Skip to comments.Obesity-related disease trigger found, says UCSD team
Posted on 06/24/2014 10:50:26 PM PDT by 2ndDivisionVet
Obesity-related diseases such as Type 2 diabetes and metabolic syndrome are triggered by a lack of oxygen in adipose cells, according to a study led by UC San Diego researchers.
An excess of fatty acids causes an increase in oxygen consumption, which outstrips the supply, triggering hypoxia, the study found. This leads to inflammation in the adipose cells, which in turn leads to insulin resistance, obesity and related diseases.
And that's the short version. The full chain of events is even more complicated.
The study, performed in mice, points to possible therapies in people, said researchers led by Dr. Jerrold Olefsky, an associate dean at UCSD School of Medicine. They not only identified the root cause, but were able to stop it.
The study was published June 5 in the journal Cell. Olefsky was senior author; Yun Sok Lee, Jung-whan Kim and Randall S. Johnson, also of UCSD, were co-first authors.
Olefsky's findings interest Janssen Pharmaceuticals, a Johnson and Johnson subsidiary, said Thomas Gustafson of the company's California Innovation Center. Janssen is collaborating with Olefsky to identify compounds to provide new approaches to halting insulin resistance and the diseases it triggers.
"Current therapies are just not adequate so we really need to find novel insulin-sensitizing mechanisms that do not have the side effects of the current therapies," Gustafson said. "I think that would really be game-changing for Type 2 diabetes. That's why we're very excited to work with Jerry."
Inflammation has long been suspected to be involved with obesity-related diseases by causing insulin resistance, Olefsky said. The common assumption was that obesity causes the population of fat cells to increase beyond the reach of blood vessels and capillaries, depriving the tissue of oxygen.
"We operated with that idea when we got into this field," Olefsky said. "Then we said, wait a minute, let's not assume anything. Maybe that's not right. Because in other kinds of diseases, like cancer, where there's a problem with hypoxia, most often the cell is consuming too much oxygen, and that's the cause of the relative hypoxia."
Study of mouse adipocytes taken from inflamed fat tissue showed that the cells consumed excessive amounts of oxygen, Olefsky said. Moreover, the researchers found the molecular mechanism: The fatty acids, especially saturated fatty acids, activated ANT2, a mitochondrial protein involved in metabolism. Increasing the metabolic rate increased oxygen consumption, causing hypoxia. The hypoxia caused production of a protein called HIF-1alpha. That protein caused release of cytokines, which launched the inflammatory response.
As part of the response, white blood cells called macrophages migrate to the adipose tissue, Olefsky said. As much as half the cells in inflamed adipose tissue are made up of macrophages.
The researchers tested the hypothesis by producing mice with the gene for making HIF-1alpha inactivated. These mice would get fat, but didn't develop inflammation, elevated blood glucose levels or insulin resistance.
In human terms these mice could match the profile of the so-called "healthy obese," Olefsky said. These people apparently don't get the metabolic diseases associated with obesity, although this is disputed. And they still incur the mechanical effects, such as arthritis, caused by increased strain on joints.
Whether in mice or men, this cascade of events is partly the result of excess eating, Olefsky said.
"It's related to diet, because in order to get obese, you have to eat too many calories. And rats, mice and people accomplish the eating of too many calories by eating high-fat diets."
However, the inflammation process starts well before obesity begins, when HIF-1alpha is activated, Olefsky said.
"We found that it happens within one or two days of putting mice on a high-fat diet. So this isn't the result of obesity. This is something that occurs very, very early on."
Janssen's Gustafson said the end result is diabetes, as the insulin-producing pancreatic beta cells are strained beyond their capacity.
"Insulin resistance leads to increased insulin secretion and increased stress on the beta cells, and over time the beta cells fail," Gustafson said. "That's when diabetes really comes on. Once beta cells fail, we have no therapies to bring them back."
But if a drug could knock down HIF-1alpha or ANT2 production in obese people, it should prevent metabolic syndrome and related diseases, reducing the health damage of obesity, Olefsky said.
ANT2 in particular is an attractive target, Olefsky said, because it is "quite a druggable protein."
