Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

A new study from the Patel Group sheds light on the mechanism by which DNA damage suppresses appetite, a finding with implications for understanding the appetite lowering side-effects of chemotherapy.

© Shutterstock/Kateryna Kon

In the paper, published in the journal Nature, researchers from the MRC Weatherall Institute of Molecular Medicine along with colleagues at the MRC Laboratory of Molecular Biology in Cambridge, and Hubrecht Institute in Utrecht, describe a mechanism by which our bodies recognise and respond to toxins and chemotherapy.

Clues to this process came from patients with a rare illness, Cockayne syndrome. Children with Cockayne syndrome develop debilitating symptoms including premature ageing, kidney and brain degeneration, and severe weight loss. The genetic cause of this syndrome, loss of a Cockayne syndrome gene, leaves sufferers unable to repair DNA damage. However, a mouse model of the disease mimicking the loss of a Cockayne gene was unable to recreate the disease profile seen in humans.

The researchers engineered this model so that the mice would accumulate formaldehyde. Formaldehyde is a very toxic molecule often used in embalming, but previous work from the Patel Group showed that formaldehydes accumulate normally in cells as by-products of metabolism and cell growth. Some of this formaldehyde likely comes from dietary sources. Remarkably, the mice that both could not clear formaldehyde and also could not repair damaged DNA, developed all the features of Cockayne syndrome in humans.

They then asked why these mice developed kidney failure and severe weight loss. This analysis led them to discover that DNA damage in a particular cell type in the kidney (proximal tubule cell), causes it to secrete a factor called GDF15 into the blood stream that signals to the brain to suppress appetite.

New research shows that the accumulation of formaldehyde through metabolism, ingestion or chemotherapy can lead to DNA damage which in turn leads to secretion of GDF15 into the blood stream, resulting in loss of appetite.© New research shows that the accumulation of formaldehyde through metabolism, ingestion or chemotherapy can lead to DNA damage which in turn leads to secretion of GDF15 into the blood stream, resulting in loss of appetite. (Credit: Dr Juan Garaycoechea)

The blood is constantly filtered by the kidneys to make urine. Formaldehyde and perhaps other food derived toxins in the urine then damage the DNA in the kidney cells, driving the secretion of GDF15 into the blood. GDF15 then binds to its receptor that resides in the feeding centre in the brain. In Cockayne syndrome, the failure to repair the toxin-derived damaged DNA results in the failure to stop the release of GDF15, thereby explaining the relentless weight loss present in patients with this illness.

The researchers also report that when mice are treated with the chemotherapeutic agent Cis-Platin, the kidney cells are activated to secrete the same hormone. The similarity in mechanism and response suggests this process may be an important target for treating the appetite suppressing side-effects of cancer treatments.

“The discovery of the unexpected connection between DNA damage and food intake opens up opportunities to therapeutically interfere with this response, in order to improve the nutritional state of the many people undergoing cancer chemotherapy and children with Cockayne syndrome.” says Professor KJ Patel, Director of the MRC Weatherall Institute of Molecular Medicine and the MRC Molecular Haematology Unit who led the study. He added “we think that this food aversion response might have evolved in mammals to provide protection against the ingesting toxic food sources”.

Read the full paper in Nature.

Similar stories

Spin-out company Alethiomics launches

The enterprise will focus on developing targeted therapies for a specific family of blood cancers.

Study links the onset of circulation to changes in metabolism affecting blood stem cell development

A new paper published in Cell Reports by the de Bruijn Group indicates that the onset of circulation triggers a metabolic switch associated with the maturation of haematopoietic stem cells.

Interview with Excellence Award winner Dr Susan Shapiro

A member of the Oxford Centre For Haematology, Dr Shapiro, was recently interviewed by the Royal College of Pathologists.

Mohsin Badat receives ASH-BSH Abstract Achievement Award

Dr Mohsin Badat, a Clinical Training Research Fellow from the Higgs and Davies Groups has been awarded the ASH-BSH Abstract Achievement Award by the American Society of Haematology and the British Society of Haematology.

Iron integral to the development of life on Earth – and the possibility of life on other planets

A collaboration between researchers at the MRC WIMM and Department of Earth Sciences uncovers the importance of iron for the development of complex life on Earth.

Strong cytotoxic T cell responses to an internal viral component are associated with mild COVID-19 disease

Study from the Dong Group reveals key differences in the adaptive immune responses of patients with mild vs. severe COVID-19, highlighting a potential new vaccine target.