A fat-heavy diet triggers an immune response that may lead to
diabetes and other health problems, according to a study of fruit
flies from King's College London.
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 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 of King's College London said: "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, also of King's, said: "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."
The paper, Macrophage-Derived
upd3 Cytokine Causes Impaired Glucose Homeostasis and Reduced
Lifespan in Drosophila Fed a Lipid-Rich Diet, is published inImmunity.