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.


Guest Post on Scientific American!

Check out my guest post on the SciAm guest blog! I was asked to write about the nutritional differences between organic and conventionally-grown foods. Let me know what you think! http://blogs.scientificamerican.com/guest-blog/2011/08/11/nutritional-differences-in-organic-vs-conventional-foods-and-the-winner-is/

Folic Acid & Vitamin D: Deficiency as a Risk Factor for Autism?

Autism is one of three disorders that falls under the umbrella of Autism Sprectrum Disorders (ASD). It is characterized by impaired communication and social skills and repetitive/restricted behaviours, all occurring prior to 3yrs of age. The other two disorders falling under the ASD are Asperger’s syndrome, which lacks the cognitive impairments present in autism, and Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS) which is diagnosed when all characteristics for either autism or Asperger’s are not present.

Autism rates worldwide have steadily increased since the 1980’s, although there is controversy as to whether this represents an actual increase in the occurrence of the disorder, or improved diagnostics. Nevertheless, the cause of autism remains unclear and is likely due to a multitude of genetic and environmental factors, that differ between individuals. First, let’s dispel the elephant in the room. Because the symptoms of autism begin to present at approximately the same time as the child’s MMR vaccination, the blame turned to the vaccine. Unfortunately, this theory was bolstered by Andrew Wakefield, who published a paper in The Lancet in 1998 suggesting that there was a link between the MMR vaccine and autism. This paper has since been retracted and Wakefield’s work has been called by some “an elaborate fraud”, involving misreporting of data, unethical treatment of subjects (children in this case), and conflicts of interest. What’s sad is that all of this caused many parents to stop vaccinating their children, leading to a resurgence in the occurrence of measles, resulting in preventable deaths. ANYWAYS, this could be a whole post on its own, so I’ll move on.

It is well known that factors in our environment (be it pollution, nutritional intake, physical activity, etc.) can alter normal functions of some of our genes, thereby producing phenotypic (ie. traits that we can see such as morphology, development, behavior, etc) differences. Nutritional factors play a huge role in the normal functioning of our genes, and therefore deficiencies or excesses can cause abnormal gene products to be produced. There is some indirect evidence that nutritional factors may play a role in the development of autism. The potential role of two of these factors, folic acid and vitamin D, were the subject of a review paper (cited below), which also reviewed genetic abnormalities, the role of the immune system, and heavy metal effects.

Folic acid is a B vitamin important for many functions including DNA synthesis and repair, and the production of red blood cells. Perhaps its most well-known role is that of preventing neural tube defects (NTDs, specifically spina bifida) in the developing embryo. Approximately 20yrs ago health agencies began advising women of child-bearing age to take a folic acid supplement and this has resulted in a 70% decrease in the incidence of NTDs as well as a decrease in the severity of defects when they occur.

So, what does folic acid have to do with autism? Due to a genetic polymorphism (a difference in DNA sequence between individuals) autistic individuals tend to show 50% decreased activity of a certain enzyme (MTHFR) that is required to metabolize folate. So even if these children have a sufficient intake of folate in their diets, their ability to metabolize it is only 50% of normal, and therefore deficiency may occur. In a strange way, the push for women to pre-natally supplement with folate may have contributed to the increase in autism rates that seemed to begin around the same time. Without maternal folate supplementation, miscarriage rates of fetuses with the abnormal MTHFR enzyme would have been higher than that resulting from pre-natal folate supplementation. So more children with the decreased ability to metabolize folate survived, which may be linked to the increased occurrence of autism. So the suggestion is to supplement children with folate to ensure those with the abnormal MTHFR enzyme get enough to make up for the decreased ability to metabolize.

Vitamin D is another factor that may play a role in the development of autism in some individuals. Vitamin D plays many roles in the body such as growth and remodeling of bone, neuromuscular functions, decreasing inflammation, and affecting genes that are involved in cell survival and death. Vitamin D is also important for neural development as a regulator of cell division and up-regulator of neurotrophins, which are crucial to the development, survival, and function of neurons. The majority, 90% actually, of our vitamin D supply comes from sun exposure, rather than diet. UVB light causes the transformation of a precursor molecule in our skin into an inactive form of vitamin D which is then further processed by the liver and kidneys into the active form (also called calcitrol).

Due to rising skin cancer rates in the late 80’s, sun avoidance was being recommended, and it was around this time that autism rates began to increase. There is lots of indirect evidence suggesting that a decrease in vitamin D production may be linked to the development of autism. Estrogen can increase vitamin D metabolism into the active form, while testosterone can not, possibly explaining the greater prevalence of autism in boys compared to girls (4:1). Autism rates are also higher in African Americans vs caucasians. Darker skin requires a greater amount of UVB rays to produce sufficient amounts of vitamin D. Shockingly, one study carried out in the US found that only 37% of white women and 4% of black women had sufficient amounts of vitamin D during pregnancy. While possible mechanisms of vitamin D deficiency-induced autism have not yet been shown, it is likely to again be due to a genetic polymorphism present in certain individuals. A candidate gene is CYP27B1, an enzyme that is required for the transformation of inactive vitamin D into its active form. A genetic polymorphism of this gene may lead to vitamin D deficiency, however the role this may have in the development of autism has not been examined yet.

So, in summary, both folic acid and vitamin D deficiency may contribute to the increase in autism seen in the past 20yrs or so. While potential mechanisms have not yet been verified, it is likely that some autistic individuals carry genetic polymorphisms resulting in a decreased activity of enzymes involved in the normal functioning of these important vitamins. While the indirect evidence is very interesting and indeed warrants further investigation, it is important to note that as of yet there is no direct evidence of these theories. Even if one or both of these theories are verified, they will only explain a proportion of cases, since there are many autistic children who do not show, or never have shown, deficiencies of either of these vitamins. It has proven difficult to determine a single mechanism, gene, or environmental factor responsible for the development of autism and therefore there is likely a variety of different factors, that when expressed alone or in combination with each other, in the “right” embryonic and genetic environment, lead to children who will be at higher risk of developing neurological disorders.


Citation: Currenti SA. Understanding and Determining the Etiology of Autism. Cell Mol Neurobiol (2010) 30:161–171. DOI 10.1007/s10571-009-9453-8