PTP1B protein and leptin

Obesity is a disorder of leptin resistance (in general). Researchers have found a protein that is necessary for this leptin resistance, so it seems.

Obesity Researchers Identify Protein That Overcomes Leptin Resistance

Nearly all obese individuals are resistant to leptin, the hormone that signals the brain that our appetites are satisfied and we can stop eating. For this reason, explains study co-senior author Barbara Kahn, M.D., Chief of Endocrinology and Metabolism at BIDMC, efforts made several years ago to use leptin in drug form to treat obesity were largely unsuccessful. "The majority of obese people actually have high levels of leptin," explains Kahn, who is a Professor of Medicine at Harvard Medical School. "But they are unable to put it to use."

In this new research, Kahn, together with co-senior author Benjamin Neel, M.D., Ph.D., -- Director of the Cancer Biology Program at BIDMC who studies the biological functions of molecules known as protein-tyrosine phosphatases -- initially began studying PTP1B (protein tyrosine phosphatase 1B) to determine its role in regulating insulin receptor signaling. "We hypothesized that in the absence of the PTP1B protein, you would have increased insulin sensitivity and protection against type 2 diabetes," adds Kahn.

....

"What was unanticipated, however, was that the [knockout] mice were surprisingly lean."

[Emphasis mine]

This is more good evidence that leptin resistance is a large part of the problem in obesity, suggesting that it is a valuable avenue to explore.

It would still be better for people to not eat foods that dysregulate their systems in the first place. However, it isn't obvious that people can go back from serious leptin resistance to normal without help, even if they are able to fix their diets.

Concrete progress

Well, concrete forms ...

 

and gravel too ....

 

Looks like a construction site.  :-)

Dig like you mean it

That big digging machine?

I used to go down a step to get into my basement




Then it got a bit harder



Now? It's a scramble up. I think that's a 3' jump, at least.



There's a hole out there, yep.







And a pile of dirt, oh yeah.

People here

I went outside this morning & found people spray painting my yard:



That's Jake with the paint sprayer and Nate helping with laying the string to paint along.

They put up a fence to isolate their area from the front yard.



I should have mowed the front yard over the weekend, while it was easy to get the lawnmower from the basement.

Triglycerides induce leptin resistance at the blood-brain barrier

And you say, so what?

Leptin resistance (in a nutshell) induces feelings of hunger.   It causes the body to conserve energy (e.g. slow down the metabolism and movement, hence burning less energy) and causes the animal in question to eat more.   In short, leptin resistance means that the brain thinks that the animal is starving and should fix the situation post haste.

I just read this paper:  Triglycerides induce leptin resistance at the blood-brain barrier The short summary is that triglycerides (aka TG or TAG) cause the brain to not see the leptin in the body.   They tested TG concentrations in various ways and discovered the conclusion listed -- but there is a twist.   It isn't just an random TG that causes leptin resistance:

These results suggest that leptin transport will be inhibited by triglycerides endogenous to blood.

 

So, what causes the body to make TG?   Hmm ... has this been heard of before?  Here's another paper:

Fructose induced lipogenesis: from sugar to fat to insulin resistance

And the pullquote:

Fructose, in contrast to glucose, is known to potently stimulate lipogenesis

Lipogenesis means that the body makes fat -- that is, it is making endogenous TGs.

In other words, there is evidence that fructose makes people fat by tricking their bodies into thinking they are (literally) staving -- so the people eat like that is all that is standing between them and instant death.   At an even more basic level -- eating foods made with sugar and HCFS will make people fat and sick.

Digging ...

We have digging!

There is a hole by the basement door ....



There is a digger ...



The birds are liking all this new dirt ... yummy worms have been turned up, they say.



On the way!

New top, done

I finished the top I had started:



The water blotch is from the iron (I was eager to get it posted). I tried it on, I can get it over my head even though it is supposed to be sized for super stretch knits.

I cut a B cup, which seems to be big even on the dress form. Hmmm ... It has a funky place in the front, I must have not been careful sewing it there. Aside from that, it might be wearable. The dress code at work is pretty lax. :-)

I put elastic around the neckline, in the hopes it would not stretch out. The pattern called for seam binding, but I didn't have any on hand, so I used a strip of the pink knit instead.

The back. The arms are actually symmetrical, I just didn't spread them both out.



Not great, but it fits reasonably well & I did learn by doing.

New project

I looked at my pile of possible projects and picked one:

I plan to make the short sleeve version, A.

