Low-grade aldehyde stress protects mice from diet-induced obesity
DNA damage is a form of cellular stress that can have drastic consequences on the level of the cell, tissue, and whole organism. In mammals, DNA can be damaged through endogenous and exogenous damaging agents and intricate protection pathways have evolved to safeguard the genome, which include enzymatic detoxification of reactive metabolites and DNA repair pathways. Responses to DNA damage go beyond repair of a particular lesion and encompass complex reactions to stress, which are specific to cell- and tissue type as well as strength of insult. One of many endogenous sources of genotoxic stress are aldehydes, reactive metabolites that have been shown to cause interstrand crosslinks and transcriptional stress. In this work, the response to aldehyde stress of different strengths and in various contexts is analysed, which reveals the specificity of the DNA damage response *in vivo*. Aldehydes are produced in haematopoietic stem cells, which critically rely on enzymatic detoxification and DNA repair pathways to maintain genome integrity. We demonstrate that increased chronic endogenous aldehyde stress causes an aged HSC phenotype characterised by loss of self-renewal, an aged transcriptional signature, altered surface protein expression, and a myeloid-biased output. This accelerated ageing phenotype is dependent on P53, and genetic disruption of this key gene restores transcriptional age and output of aldehyde- stressed HSCs. Subsequently, I utilise a whole-genome CRISPR screen to identify mediators of aldehyde stress in a cell line model. This suppressor screen revealed that glucose and fat metabolism mediate aldehyde toxicity indirectly and change cellular fitness as measured by growth without changing aldehyde levels in cells. Further investigating the role of aldehyde-stress in combination with fat and sugar metabolism *in vivo*, I find that mice subjected to low-grade endogenous aldehyde stress are resistant to obesity and onset diabetes induced by high glucose and fat dietary challenges. This protection is mediated by GDF15, a hormone that is elevated in response to endogenous formaldehyde stress when DNA repair is intact and causes a decrease in food consumption during the dietary challenge. By genetically disrupting GDF15, I demonstrate that this hormone is necessary and sufficient for the observed protection against obesity. A similar phenotype has been observed in humans, where people that are deficient in acetaldehyde detoxification have been found to have a lower BMI in GWAS studies. Taken together, these findings show that responses to DNA damage are diverse and specific, ranging from complex tissue remodelling during ageing to adaptive changes in normal physiology such as alterations in weight homeostasis and feeding behaviour.
Diabetes, DNA damage, GDF15, Metabolism, Obesity, p53
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