As human beings, we have a virtually constant body temperature. This is absolutely essential for our survival. The same is true for all mammals. We all know how unpleasant it is to stand waiting for a bus on a miserable November morning with wind and rain beating down on us. We start to shiver: this increases our metabolism and thus generates heat to defend our body temperatures. However, shivering is very uncomfortable and can only be maintained for a short time.

Fortuitously, if we are exposed to such cold conditions for a prolonged time, we instead start to develop a remarkable new ability, an alternative to shivering: the ability to generate heat by comfortable non-shivering means.

This comfortable heat generation occurs in brown adipocytes, cells filled with specialised mitochondria. These mitochondria can convert energy from our food directly into heat, without needing to first synthesise and then degrade ATP. They have acquired this unique ability because of the presence in the mitochondrial membranes of a protein termed uncoupling protein 1 (UCP1).

TRIGGERING THE RELEASE OF HEAT

When our body temperature is threatened, areas in the brain will be activated, located in the hypothalamus. From these areas, signals are sent down the spinal cord and ultimately to nerves that innervate the brown adipocytes in the brown adipose tissue depots. These nerves are part of the sympathetic nervous system and their stimulation leads to the release of norepinephrine in the tissue.

We seldom allow ourselves to feel uncomfortably cold, but rather stay in warm rooms or put on extra clothing; we thus live under thermoneutral conditions. Because of this, the thermogenic capacity of the brown adipocytes is normally very limited. Nonetheless, the small heat-producing capacity that we have is activated by the sympathetic signal. The norepinephrine binds to β3-adrenergic receptors on the mature brown adipocytes, and heat is produced.

Since the capacity is initially inadequate to meet the demands of a cold stress, the sympathetic signal also interacts with stem cells in the tissue that start to proliferate and subsequently to differentiate into fully mature new brown adipocytes. This thus increases the capacity of the tissue for heat production, and the need for the uncomfortable shivering consequently diminishes.

SOURCING FUEL

To produce heat, it is necessary to have something to burn. The brown adipocytes contain stored triglycerides in numerous small lipid droplets. This fat is what is initially used for heat production: the fatty acids generated by lipolysis of the fat droplets are delivered to the mitochondria.

However, this supply is limited, and it is necessary to import additional substrates from the circulation. These can be in the form of fatty acids or glucose, both of which are readily taken up and combusted by the brown adipocytes.

A ROLE IN COMBATTING OBESITY?

Since the process of heat production in brown adipose tissue thus  combusts substrates, it can be envisaged that it could combust excess food that we consume. This process was suggested as long ago as 1979 to have a significant effect on regulation of body weight. Tasty diets were served to animals, and the more brown adipose tissue the animals had, the less weight they gained on the tasty diets. Remarkably they obtained more brown adipose tissue merely through eating these diets.

Although this observation created considerable interest at the time, it was nonetheless thought not to be readily applicable to adult humans, since it was believed that brown adipose tissue in humans disappeared in the first years of life. However, about 10 years ago, positron emission tomography (PET) scans of adult human patients indicated that brown adipose tissue was indeed present in many adult humans.

Most adult humans probably have some brown adipose tissue until they reach their 40s or 50s. The depots of identifiable brown adipose tissue are fairly small and their contribution to whole body metabolism has not yet been adequately determined. It seems perhaps unlikely that the physiological capacity would be such that it could treat human obesity. A more attractive possibility would be to be able to keep the brown adipocytes active for the whole life course, which could potentially reduce the development of ‘middle-aged spread’.

DISCOVERIES IN WHITE ADIPOSE TISSUE

In addition to the brown adipocytes found in the classical brown adipose tissue depots in mice, there are adipocytes within classical white adipose tissue depots that have the ability to express UCP1 and potentially become heat-generating and energy-consuming. These cells are termed brite (brown-in-white) or beige or recruitable, and the process of their development is termed ‘browning’.

In mice, in addition to enhanced sympathetic drive, numerous compounds and treatments have been shown to induce browning. In many cases, this is associated with a less marked development of body weight in animals fed a high fat, high sugar diet. To what extent it is the browning process and not acquiring more real brown adipocytes that actually leads to weight regulation is not really clear. Even more debatable is whether this browning of white adipocytes is valid in humans.

There are two aspects here. One is the nature of the brown adipose  tissue present in humans. It has been claimed that the human tissue is more similar to the rodent brite/beige adipose tissue, but this has also been said not to be the case. This may be of importance, since the different UCP1-containing adipose tissue depots have different cellular origins, and the cells may therefore be responsive to different stimulatory agents. This could influence the development of relevant therapeutic agents to both activate existing UCP1-containing cells and to recruit new such cells. The other issue is whether adult humans do, in fact, have a significant set of recruitable UCP1-containing adipocytes in their classical white adipose depots. This is as yet unclear.

THE ADIPOCYTE SECRETOME

A further aspect of adipose tissue metabolism that has attracted interest recently is the so-called secretome, that is to say the array of molecules that are secreted from adipocytes under different circumstances.

For white adipocytes, the most well known is the hormone leptin, though dozens more are also secreted. The studies are still on-going in brown adipocytes. It will be of considerable interest to evaluate to what extent the brown adipocytes may influence human metabolism and physiology, not only through their thermogenic and energy-expending properties, but also by functioning as an endocrine and paracrine organ.

Barbara Cannon & Jan Nedergaard, Emeritus Professor & Professor, Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Sweden