The sugar-responsive enteroendocrine neuropeptide F regulates lipid metabolism through glucagon-like and insulin-like hormones inDrosophila melanogaster

Abstract

The enteroendocrine cell (EEC)-derived incretins play a pivotal role in regulating the secretion of glucagon and insulins in mammals. Although glucagon-like and insulin-like hormones have been found across animal phyla, incretin-like EEC-derived hormones have not yet been characterised in invertebrates. Here, we show that the midgut-derived hormone, Neuropeptide F (NPF), acts as the sugar-responsive, an incretin-like hormone in the fruit fly, Drosophila melanogaster. Secreted NPF is received by NPF receptor in the corpora cardiaca and in insulin-producing cells. NPF-NPFR signalling resulted in the suppression of the glucagon-like hormone production and the enhancement of the insulin-like peptide secretion, eventually promoting lipid anabolism. Similar to the loss of incretin function in mammals, loss of midgut NPF led to significant metabolic dysfunction, accompanied by lipodystrophy, hyperphagia, and hypoglycaemia. These results suggest that enteroendocrine hormones regulate sugar-dependent metabolism through glucagon-like and insulin-like hormones not only in mammals but also in insects.

Interorgan communication through peripherally derived peptide hormones in Drosophila

“…Although both the NPF receptor (NPFR) and AstC receptor 2 (AstC-R2) are expressed in the CC, NPF and AstC have an inhibitory and facilitatory effect on secretion of Akh, respectively [ 186 , 187 ] ( Figure 3c ). NPFR is also expressed in the brain IPCs, where it facilitates secretion of Dilps [ 186 ] ( Figure 3c ). Therefore, EEC-derived NPF, in response to dietary sugars, regulates the balance between Dilps and Akh, promoting assimilation in peripheral tissues, such as the fat body [ 186 ].…”

“…Dietary sugars positively regulate production and secretion of NPF from the gut EECs, whereas AstC secretion is induced by nutrient restriction ( Figure 3c ). Although both the NPF receptor (NPFR) and AstC receptor 2 (AstC-R2) are expressed in the CC, NPF and AstC have an inhibitory and facilitatory effect on secretion of Akh, respectively [ 186 , 187 ] ( Figure 3c ). NPFR is also expressed in the brain IPCs, where it facilitates secretion of Dilps [ 186 ] ( Figure 3c ).…”

“…NPFR is also expressed in the brain IPCs, where it facilitates secretion of Dilps [ 186 ] ( Figure 3c ). Therefore, EEC-derived NPF, in response to dietary sugars, regulates the balance between Dilps and Akh, promoting assimilation in peripheral tissues, such as the fat body [ 186 ]. The action of EEC-derived NPF resembles that of the mammalian enteroendocrine hormone glucagon-like peptide 1 (GLP-1).…”

“…For example, Burs-α and NPF are produced in EECs in the posterior and anterior midgut, respectively. Dietary sugars induce production and secretion of Burs-α and NPF through different solute carrier family 2 (SLC2) sugar transporters, Glut1, and Sut1, respectively [ 181 , 186 ] ( Figure 3c ). In addition, TK-, and DH31-producing EECs, which express many gustatory receptors (Gr), appear to be activated by dietary proteins and amino acids [ 198 , 199 ].…”

“…These hormones activate EcR and NPFR in ovarian somatic cells, where they enhance bone morphogenetic protein (BMP) signalling levels in the GSCs, promoting their proliferation [ 185 , 225 ]. EEC-derived NPF thus has diverse functions, regulating energy metabolism in response to dietary nutrients [ 186 ] ( Figure 3b ) and inducing GSC proliferation in post-mating responses [ 185 ] ( Figure 4b ).…”