Fruit fly provides insight into carbohydrate and fat control

Incretins are hormones secreted by intestinal cells that regulate pancreatic insulin and glucagon to control sugar metabolism in mammals.

Although homologues of insulin and glucagon have been identified in invertebrates, no hormone equivalent to incretin has been described. Today, researchers at the University of Tsukuba are showing that neuropeptide F (NPF), a hormone produced by the midgut, plays this complex role in the fruit fly.

Life processes are orchestrated by various neuroendocrine feedback systems that maintain fundamental similarities across the animal kingdom. In response to dietary sugars, incretins in the mammalian gut stimulate pancreatic cells to produce insulin and suppress its counter-regulatory hormone, glucagon. Together, they antagonistically adjust sugar levels: insulin clears circulating carbohydrates and promotes fat storage while glucagon plays a modulating role.

Having earlier discovered the reproductive function of NPF in fruit flies, Drosophila melanogaster, the research team questioned its role in other biological processes, in particular in energy homeostasis. Their research strategy included advanced genetic engineering to generate mutant flies of specific gene knockout strains (in which gene expression was inactivated or suppressed) and knock-in strains (in which a one-for-one substitution of a genetic sequence has been created in a particular place). State-of-the-art laboratory techniques have been used to reveal genetic and molecular signaling pathways and underlying cellular mechanisms.

Researchers were able to demonstrate that NPF is secreted by intestinal endocrine cells in response to dietary sugar. It signals the NPF receptor in heart bodies, a gland-like organ in insects, and stimulates insulin-producing cells in the brain of insects to suppress the glucagon-like hormone while enhancing the production of type peptides. insulin. This increases the level of glucose in the hemolymph (the circulatory fluid in the insect’s body cavity) and promotes the accumulation of lipids in the body fat.

Our investigations showed that loss of midgut NPF or disordered MFN / NPFR signaling in fruit flies produced metabolic disorders similar to the loss of incretin in mammals, such as lipodystrophy (loss of healthy fat ), hypoglycemia and overeating (overeating). Significantly, although NPF is also produced by the brain, we have shown that brain-derived NPF does not have this function and that Drosophila NPF is structurally distinct from mammalian incretins. However, further research to investigate the role of NPF in other potential target tissues is needed.. “

Ryusuke Niwa, lead study author and professor, University of Tsukuba

This study highlights the underlying similarities in sugar-dependent metabolic processes between insects and mammals. A better understanding of the functional role of incretins may inform therapeutic strategies for medical conditions associated with their dysfunction such as obesity and type 2 diabetes.