Fighting Obesity: New Hopes From Brown Fat

Artist rendition of a xray showing brown fat as glowing green

Caption: Brown fat—actually marked in green on this image—is wrapped around the neck and shoulders. This “shawl” of brown fat warms blood before it travels to the brain.
Illustration: John MacNeill, based on patient imaging software designed by Ilan Tal. Copyright 2011 Joslin Diabetes Center

If you want to lose weight, then you actually want more fat, not less. But you need the right kind: brown fat. This special type of fatty tissue burns calories, puts out heat like a furnace, and helps to keep you trim. White fat, on the other hand, stores extra calories and makes you, well, fat. Wouldn’t it be nice if we could instruct our bodies to make more brown fat, and less white fat? Well, NIH-funded researchers have just taken another step in that direction [1].

A while ago, I told you about proteins that influence the development of brown fat cells, but the unraveling of this biological mystery continues. Today, I’m sharing the work of researchers at the University of California, San Francisco, who have discovered a key gene driving the engine of brown fat production. Even more exciting, they have linked mutations in this gene to obesity in humans.

A few years ago, members of this team discovered two master regulators of brown fat development [2]. When they inserted both of these genes into ordinary skin cells, they could reprogram the cells and transform them into brown fat. A major achievement, but neither of the genes seemed to be a good target for drug therapy. So, they began to study one of the proteins, called PRDM16, in detail to figure out exactly how it coaxed precursor cells to become brown fat. In the newly published work, they found that PRDM16 needs to interact with an enzyme called EHMT1 to produce brown fat.

Searching a database of human genetic mutations, the researchers discovered that people with rare mutations in the EHMT1 gene are obese. That finding is important because it’s the first evidence in humans suggesting that deleterious mutations in genes controlling brown fat production can cause obesity.

To probe EHMT1’s activity, the UCSF team created a strain of mice in which the gene that codes for this enzyme was deleted, not from the whole animal, but just in the precursor cells destined to develop into brown fat. Without EHMT1, these precursor cells failed to develop into brown fat. The mice lacking EHMT1 were heavier than normal mice, even though they ate identical diets. They also had higher glucose levels, greater insulin resistance, and more fat in their livers—traits characteristic of diabetes and other metabolic diseases.

These findings suggest a new approach to treating obesity, which is urgently needed because more than one in three U.S. adults is obese, and current treatments are far from ideal. Some anti-obesity medications suppress appetite, while others block fat absorption. But both types can cause undesirable side effects.

Moving forward, the UCSF group hopes to team up with collaborators to find chemical compounds that will activate the EHMT1 enzyme. If they succeed, perhaps we will someday be able to use medication to increase production of brown fat—and, in turn, burn up extra calories and white fat.

References:

[1] EHMT1 controls brown adipose cell fate and thermogenesis through the PRDM16 complex. Ohno H, Shinoda K, Ohyama K, Sharp LZ, Kajimura S. Nature. 2013 Nov 6.

[2] Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-beta transcriptional complex. Kajimura S, Seale P, Kubota K, Lunsford E, Frangioni JV, Gygi SP, Spiegelman BM. Nature. 2009 Aug 27;460(7259):1154-8.

NIH support: National Institute of Diabetes and Digestive and Kidney Diseases

 

12 thoughts on “Fighting Obesity: New Hopes From Brown Fat

  1. I would like to volunteer for your study.I cannot get rid of belly fat.I have DM2 and I am an RN diabetes educator

    • Thanks for your comment, Nancy! The research described above used genetically engineered mice and databases of human genetic information.

      However, there are many human clinical trials focused on obesity an/or type 2 diabetes. A searchable database is available at http://www.clinicaltrials.gov.

  2. I’ll volunteer for a study if one begins. I was 165 lbs, a bicyclist, and when I was 26, I gained 60 lbs in 3 months and 40 lbs in the next year. That’s 2/3rds of a lb per day! With no change in diet. My thyroid had failed. So, I went on thyroid. Despite the replacement, I’m still 100 lbs overweight. I’ve exercised heavily since 7th grade (1980)

    I went from biking in 2001 to running. I run 6 times per week, 30 to 60 minutes. It lowered my blood pressure, but it hasn’t helped the weight much. I have to avoid anything with carbohydrates because I start gaining weight with incredible speed. Scans not surprisingly show my stomach is normal-sized. Even when I could eat real food, I never over-ate, not even as a teen. I miss a real diet. I miss cause and effect.

    William Hunt
    M.S.E.E. (conservation biology); B.S. Geology; B.S. Civil Engineering Tech. (OIT); etc.

    • @william I was about the same age as you when I was Dx with hypothyroidism, and thirty one years later I, too, cannot shed those “first” thirty pounds. I acknowledge your commitment to regular exercise.

  3. How long would it be when the researchers are done with this study and are they sure it would work on obese humans?”

  4. I too was 110 lbs as a young adult. I gained weight with pregnancies and stayed at about 124 lbs. All of a sudden I started to gain. I went from 124 to 232 in about 15 years. Thyroid OK. The changes started post-op after kidney stone surgery 1984. I had to fight to keep my weight down, had a 3rd child and went to a diet doc to try and keep controlled and lost all the weight in 1990. It crept back on even with exercise. I have given up and am miserable. Are there clinical trials?

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