Obesity is not just a matter of metabolism. Your behaviour changes and even knowing the unhealthy effects of high fat/high energy diet you cannot stop consuming it. Now scientists at the Centre for Genomic Regulation (CRG) in Barcelona have found out how our genes respond to the foods we eat. They fed mice an obesogenic diet and found that it triggers coordinated gene expression changes in different areas of the brain. Their work, published in the journal eNeuro, shows that small changes in the expression of many genes correlate with physical and behavioural changes in the mice, giving clues about how an obesogenic environment can produce behavioural as well as physical alterations that lead to obesity.

Obesity is a growing problem across the world - in 2016, more than 1.9 billion adults 18 years and over were overweight, and of these, over 650 million were obese. In the USA, experts predict over 85 per cent of adults will be overweight or obese by 2030. Obesity greatly increases the risk of developing other chronic diseases, including type 2 diabetes, heart and circulatory disease, depression, certain cancers and dying earlier.

CRG researchers Ilario De Toma, Marta Fructuoso and Mara Dierssen in collaboration with Bartek Wilczynski from the University of Warsaw, studied how gene expression changes in certain brain regions associated with energy balance and reward when animals eat so-called ‘obesogenic’ diets. They believed this work would reveal why mice become overweight and overeat when they have free access to a chocolate diet. Until now, we knew little about how this diet leads to gene expression changes in the brain and how these changes are coordinated.

In their research, they studied gene expression changes in mice which have access to an energy-dense diet. Mice fed the high-energy diet became overweight and compulsive, mimicking what happens as obesity develops in humans. They discovered that the observed gene expression changes are controlled by two main regulatory processes – one molecular ‘switch-like’ process that leads to changes greater than 1.5-fold in a limited number of genes, and another ‘fine tuning’ process which controls genes using a subtler process. Surprisingly, the subtlest molecular changes were the ones associated with body weight and compulsivity.

“We found that genes responding to diet in a similar way were not randomly distributed but tended to cluster in the same region of the genome called topologically associated domains, or TADs” explains Dierssen. “TADs are areas of the chromosome that are evolutionarily conserved across tissues and species, and the genes present in TADs usually exhibit similar expression profiles, forming clusters that are regulated together. In fact, it is not just homeostatic mechanisms regulating food intake and energy expenditure that control obesity development, but also by reward, emotion and memory, attention, and cognitive systems that may lead to addictive-like behaviours such as compulsive-overeating and inflexibility. These are controlled by metabolic and hedonic brain areas - the hypothalamus, the frontal cortex and the striatum – and these needs to be coordinated to allow people to ingest a higher more calories than they need”, concludes Dierssen.

In their study, the team discovered that how the genes within TADs responded to diet depended on the brain region. For example, the same domain could contain mainly upregulated genes in the striatum and cortex, and downregulated genes in the hypothalamus.

“We did expect gene expression to go awry when animals eat an obesogenic diet. But we did not expect the genes linked to body weight to increase, and for inflexible and compulsive behaviours to be only subtly regulated,” Dierssen continues. “We found the genes that correlated with behavioural or physical changes that we see only went moderately up or down as a result of the chocolate diet, whilst other genes changed their levels more,” says Dierssen. “It was really exciting to find the physical and behavioural changes being reflected by the genes changing in the brain area controlling those functions. For example, gene changes in the hypothalamus, which controls appetite and body weight, correlated with body weight of the mice, while levels of genes expressed in the striatum and frontal cortex correlated with the degree of compulsivity, inflexibility and overeating.”

The research suggests that the gene expression changes induced by a highly palatable and energy-dense diet across different brain regions are orchestrated by chromosomal domains, which allows a coordinated and region-specific response across different brain regions. The fact those genes cluster together in three-dimensional domains suggests epigenetic therapy could be very important, and needs to affect gene expression in a specific 3D region of the genome. We need treatments for obesity that tackle a whole network of genes belonging to key biological processes, rather than a single gene.

The team are now searching for ways to reverse addictive behaviours such as compulsivity and inflexibility by rescuing incorrect gene expression. Research like this, that gives insights into molecular mechanisms underlying conditions, is needed to identify new ways to treat the growing number of people affected by obesity around the world.

For more information and interviews, please, contact: Gloria Lligadas, Head of Communications & PR, Centre for Genomic Regulation (CRG) – gloria.lligadas@crg.eu – Tel. +34 933160153 – Mobile +34608550788

Funding information: Research leading to these results has been supported by the Spanish Ministry of Economy and Competitiveness (Severo Ochoa 2013-2017' SAF2013-49129-C2-1-R and SAF2016-79956-R), Marie Curie IMPULSE, the Centre for Industrial Technological Development (CDTI) Smartfoods, Era-net-Neuron (PCIN-2013- 060) and the Polish National Center for Research and Development (Era-net-Neuron/10/2013).

Reference: Research in this press release is based on findings published in the following academic paper:

I De Toma, I., Grabowicz, I.E., Fructuoso, M., Trujillano, D., Wilczynski, B., Dierssen, M. Overweighed mice show coordinated homeostatic and hedonic transcriptional response across brain. eNeuro (2018). DOI: 10.1523/ENEURO.0287-18.2018 http://www.eneuro.org/content/eneuro/early/2018/11/22/ENEURO.0287-18.2018.full.pdf

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