Environmental enrichment leads to leaner mice!

A recent paper published in Cell has shown just how much our environment can affect our health. Environmental enrichment (EE) refers to living in a complex environment with physical and social stimulation and is most often studied in laboratory rodents, where these factors can be controlled. The authors of this paper had previously found that mice living in EE showed increased neurogenesis (birth of new neurons), enhanced learning and memory, and resistance to brain insults, but had also noticed that mice living in EE appeared leaner than those living in standard housing. This observation lead the authors to further investigate the fat profile of these animals.

A little background. There are two types of fat tissue, or adipose, in mammals. White adipose tissue (WAT) and brown adipose tissue (BAT). WAT is likely what you would think of when you think of fat. It accumulates energy, stores heat, and cushions. BAT releases energy as heat and is crucial in body temperature regulation. For this reason it is abundant in newborns and in hibernating mammals. BAT cells appear brown due to the iron present the numerous mitochondria. Just to confuse things a little more, there is a third type of adipocytes, called brown-in-white cells (or brite cells) which are thermogenically like brown adipocytes (dissipate heat), but appear in WAT and are developmentally and molecularly different from brown adipocytes. The important thing about brite cells is that they appear to be associated with resistance to obesity and metabolic diseases.

So, on with this study. As mentioned, mice were housed in either standard housing (group housed in regular cages) or EE which consisted of larger cages, running wheels, and regularly changed toys and mazes. All mice ate the same kind of food to which they had free access. After 4 weeks, EE mice were found to have a lower body weight as well as lower WAT mass. To determine whether the effect of EE were due to simply more exercise, a third group was introduced. This group had access to a running wheel, but none of the other stimulants present in the EE group. While adiposity was decreased in the wheel running group, it was not to the same extent as the EE group. This finding was not due to increased motor activity in the EE group as these animals actually ran less total distance than the wheel-runners. Food intake measurements also ruled out appetite suppression as a reason for the loss of adiposity as EE mice actually showed increased food intake.

To further investigate the effects of EE, researchers looked at changes in gene expression in both WAT and BAT. While not many changes were found in BAT, 15 of 19 genes examined in WAT were found to be altered by EE. Most interesting was the upregulation of Prdm16 which serves as a switch in the formation of brown adipocytes. Along side this upregulation was increased induction of several genes typically functional in BAT. So here we have many indicators that a BAT phenotype is being increased in WAT in animals exposed to EE. The authors propose that “EE induced a ‘browning’ molecular signature in white fat suggesting that an individual’s interaction with its immediate environment could switch a white fat energy storage phenotype to a brown fat-like energy expenditure phenotype and regulate adiposity.” To further test this, mice assigned to control or EE housing were fed a high-fat diet. After 4 weeks on this diet, EE mice gained significantly less weight and had increased body temperature with no change in food intake. This suggested that energy expenditure was responsible for the resistance to obesity, as well as its associated morbidities (hyperinsulinemia, hyperleptinemia, hyperglycemia, and dyslipidemia). And again, EE mice fed the high-fat diet also showed the “browning” molecular signature as described above.

Other findings included stronger WAT “browning” with longer exposure to EE (3 months), the involvement of the sympathetic nervous system in the changes in gene expression occurring in EE, as well as increased expression of the neurotrophin BDNF (which is involved in neuronal health and survival, brain plasticity, protection against insults, learning and memory, and the list goes on and on) in the hypothalamus. It is still not clear exactly what is occurring in this phenotypic switch within WAT: either transdifferentiation of white adipocytes to brown, or the activation of the brite cells. In any case, the authors propose that the complex environmental stimuli experienced in EE causes induction of BDNF in the hypothalamus which then leads to increased sympathetic activation to WAT. Then a functional transformation from WAT to BAT occurs leading to release of energy as heat with subsequent benefits including decreased adiposity and resistance to obesity. The authors believe that with further investigation into the origin of these brown-like cells induced by EE, potential treatments for obesity could be developed.

Overall this is was a really well-carried out, comprehensive study which highlights how drastically the physical and social environment can affect our health. Would these findings hold true in humans? (check out this blog!). Obviously our environment is much more complex with much greater physical and social stimuli. However, that brings with it negative stimuli as well, ie. stress. While certain stressors can be a good thing (ie. exercise is known to increase BDNF as does caloric-restriction), too much stress is definitely detrimental. So again, the take home message would be eat healthy, exercise, enjoy a social life, but decrease the negative stress.

Reference: Cao L, et al. White to brown fat phenotypic switch induced by genetic and environmental activation of a hypothalamic-adipocyte axis. Cell Metabolism 2011;14:324-338.