"Adipose tissue is an underappreciated and misunderstood organ." It's with these words that Aaron M. Cypess, MD, PhD, begins his recent review published in the New England Journal of Medicine.
As obesity rates steadily rise, "the riskiest approach to human adipose tissue is to dismiss its importance," he adds, especially because there has been "an explosive growth" in our understanding of white and brown adipose tissue over the past 5 to 10 years.
Medscape Medical News asked Cypess, a National Institutes of Health (NIH) scientist whose research focuses on brown fat, to discuss some of the main points in his review, entitled, "Reassessing Human Adipose Tissue," and clear up some misconceptions about fat.
You write that, for people who struggle to lose weight, "fat is often a source of misery, not marvel." Why is fat a marvel?
When I started medical school in 1992, fat was just a thing that stored calories. You had to get it out of the way when you operated on the stomach or intestines. Now we know it's not just one cell, it's multiple types of cells, including immune cells and some blood cells. There's cell turnover, and cells can get bigger or smaller, so it's a dynamic tissue. It impacts the immune system and affects insulin sensitivity.
Why use the term "adipose tissue" and not just "fat"?
People think of fat cells and that's it. However, adipose tissue (fat) has multiple cell types, and they each matter. There are adipocytes (fat cells) — which can be white, brown, beige, or pink — as well as immune cells, fibroblasts, blood vessels, and parts of nerve cells.
The main function of white adipose tissue is to store energy in the form of triglycerides. Brown adipose tissue consumes glucose and triglycerides, generating heat. Brown fat cells within depots of white fat are termed brite cells (a portmanteau of brown and white) or beige cells. Pink fat cells have been found in breast tissue in mice.
What do we now know about white fat and brown fat? Can brown fat change to white fat or vice versa?
White adipose tissue is commonly separated into visceral fat and subcutaneous fat, which have negative and neutral or positive metabolic effects, respectively. It is capable of more than doubling in mass and then returning to baseline.
White adipocyte-derived hormones include leptin, which is low in starvation, and adiponectin, which regulates glucose and lipid metabolism. White adipose tissue is essential for the proper function of the reproductive system, including secretion of hormones and lactation.
Brown adipose tissue protects newborns from cold as they develop the ability to shiver, and in adults it is found in depots in the neck, shoulders, posterior thorax, and abdomen. The amount of brown adipose tissue varies according to sex and lowers with increasing age and increasing body mass index (BMI).
There is much more white fat in the body than brown fat. It appears that activating brown fat leads to beneficial effects on metabolism, though we don't know yet all the steps for how that happens.
In mice, you've got white fat depots and brown fat depots, and some brown fat can be found in the white fat.
With humans it's much more complicated, and I've seen this in the operating room myself, and on slides. Where you find brown fat cells you also find a certain proportion of white fat cells, not an exclusive brown fat depot like you see in a mouse.
It is hotly debated right now whether brown fat can change to white fat and vice versa (transdifferentiation). The beige fat cells are supposed to be the kind that can shuttle between more white-like or brown-like. They can sometimes be white or sometimes brown. It can be very contentious in [scientific] papers and meetings.
Are humans born with all the fat cells they will ever have?
No. New fat cells are made throughout our lives. When the white adipocytes store too much triglyceride, they get really big and they get "sick" and die faster. It's the rate at which the white cells take up the fat to store it and then get rid of it that can impact whether someone gains a lot of weight and whether they can successfully lose it after reasonable effort.
The average lifespan of a white fat cell is 15 years. We have no idea yet of the lifespan of a brown fat cell.
Is there a single "fat gene"? What role do fat genes play in the likelihood of developing metabolic diseases and type 2 diabetes?
Genes are very important for influencing the development of obesity and probably influence 50% to 70% of obesity, based on studies in populations of predominantly European origin. But that high percentage reflects the impact of hundreds of genes. For most people, there is no one gene that exerts all of the effects. There are extremely rare diseases where one gene is responsible. Currently, only 20% of the entire phenotypic variation in obesity can be explained by the thousands of loci identified so far.
Why is it "correct but too simplistic" to attribute the increasing rates of obesity to excessive triglyceride storage in white adipose tissue?
Saying obesity is caused by too much triglyceride storage ignores the reasons how and why the triglycerides got there. There are likely to be multiple contributing factors to drive obesity, and those have billions of dollars of policy implications. Is obesity resulting from portion sizes? Then we should work on educating the public on how to estimate their caloric intake. Is it the types of foods, such as ultra-processed foods? Then we can discourage eating certain food groups while promoting others. Is it about physical activity? Then we should prioritize exercise programs.
Why is obesity "not simply a failure of will power"?
Genetic factors in adipose tissue impact how easy it is to store triglycerides, how easy it is to get fat out of the tissue and burn it up, and what kinds of hormones are released by the tissue to regulate appetite, insulin resistance, and inflammation. Ten different people can all overeat the same amount of the same foods, yet there will be differences in the amount of weight gain and metabolic complications experienced. And at the brain level, some people will feel "full" sooner than others.
How can excess adipose tissue lead to disease? Do some people have "metabolically healthy obesity"?
Excess adipose tissue leads to chronic inflammation that can then cause insulin resistance, hypertension, fatty liver disease, and other complications. It appears that there are metabolically healthy obese people, but it is not clear if that is only a temporary state.
Could long-term brown adipose tissue activation help treat obesity or related metabolic disease?
Our research group at the NIH and others have shown that long-term brown adipose tissue activation produces metabolic benefit such as improved insulin resistance, lower plasma glucose, and higher HDL [good] cholesterol. However, there is no evidence yet that it will lead to actual weight loss.
We are trying to use brown adipose tissue activation to treat obesity-related metabolic disease to see if it could lead to reduction in inflammation, improvement in the cholesterol profile, and decrease in blood pressure.
A large observational study recently published in Nature Medicine by Paul Cohen's group at Rockefeller University in tens of thousands of people at Sloan Kettering cancer hospital reported that people who had brown fat were generally healthier and had less high blood pressure and less cardiovascular disease. This study could not show causation, but at every BMI, people were healthier if they had more brown fat than if they had less. So, there's something going on. We're still trying to figure that out.
Cypess has no reported no relevant financial relationships.
N Engl J Med. Published online February 24, 2022. Full Text
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