be the consequence? Well, a rise in insulin will stimulate fuel storage.
00:04:20 - and you'll become hypoglycemic. So in response to excess fuel, let's say in, in that case, you would, you, you, if that were happening in response to normal eating, you would keep eating and you'd become obese. But this didn't seem to be a reasonable explanation. However, if some of that junk in our food was generating raw, it would be generating a fake signal saying, well,
00:04:49 - and raw, you know, stimulate insulin secretion, which it does, and now you have to eat in order to maintain blood glucose. So I think that this is the sort of the sequence that we came. So if, if something generates Ross or inflammation inappropriately appropriately, that will confuse the cells and put them in a storage mode when stores are not needed, and that will lower the fuel supply in the blood
00:05:25 - So that's the, that's the, the model in a nutshell. There are like 4,000 new things in our food supply. And I was running one single small lab, but I decided to tackle it. And we, we set up a high throughput screening, core measuring the effect of different things on basal insulin secretion. And the first 50 thing of the first 50 things
00:05:56 - So, my god, you know, a lab with three or four people, how are we gonna, you have to do dose responses, you have to know what the levels are in people. This seemed like an almost hopeless task. We started with three of them and all three of them generated Ross. And I thought, my God. And there were 4,000. So the answer is, as far as I know, it hasn't yet been looked at. And, it, it is not an e easy job

Need for a Library of Compounds in Research

00:06:28 - So what we need, you know, I, I've done high through throughput screening. I had a little company at one point. What we need is a library. And I've actually written that we need such a thing in my review articles so that I don't have, and, and I had to by each one of these. By the way, these five that I tested separately, from different companies, they were not available easily. And so, you know, to do so, you need
00:07:00 - to have measure Ross production in some sort of a model cell system. It's an easy thing to do. But in order to do that, you need a library of these four that includes these 4,000 compounds. And we don't have that. So that's where we're stuck at the moment. And I'm retired still. Very, Still very intrepid though. Sounds fantastic. Okay, final two questions. How can we reverse the redox potential metabolize?
00:07:31 - that are giving false signal, which requires that we identify them first. The second easiest thing, and the, and the approach that I've taken, you know, in my little world of diabetics and metabolic disease is to eliminate as much processed food from my diet is possible. It's not going to do the whole job beyond any reasonable doubt, because so many things are different
00:08:01 - And for example, milk that you buy lasts for weeks. When I was a child, the milkman delivered it every morning and the milk didn't last more than a, a couple of days. So something's different about that milk, right? It's not milk anymore. And if you look at the list of ingredients in the milk, it's really, I mean, one of the ones is the one I tested that causes hyper secretion. I don't know if it reaches that level
00:08:33 - But as I say, eliminating as much as possible and you can't do it all, has a beneficial effect. And we've, several people have tested that. And one of my colleagues has actually done a very nice experiment with humans in which he gave the same composition of diet, carbohydrate, protein and fat. in one case was from processed food and the other from as pure food as he could get,
00:09:01 - And then he crossed over. So during the time of eating processed food, I think the people gained eight pounds on average. And during the time when they crossed over to non-processed food, they lost it. So it, it has some value whether it, it's not gonna cure the obesity epidemic, but it is beneficial and maybe it would encourage commercial enterprises to produce foods that are contain less

Reassessing Obesity: A Disease, Not Behavior

00:09:36 - Well, I think that it has to, the issue of obesity is a big problem because it's considered a, bad behavior as opposed to intoxication by, environmental agents. And because it's a bad behavior and everybody thinks that humans can control their own weight, even though the evidence from the entire animal world is that every, every other creature, including us prior to the 1970s,
00:10:06 - But now it's our fault. And as a consequence, our governments do not support research in this area. So it's terribly underfunded and, you know, for example, cancer research gets thousands times more funding to understand and to find treatments than obesity research. So my, I think that, that my main bottom line is we need to study this area. We need to recognize that obesity is a disease caused
00:10:45 - and we need to, approach it in that manner and try to find solutions.

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