"I think this is very feasible, to launch a program that would yield a small-molecule ANT2 inhibitor, and if such a molecule came about, it has therapeutic potential," he said.
HIF-1alpha provides another feasible target, indeed, drugs affecting this molecule are already being studied by pharmaceutical companies for other purposes, such as treating cancer and anemia, he said. The actual target is a class of molecules called HIF prolyl hydroxylases, for which inhibitors are being developed. Since these molecules boost production of HIF1, inhibiting HIF prolyl hydroxylases should also inhibit HIF1.
It has been recently discovered that inhibiting HIF is beneficial to maintaining proper metabolism and glucose levels, Olefsky said.
Janssen and Olefsky are working together now to identify the proper candidate molecules that can then be advanced into clinical development, Gustafson said.
Strange, when I eat a high fat low carb diet, I lose weight.
I’m thinking that’s because so many more calories are available from carbs, so it’s the “low carbs” that lower the calories. Also, anecdotally, it seems to me that a meal of bacon and eggs satisfies the appetite in a way that leads to lower food intake in general, including carbs of course.
whathe said about hi fat diets is bunk and been proven so. its about too many calories in, period.
its about too many calories in, period
For everyone? Not necessarily.
Needed a tweak.
“whathe said about hi fat diets is bunk and been proven so. its about too many calories in, period.”
You are repeating a myth that is all too common even among some physicians. The calories are not necessarily responsible for causing the obesity in many Type II diabetics. The genetic inheritance results in a malfunctioning metabolism which causes obesity no matter how many or how few calories are eaten and no matter how fat or skinny you were before the presentation of the diabetes. You can eat the equivalent of a WWII concentration camp diet of 800-900 calories per day for 6 months and still have the adipose fat deposited on the waist line making you obese.
The malfunctioning metabolism simply replaces the lost food intake by slowing down the metabolism even further resulting in profound lethargy and sleepiness, the dissolution of the muscle mass, and the conversion of the calories from that muscle mass into fat depostied on the waistline as a response to the perception of starvation. The diabetic increasingly looks like one of thsoe starving children with a gigantic belly superimposed on the bony stick figured frame of the starving child. That is because the insulin resistant cells are behaving as if they really are in starvation mode, being unable to pass the glucose through their cellular walls. In response to what the body misperceives as starvation, the body dissolves muscle tissue, tries and fails to feed the cells with the resulting glucose, and then stores much of the glucose from the dissolved muscle as fat on the body.
It becomes a vicious circle with the cells signalling the need for more glucose, making the diabetic all the more hungry. Yet, the provision of more glucose from the food simply makes the insulin resistance kick-in just that much worse, which in turn denies the ability of the insulin to pass the glucose through the hungry cellular walls. Instead of burning off the glucose in the hungry cells, the glucose remains in the bloodstream, where the glucose damages all of the organs before it can be converted into fat on the body to be stored against the false starvation needs.
So, even those Type II diabetics who eat half or less of the calories normally required for their gender, size, and age and exercise properly, the food they eat is too often stored as fat on the body instead of being burned off as it should have been.
Exactly, but it makes Big Gov’s food pyramid look silly. So silly, it’s almost like the corn and grain lobbies paid somebody off!
Not in my case. Eating a calorie restricted diet only makes me mean because I’m hungry all the time. After all that suffering I never lost a pound. Now that I’m low carb, I lost the weight I wanted to and maintain my weight easily, and I eat many more calories than Big Gov suggests that I do.
I’ve also given up on cardio for weight loss and weight maintenance. It’s strictly weight training for me. Pumping iron works. Plus it’s easier to tote my little ones around.
Really short version: get off you ass and burn the fat calories in your diet...
I disagree. If what you say was true there would have been AT LEAST a few fat people in the concentration camp photos. There weren’t, as I recall.
Disagree. My mother had Type 2 diabetes; she was overweight and a classic apple shape, with the weight in her belly. I'm 51. I restrict my carbs, but other than that I eat what I want and I don't diet. I am not overweight, and I have a small waist instead of my mom's apple shape.
