New Target for Fat-Burning Drugs Discovered in Mice Study
METHODOLOGY:
Brown and beige fat tissue burns energy to produce heat in response to cold exposure and, in rodents, protects against obesity and its metabolic consequences; inducing the browning of white adipose tissue in people may be a promising treatment strategy for obesity.
Researchers in China conducted animal experiments to investigate the role of BAP1 in the browning of white adipose tissue and its underlying mechanisms.
They examined BAP1 and its key molecular partners using several genetic variations in mice, including those with BAP1 knockdown or overexpression, those with a knockout of the principal brown fat mediating protein, and wild type.
Mice were evaluated under several conditions, including obesity induced with a high-fat diet and a cold challenge.
They assessed serum and tissues, as well as isolated cells from a fat deposit (inguinal) equivalent to human gluteal and thigh fat, for molecular and phenotypic changes, as well as metabolism-related parameters.
TAKEAWAY:
BAP1 expression was lower in the inguinal white adipose tissue of cold-induced mice but higher in obese conditions.
Overexpression of BAP1 suppressed browning of the white inguinal fat and blocked an energy-burning thermogenesis response.
On a high-fat diet, knockdown mice without BAP1 were spared most of the weight gain, impaired glucose tolerance, and insulin sensitivity experienced by mice with BAP1.
Mechanistically, BAP1 negatively regulates the browning of inguinal white adipose tissue, possibly through a mechanism that inhibits expression of genes essential for browning.
IN PRACTICE:
'Our findings unveil a novel function of BAP1 mediated by KDM1B in iWAT [inguinal white adipose tissue] browning, thereby offering a promising therapeutic target for the treatment of obesity and related metabolic disorders,' the study authors wrote.
SOURCE:
The study was led by Pengchao Wang, Medical College, Huazhong University of Science and Technology, Wuhan, China. It was published online in Diabetes .
LIMITATIONS:
While the study demonstrates BAP1 can inhibit the direct conversion of white fat into beige fat, it may also influence browning by modulating beige adipogenesis. Also, though BAP1 expression remains unchanged in brown adipose tissue during cold exposure, the researchers could not exclude its potential role in thermogenesis, suggesting the existence of other signaling pathways that bypass BAP1 in regulating thermogenesis in brown adipose tissue. Further animal studies are required to provide more compelling evidence, the authors noted.
DISCLOSURES:
The study was supported by grants from Non-Communicable Chronic Diseases – National Science and Technology Major Project, National Natural Science Foundation of China, and Natural Science Foundation of Hubei Province. The authors declared having no conflicts of interest.
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But still, we can get around it and get a very good result on diabetes treatment. Jain: This is fascinating. We are unmasking hypercortisolemia as an underlying reason for insulin resistance. Fonseca: I wouldn't say unmasking. We are recognizing it in a novel way for the first time, and are able to treat people who we were throwing many drugs at [the problem] — wasting those drugs, if you ask me — when we were not treating the fundamental problem. Jain: When should clinicians think about this as an underlying issue? Fonseca: The way I translate every clinical trial, you do it for what the trial was done for. You have people who are uncontrolled, or you may say difficult to control, uncontrolled or on many medications. Often, you find comorbidities. They have had this problem for a while. Many of them have complications of diabetes, and a significant number had heart disease. You treat them with a very specific treatment, and you get a good result. Now, in some people the treatment may be surgical. You could use this drug or other drugs, and there are some new ones. This has become an important target for therapy, so we will see this approach. That also leaves the question as to [the fact that] there were 24% with this abnormality. What's happening in the other 75%? Maybe there are other abnormalities that we haven't recognized. I think you and I still have a large amount of work to do. Jain: We do indeed. Your target population was individuals with type 2 diabetes. Fonseca: Type 2 diabetes that was not controlled. Jain: Do you think this could be an underlying problem in type 1 diabetes as well? Fonseca: Hypercortisolism can occur in anybody. If you're finding many challenges in type 1 diabetes, you could do it. Obviously, people who are not doing well in their general health without diabetes could have hypercortisolism. This is not what we recognize as the textbook Cushing syndrome. These people did not have those features. The obesity was mild and low central. They had little features, but not the full-blown textbook description, which comes after many years of having very severe hypercortisolism. Jain: For those individuals who, say, are on birth control, would you then recommend doing a urine test? Fonseca: That's a very important question. We excluded those people from the study because you get a false elevation due to raising cortisol-binding globulin with estrogen. We did it in people who had a probability based on some anecdotal things and studies in Europe that were done before, and also excluding people who would have a false positive or a false negative, such as [those with] estrogen use. We don't know how to really identify those people well, without stopping the therapy. Jain: Any final key pearls of wisdom from this trial? Fonseca: I think, like anything that's new, it's exciting. Many of these people were very glad that we found an abnormality. I mean, it sounds bad, but they were blaming themselves, they were being labeled as noncompliant, and they were very frustrated with this. Jain: And the medication burden that they were facing. Fonseca: We actually withdrew a number of medications on several people. Jain: Great. Those are the results of the CATALYST trial. Thank you so much, Dr Fonseca, for joining. Fonseca: Thank you. It's a pleasure to be here.
