A fat-rich diet has been linked to obesity, insulin resistance and type 2 diabetes, cardiovascular disease and a shortened lifespan in many species. The King’s team set out to understand the relationship between a chronic high fat diet, the immune system, and insulin resistance and lifespan.
The study, published in the journal Immunity, used drosophila or fruit flies as a model to explore the molecular pathways involved in the immune response to excess dietary fats and metabolic stress, and identify the role of macrophages (immune cells that scavenge fat) in blood sugar regulation, fat storage and lifespan.
After chronic feeding with a high fat diet, flies exhibited strikingly similar effects to humans; they accumulated excess fat, their blood sugar levels rose, they became insulin-resistant and their lifespan dropped.
In addition, fly immune blood cells known as plasmatocytes became filled with fat droplets whilst also triggering the production of a pro-inflammatory cytokine molecule known as unpaired3 . Unpaired3 has a counterpart in mammals called Interleukin-6, which has previously been associated with diseases induced by high fat diets.
The King’s team demonstrated that unpaired3 produced by macrophages is responsible for insulin resistance high blood sugar, and reduced lifespan, whilst fat storage in itself did not affect longevity and blood sugar levels. They also defined the signalling pathway responsible for unpaired3 production by macrophages, and found that blocking any step of the pathway that led to cytokine production was sufficient to prevent the elevated sugar levels and insulin resistance observed in the flies and boosted their lifespan, even though fat continued to accumulate in the flies’ tissues.
Dr Katie Woodcock, the first author of the study at the CMCBI, Division of Immunology, Infection and Inflammatory Diseases at King’s College London, says: “We have discovered the mechanism which may be responsible for the detrimental effects of excess dietary fat. This immune pathway may offer potential future therapeutic targets for the treatment of diet-related diseases such type II diabetes. However, further work is needed to establish whether similar pathways might operate in mammals and whether these would be useful targets for health interventions.”
Professor Frederic Geissmann, Division of Immunology, Infection and Inflammatory Diseases at King’s College London, says: “This is an increasingly important and relevant research. The next stage of our work will be to determine which tissues or organs in the fly are the critical targets of the cytokine produced by fly immune blood cells.”
Notes to editor
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‘Drosophila macrophages promote systemic JAK-STAT signaling, impaired glucose homeostasis and reduced lifespan in response to lipid-rich diet’ by Woodcock et al is published online in the journal Immunity on 15 January 2015.
The study was funded by European Research Council and Wellcome Trust.