How to teach fat cells to burn calories?
New target for obesity treatment found in fat cells
LifeSciencesToday based on UCSF Materials: Teaching Fat Cells to Burn Calories
In the fight against obesity, a person's own fat cells may, at first glance, seem an unlikely ally. However, scientists from the University of California at San Francisco (University of California, San Francisco, UCSF) believe that white fat cells can be reprogrammed to burn calories, turning them into brown fat cells. By studying how one of the well-known drugs prescribed for type 2 diabetes works in mice, researchers have found that the protein PRDM16, found in both humans and mice, can work as a "switch" that turns calorie-storing white fat cells into calorie-burning brown fat cells.
This discovery makes the PRDM16 protein a possible target of future drugs for the treatment of obesity. Chemical compounds that stimulate its activity can help the body burn calories faster. Such compounds represent a completely different approach to weight loss, since currently existing drugs either limit the absorption of calories, for example, by blocking the absorption of fat in the intestine, or suppress appetite.
"If we consider the problem from the point of view of energy balance, then another way to combat obesity is to expend energy," explains the head of the study Shingo Kajimura, PhD.
According to scientists, brown fat evolved in early mammals as a protection against cold. It helps animals maintain a constant body temperature and successfully survive in difficult and even extreme environmental conditions. Not all higher organisms have this ability.
Many of them, for example, lizards, are cold-blooded, or poikilothermic. They maintain body temperature only due to external factors – they bask in the sun during certain daytime hours and huddle together in warm, sheltered places at night. This naturally limits the area of their distribution and explains why lizards, so widely represented in tropical climates, are much less common in cold climates.
In contrast to lizards, warm-blooded, or homoiothermic, mammals produce heat themselves, using various mechanisms for this: muscle trembling, regulation of the lumen of blood vessels, etc. This is also facilitated by brown fat, which burns fatty acids, which warms the blood flowing nearby and, consequently, the entire body.
Scientists have long been convinced that new brown fat cells are formed only in infants. But now it is firmly established that this process goes on throughout a person's life. In addition, as doctors have recently proved, the amount of brown fat in the body is inversely proportional to the likelihood of obesity – the more brown fat a person has, the less the tendency to obesity.
Energy-burning brown fat cells.
Green dots are fat droplets, red dots are mitochondria, blue spheres are cell nuclei.
Brown adipose tissue dissipates energy, producing heat, and protects the body from cold and obesity. PPAR-gamma ligands transform white fat cells into brown fat cells, but the main mechanisms of this transformation remained unclear. UCSF scientists have shown on cell cultures and animal models that in order to include a genetic program of transformation into brown fat cells, mainly in adipocytes of subcutaneous fat, PPARy ligands need complete agonism with the protein PRDM16 – a factor controlling the development of classical brown fat. Reducing the amount of PRDM16 suppresses the effect of the PPAR-gamma agonist rosiglitazone on the induced genetic program of brown fat formation. On the other hand, PRDM16 and rosiglitazone synergistically activate this genetic program in vivo. This synergy is closely related to the increased accumulation of the PRDM16 protein, largely due to an increase in its half-life in agonist-treated cells. Identification of protein-stabilizing PRDM16 compounds may lead to the development of drugs for the treatment of obesity and diabetes.
The possibility of using brown fat for weight loss began to be seriously considered after receiving clinical data that some medications can change its amount in the human body. In particular, it has been shown that an increase in the amount of brown fat is promoted by a well–known class of drugs prescribed to patients with diabetes - PPAR-gamma ligands, or thiazolidinediones. But the molecular mechanism causing this effect remained unknown.
It was deciphered by Dr. Kajimura and his colleagues from UCSF. In their study published in the journal Cell Metabolism (PPARgamma agonists Induce a White-to-Brown Fat Conversion through Stabilization of PRDM16 Protein), they showed that thiazolidinediones interact with the PRDM16 protein they discovered, making it more stable, which leads to its accumulation in cells. In fact, this interaction involves a genetic program for converting white fat cells into brown fat cells – at least in mice.
Is it possible to achieve the same results in the human body and, if so, how?
According to Dr. Kajimura, the question is no longer how to get brown fat – it has become more specific: can we achieve stabilization of this protein?
Drugs of the thiazolidinedione group have serious side effects, which include heart and possibly liver failure, weight gain, etc. Therefore, scientists are faced with the task of creating a drug that specifically stabilizes the PRDM16 protein and does not have serious side effects.
Although new drugs targeting the PRDM16 protein may not appear until many years later, knowledge of this target can accelerate their development, Dr. Kajimura believes.
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11.03.2012