I went though my pile of clothes a bit ago & got rid of a lot of them. However, a few items fell into the "I could remake this" category. In particular, there were some long T-shirts that I planned to use for "muslims". When I dragged them out I decided I could perhaps use them to make a garment -- at worst, it won't work, but I'll learn more about how the patterns works, which is the idea.

Here are the victims:

Color blocking, yep, yep, yep.

Just saying ....

²⁸And we know that all things work together for good to them that love God, to them who are the called according to his purpose.

 

Romans 8:28

King James Version (KJV)

And who is not in that group?   In the depths of the heart for everyone, the light of God shines and shines forever, shining with perfect love on all of God's creation.

 

 

No more back porch

I looked out my back window & noticed a pile of wood in my back yard:

 

Gray wood, the color of my house.   I went over to the back door & opened it, to be greeted by a piece of plywood.   The contractors had come by & torn off the back porch.

 

 

A few days ago it had looked like this:

They put in metal posts to show the corners:

I think the new porch will overlap the existing basement window a little bit, but the stairs are supposed to be offset from the wall, so it shouldn't block out too much light.

I am told that the permit has "conditional approval", so hopefully that means that the contractors can start digging and all soon.   With luck, we should be able to pick it up Monday.

 

 

Joe Walker Harvey Memorial

We had the memorial service for my nephew, Joe Walker Harvey, on Wednesday, 15 June 11.

 

Joe Walker Harvey

It was held at the Salvation Army center in Tucson, led by Captains Jason & Angelina Koenig.   Joe had spent time at the center, so the people there knew him.   They were totally sweet at helping us, which we very much appreciate.   If anyone were inspired to give a donation in Joe's name, I can recommend the Amphi center of the Salvation Army as a group that is doing good work in the world.

There were over 50 people who came, including teachers and the president from the school he was attending, friends from a program called Camp Wellness and friends from previous schools, from the Salvation Army, from the neighborhood and friends of his grandmother.

Before the service, the family sat in the antechamber to the chapel, where mourners stopped to view the photos and mementos that my mother had put out and to sign the guestbook.

 

Joe's grandmother, with friends from Sonoita

Joe's uncles John and Loren.   Loren was in a car accident, which damaged his hand.

The photo table

A friend of Joe's from Camp Wellness and a friend from Sonoita

The chapel before the service

There was a reception after the service, where people congretaged to talk about the good from Joe's life.

Joe's mother is in purple and his uncle Loren is in the black shirt.   His mothers SO, Richard, is in the red shirt

There were nummy nibbles to nosh on while talking.

 

Complexity in physiology and in society

I was thinking about the amount of complexity in human physiology compared to the amount in social affairs.

The amount of complexity in physiology is very large, but it is arguably bounded.    There are a certain number of molecules that interact in certain ways.   These numbers are both large, but in general, they don't change or grow arbitrarily.   That makes the problem huge, but within reason, bounded.   Hence, it is imaginable to get a good understanding by putting out an immense amount of work and creativity.

This isn't true for social situations.   In society, the actors are changing all the time and the ways they can and do interact change in unpredictable ways.    I would not call these changing patterns random, but the situations in which they occur are so complex and subject to change that it seems like an almost impossible problem to gain a complete understanding.

It's a bit like the difference between Newton's laws of motion (F  = ma), where the basic law is simple, but the effects are vastly complicated, and Boltzmann's statistical mechanics, where he didn't even begin to try to try to predict the actions of individual molecules, but with the difference that the individuals involved having a much larger range of potential actions.

We do try to predict social trends, but with uncertain success.   It still seems to me that it should be possible to get enough of a clue to be able to do some degree of meaningful modeling, but modeling that should be used with a lot of care and checking to see the effect of any changes.

 

More on fructose and obesity

There seems to be a fairly straightforward pathway here:

1. Eating fructose causes the body to make high levels of triglycerides (1)
2. High levels of triglycerides cause leptin resistance, by an unknown mechanism (2)
3. Leptin resistance causes hyperphagia (overeating), presumably due to increased hunger
4. Overeating causes obesity

It is reasonable to think that anyone who expresses the fructose receptor on their liver will get leptin resistance and thus, will get fat, if they eat enough fructose. I have heard that not everyone does express the fructose receptor and people that don't have it don't get fat, but I haven't found the reference. I'll post it if I do.

At any rate, for a given level of fructose processing, increasing ingestion of fructose would increase TG output, thus increasing leptin resistance. Thus, with a reasonable level of certainty, eating large amounts of sugar or HCFS will make people fat. How much it takes would depend on the person and how much of the fructose they process.

