An interview with Dr. Tobias Fromme conducted by April Cashin-Garbutt, MA (Cantab)
What is brown fat and how does it differ to white fat?
Brown fat is a tissue well studied in small mammals, where it acts as a heat-producing organ to stay warm in a cold environment.
Its unequivocal identification in adult, healthy humans about a decade ago is of major importance due to its immense capacity to convert chemical energy into heat. In other words, activated brown fat burns fat and sugar instead of storing it like white fat.
Pharmacological activation of brown fat may provide a treatment option for some of the most widespread metabolic disease states of our time, namely obesity, diabetes, hepatic steatosis and dyslipidemia.
Up until now, how much brown fat were humans thought to have?
The range most often reported is 0.05-0.1% of body mass or around 70g in a 70kg individual. The amount of brown fat is important, because it allows us to estimate the effect size of brown fat activation.
Full activation of 70g of brown fat would theoretically result in a body mass loss of around 4kg per year in obese and in a glucose disposal of 2g per day in diabetic patients. These values are rather low compared to existing interventions.
It is generally assumed that the successful utilization of brown fat as a therapeutic target requires both recruitment of more brown fat (e.g. from white fat) plus subsequent activation.
What did your recent research find?
We report a mean brown fat mass of around 300g in normal weight individuals. This value is more than three-fold higher than previously assumed.
Since the effect of pharmacological brown fat activation will increase proportionally with mass, the direct targeting of existing brown fat without prior recruitment now seems a plausible option.
How did you analyze the patients? What techniques were used?
In humans, active brown fat can be detected by its glucose uptake during a 18F-FDG-PET/CT scan. The abbreviation stands for fluoro-desoxy-glucose (a radioactive, injected sugar), positron emission tomography (an imaging method to find the sugar in the body) and computer tomography (provides a whole body background image).
This methodology is routinely applied in the oncology field to locate tumours and metastases in the body. Incidentally, it will also detect active brown fat. We analysed 2854 clinical, archived scans for our retrospective study.
Were you surprised to find such a large quantity of brown fat? How can this be explained?
Yes and no. Our result is not consequence of superior technology but of a different rationale in calculating brown fat mass.
Previously, the brown fat mass of all patients with visible brown fat in a scan was averaged. However, 18F-FDG-PET will only detect active brown fat while inactive tissue remains invisible. Thus, many patients with partially activated depots appeared to have a low brown fat mass while in reality they simply did not activate it completely.
In our analysis, we only included patient scans in which all known brown fat locations are active and unsurprisingly obtained a higher value. This procedure may overestimate mass to some extent but we are convinced that it is a very much better approximation than the previous averaging.
What impact is this finding likely to have?
The priorities of resource allocation during pharmacological development depend on many criteria, one of which is the predicted efficacy of a new drug as compared to available treatments.
Until now, it has been a recurring theme in commentary articles that human brown fat mass is simply too small to bring about metabolic effects on a competitive scale.
Our finding may convince decision makers to end the wait for brown fat recruiting agents before developing novel, safe brown fat activators.
Do some people activate brown body fat more than others?
Yes. In our study, approximatively 5% of the patients constituted a group with a tenfold increased probability to activate brown fat in a given situation. We did not find a simple, common trait that would allow us to prognostically identify such people.
We are, however, very interested in finding such characteristics both to understand the underlying regulatory processes and to predict the potential benefit of additional brown fat activation for an individual patient.
Can you please explain how creatinine clearance is thought to work?
In our study, we calculated an estimate for renal creatinine clearance. It is usually regarded a long-term measure of kidney function. We were surprised to find renal creatinine clearance to correlate with the extent of brown fat activation.
Either a common signal substance regulates both brown fat and kidney activity or creatinine is a novel brown fat metabolite. We will investigate both hypotheses in future studies.
Do you think it would be possible to use medication to activate brown adipose tissue in the future?
On a conceptual level, it is clearly possible to activate brown fat pharmacologically and the therapeutic application options in the treatment of metabolic disease are obvious.
The key challenge will be to develop such drugs with an acceptable safety profile, i.e. with negligible adverse effects on the cardio-metabolic system.
Much will depend on how pharma companies will weigh the risk associated with targeting energy expenditure against the potential for a new class of blockbuster drugs.
What further research is needed to understand brown fat in humans?
Brown fat is very well investigated and understood in small mammals. Unfortunately, we do not know how much of our knowledge is transferable to humans.
While the central heat producing components seem to work in a comparable fashion, the regulation of activity and recruitment seems different in many respects.
Important research needed includes studies on the cellular identity and origin of human brown fat cells as well as investigating neuronal and endocrine signals activating heat production in these cells.
Where can readers find more information?
The book “Adipose Tissue Biology” edited by Michael Symonds (ISBN 978-1-4614-0965-6) provides a comprehensive overview on the topic, specifically the chapter on brown adipose tissue, co-authored by myself. Furthermore, a number of authoritative review articles can be found in public literature databases (e.g. PubMed) using the search terms “brown adipose tissue”, “human” and “review”.
About Dr. Tobias Fromme
Tobias Fromme is a staff scientist and lecturer at the TUM School of Life Sciences Weihenstephan, Technical University of Munich, Germany.
He holds a Diploma in Biology and a PhD in Animal Physiology. He investigates brown adipose tissue thermogenesis, organismic energy balance and mitochondrial bioenergetics.
In Dr. Fromme’s most recent projects, he aims to transfer established insight from rodent studies into the context of human brown fat.
To this end, he and his cooperation partners combine the expertise of a state-of-the-art physiology laboratory with the possibilities of sophisticated clinical technology.