Finding the obesity ‘off switch’
Last week an international group of basic scientists and clinicians released results showing evidence of an epigenetic switch in mammals that controls obesity. Dr Tony Coll at the MRC Metabolic Diseases Unit explains why this is just the beginning of an exciting exploration of the role played by epigenetic factors in complex human diseases.
Who am I not? Cell video abstracts. Cell January 28, 2016 (Vol. 164, Issue 3)
Obesity and related metabolic diseases are major threats to public health worldwide.
There is strong evidence that our DNA plays a major role in whether or not we become obese. Many environmental factors have also been linked to our risk of developing obesity. A better understanding of how these factors interact is crucial if we are to tackle this growing public health issue.
Our group here at the MRC Metabolic Diseases Unit has been part of an exciting, multicentre study led by Dr J. Andrew Pospisilik and his team at the Max Planck Institute of Immunobiology and Epigenetics, Freiburg that has identified processes that could change our understanding of what controls our body weight.
Same genes, different looks
The Pospisilik group were looking at mice with identical ‘genotypes’. A ‘genotype’ is the specific combination of genes that determines every feature of an individual: including your height, your weight and your colouring. Usually, animals with the same genotype would have such similar body weights that, if you mapped them on a graph, they would vary in a small but continuous spectrum.
But the Pospisilik group discovered that their mouse models followed a different pattern. Instead of varying across that continuous spectrum, they found that mice lacking one copy of the gene Trim28 were landing in two distinct categories, either lean or obese.
This “either/or” pattern is fascinating because we have only ever seen ‘polyphenism’ (two genetically identical animals looking distinct from one another) elsewhere in nature – in worker ants and soldier ants, for example – and, until now, it has never been clearly reported in mammals.
Each of us has two copies of every gene, one inherited from each parent. Usually, both genes are ‘expressed’ equally in the body. However, there are also so-called ‘imprinted genes’ which are exclusively expressed from either the maternal or paternal gene copy. Dr Pospisilik’s team found that a network of imprinted genes was being expressed less in the obese mice.
Independently of Dr Pospisilik’s work, we had been investigating one of the imprinted genes in this network, Nnat, for a number of years. We were interested in Nnat because it is found in a number of different tissues in the body that we know to be important for metabolic control.
We had found that deleting one copy of Nnat in our mouse model also led to mice being either obese or lean, just like in the Trim28 mice. So we linked up with Dr Pospisilik and his network of collaborators.
They moved forward on the observations coming from mice and looked at fat tissue in lean and obese children (including groups of identical twins where one was obese and the other lean) and found similarly altered expression of levels of Trim28 and the imprinted gene network.
Can we flick the switch?
So does this mean we have a new therapeutic target for obesity? Not yet. Although the study has opened up a fascinating and novel area of study around the role of epigenetic machinery in mammals, many questions remain.
First, we need to understand why the expression of the imprinted gene network has become reduced in the obese mice. Clues from the mouse studies suggest environmental factors could be at play such as temperature and housing conditions. These look to be important starting points in future work with our mouse models.
Further studies in larger human cohorts will also help us unpick how these external factors influence this “on/off switch”. These are crucial next steps in bringing these findings to bear on the growing problem of human obesity.
Dr Tony Coll
This study is published in the journal Cell.
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