Then the situation becomes self-reinforcing. If the person quits eating sugar, there is still a lot of fat stored up. If it is released, the TG level would be high, causing the leptin resistance to remain, causing the high levels of eating to continue, so the fat cells continue to be full. Exercise might help with this (my guess) by burning off the fat as it is mobilized.

In other words, the best way to avoid being fat is to not go there in the first place. A good way to do that is to not eat sugar, at least in large amounts. A piece of pie at Thanksgiving, or ice cream on the 4th of July would be fine for people with normal metabolism. None may be a good amount for those with damaged metabolism, so the problem has a chance of not getting worse.


1: Fructose: Metabolic, Hedonic, and Societal Parallels with Ethanol
2: Leptin and the Control of Body Weight: A Review of Its Diverse Central Targets, Signaling Mechanisms, and Role in the Pathogenesis of Obesity

Leptin and the Control of Body Weight: A Review of Its Diverse Central Targets, Signaling Mechanisms, and Role in the Pathogenesis of Obesity

I just read the paper Leptin and the Control of Body Weight: A Review of Its Diverse Central Targets, Signaling Mechanisms, and Role in the Pathogenesis of Obesity

It is mostly a review of the details of what is known about how leptin fits into the system of energy homeostasis. There were a couple of things that caught my attention. One is that high triglyceride levels cause the leptin system to think it is detecting starvation:

Several factors
have been identified to influence the
rate of leptin transport into the CNS.
α-Adrenergic stimulation for example
increases transporter activity (35),
whereas hypertriglyceridemia markedly
impairs it (36). Hypertriglyceridemia
is generally observed during prolonged
starvation and it is hypothesized that
the ability of triglycerides to inhibit leptin
transport may have in part arisen as
an evolutionary mechanism to counteract
the propagation of anorexic signals
during food shortage.
hypertriglyceridemia is also associated
with obesity and may in part be
responsible for the impairment of leptin
transport that is observed in obese
individuals and defines the condition
of peripheral leptin resistance (32–34).
Peripheral resistance like central resistance
is both a cause and a consequence
of obesity, meaning that the two types
of resistance are likely to co-exist and
once established set off a vicious cycle of
weight gain

There is a food that is common in present day America that is uniquely good at causing high triglyceride levels -- fructose. See for example, Fructose: Metabolic, Hedonic, and Societal Parallels with Ethanol, in the section titled DNL. DNL is an acronym for de novo lipogenesis, which is fat that the body makes out of carbohydrates.

 DNL is markedly
increased by excess dietary CHO, rather than excess dietary
fat (78). For example, if total CHO energy intake
exceeds total energy expenditure, hepatic DNL is incremented
10-fold (79). Similarly, on a high-CHO diet, DNL
synthesis is 27 times increased in the fasting state as
compared with a low-CHO diet, and 4 times increased in
the fed state (80). Fructose is a primary driver of DNL.
Human studies demonstrate a rate of fractional DNL of
2% with glucose and 10% after 6 days of high-fructose
feeding (81,82) A recent human study demonstrated that
fructose feeding increased fractional DNL to 17% (83).

In other words, this adds up to strong evidence that eating high levels of foods made with table sugar and/or HCFS will disrupt the energy homeostasis in the body, causing the body to think it is starving and hence, driving excessive eating.

The other piece of suggestive information in the leptin article is that leptin ties into learning in the brain. The authors don't say this, but it is easy to imagine that what is happening is that the brain takes special note of the foods it is eating when it thinks it is starving and turns on what is called the hedonic reward system. In other words, the brain "decides" it really likes foods it eats when it thinks it is starving.

It's easy to see this as part of plants grand scheme to get their genes (seeds) transported far and wide. By producing high levels of a food that causes the animals to eat it to want more of it, the plants encourage the animals to eat as much as they can -- thus carrying the payload (from the plants point of view) far from the plant mother ship, where the baby plants have a better chance to grow and spread.

House addition, starting work

The crew arrived today to start working on my house. They did a lot in a day. The first thing is to get rid of some junk and a lot of blackberries.

They cut down the tree in the side yard:

Now there is a big pile of branches in the back:

From the front, looking into the back yard:

Looking towards the side yard:

From the back, looking back at the house:

New top

I made a top. It looks pretty good, according to me:

Front:

Back:

It has this cute opening in the back, at least in the picture. Someday I'll take a picture of it on me & see if I still like it.