MedicalResearch.com Interview with:
Ruth Loos, PhD
The Charles Bronfman Professor in Personalized Medicine
Director, Genetics of Obesity and Related Traits Program
Co-Director, Charles Bronfman Institute for Personalized Medicine
Icahn School of Medicine at Mount Sinai
New York, NY
MedicalResearch.com: What is the background for this study? Which type of body fat distribution carries greater risk of diabetes or other obesity-related health disorders?
Response: Obesity broadly consists of two component;  there is overall body size (assessed using BMI) and  there is fat distribution (assessed using WHR). Both are “heritable”, which mean that they are in part determined by our genome (and the other part is determined by our lifestyle).
Over the past 15 years, geneticists have used an approach to screen the whole genome of thousands of people to identify genetic variations that differ between e.g. obese people vs non-obese people.
We have applied this approach to both components of obesity and have found so far that genes for “overall body size” seem to act in the brain, likely controlling hunger, satiety, reward, etc., whereas the genes that determine where in the body the excess fat will be stored when you gain weight (i.e. fat distribution) seem to act more “locally” at the fat cell level itself, determining the storage and release of fat.
MedicalResearch.com: What are the main findings?
Response: Our new study differed from the ones we performed before. People’s genome is very big, and not all of our genetic material encodes genes, a lot of our genetic material “connect” genes. In the past, we screened the whole genome and a lot of the genetic variations we identified located in between genes – and it was very challenging to determine which gene nearby was the “causal” gene.
To overcome this challenge, in our new study, we only focused on genetic variations that locate “in” the genes, and that therefore have the potential to change the function of the gene and its protein. As such, it becomes easier to “pinpoint” the causal gene.
In the current study, we combined data of more than 400,000 individuals from >70 research institutes from around the world and identified 24 new genetic variants that are involved in determining where fat is stored. Follow up analyses shows that many of these variants also affect risk of diseases, such as diabetes, cardiovascular disease, … The genes identified seem to be involved in lipid metabolism – possibly determining how easy fat is stored and/or released from fat cells.
MedicalResearch.com: What should readers take away from your report?
Response: We have long known that storing fat at the waist (apple) is more harmful than storing fat at the hips (pear). With our study, we have identified genes that may help elucidate the biology that links fat distribution to diseases. Knowing the biology that links fat distribution to disease may eventually help us to “un-link” disease from fat distribution, possible through medication that targets the identified genes.
This is not a sci-fi idea, as there has been glucose-lowering medication (TZDs) that targets a gene (PPARG) that influences fat distribution; i.e. this medication lowers glucose through, at least in part, redistributing fat (i.e. reducing intra-abdominal fat storage).
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: The identification of genes for fat distribution is only to beginning of a long road of more research ahead. Follow up studies will need to examine how the genes function, in which pathways, which tissues, and whether they would be good targets for e.g. drug development.
Anne E. Justice et al. Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution. Nature Genetics, 2019; DOI: 10.1038/s41588-018-0334-2
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