This describes me. Not only that, but I can fast for a week and not lose a single ounce! The metabolism is the key factor. Even when walking and bike riding, I do not seem to lose weight. I don’t know what to do. I have stabilized the weight gain by exercise, but cannot lose. I eat two meals. I never eat more than 1200-1500 calories per day. It is depressing to me. When I first married, I ate less than 1000 calories/day and still had weight problems, although while living in Turkey, I was the best weight ever and had no issues with weight there. I need to go back to eating those foods more consistently! Everything was fresh and no packaged foods. I felt like a glutton there, it was so good. We ate out a lot. The worst was after turning 60, it was a constant weight gain, regardless of the amount of food, fasting, exercise, etc. I wish there was a magic pill for those of us who have this metabolic disorder.
“Disagree. My mother had Type 2 diabetes; she was overweight and a classic apple shape, with the weight in her belly. I’m 51. I restrict my carbs, but other than that I eat what I want and I don’t diet. I am not overweight, and I have a small waist instead of my mom’s apple shape.”
You have a completely wrong view of how this diabetes works. First, there are many different causes of Type I and Type II diabetes. Among those people with Type II diabetes, only some of those people will have a certain type of auto-immune disorder that we are talking about in this case. Second, the child of a parent who has this particular inheritable auto-immune disorder do not develop the symptoms. Consequently, it is to be expected that you will not develop the disorder. Instead, the disorder skips a generation, so it is the grandchildren who develop the symptoms of this disorder by inheritance. So, in your particular case, it depends on whether or not you inherited the gene/s for this particular sub-type of diabetes as to whether or not some of your children, the grandchildren of your mother, will develop this sub-type of diabetes.
The exception to the skipping of a generation when developing diabetes of this sub-type occurs in a couple of ways. In some families, the sub-type of this diabetes can be inherited through the paternal and maternal ancestry. Consequently, there can arise a situation where the children inherit the paternal gene/s for this sub-type of diabetes, while it is the grandchildren who inherit the maternal gene/s for this sub-type of diabetes or another sub-type of diabetes. You can also see a circumstance where the life-style of the family is influenced by a person in the family which results in another type of diabetes which is not the same as the sub-type we are discussing here. in the end, it appears that the diabetes has not skipped generations, when in fact the sub-type which does skip generations has done so while the other diabetes occurs in the same and/or next generation.
“I disagree. If what you say was true there would have been AT LEAST a few fat people in the concentration camp photos. There werent, as I recall.”
You have made quite a number of false assumptions, and some of the reasons are:
1. Diabetes was far less prevalent in the populations in the Second World War, so the percentage of diabetics in the concentration camp populations were much less when compared to today’s percentages in the general population.
2. Those persons who presented symptoms of diabetes such as the obese stomach in the concentration camp populations were typically exterminated upon on arrival or soon after arrival.
3. Those persons who had this form of diabetes and was not yet presenting the symptoms, such as the obese stomach, did not live long enough to present symptoms of the disease.
4. This diabetes destroys the effectiveness of the immune system, so a person who had this diabetes and escaped immediate extermination would soon die of viral and bacterial infections months and years before reaching the extreme stages of starvation seen in the concentration camp photographs.
5. There are many photographs from these concentration camps which may have depicted inmates in the loose-fitting striped uniforms who may have had obese stomachs at the time the photograph was taken. In other words, before the person was starved and worked into the extreme emaciated conditions we saw in other photographs.
All of the overly fat people that I know love, I mean LOVE bread. They can sit at a table and consume half a loaf of bread before they even look at the rest of the meal. The three that expressed a desire to lose weight successfully did so by severely reducing their bread intake then reducing their quantity intake of high carb vegetables.
Nonetheless, some obesity and diabetes is not caused by overeating. Instead, some obesity is caused by diabetes despite not overeating.
No way you can call that a reduction in calories and I have lost 20 pounds in the last 4 or 5 weeks. It helps that I seem to have lost the taste for most foods I used to love. No carbs = no hunger, try it for yourself.
The rising cost of food may force me into the cheaper carbs to survive, but that will not negate the reality that a carbless diet lowers cholesterol, and blood pressure, also fixes HBA1c.
You say I am making assumptions? Really? Read your last.
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