Macrophage-Derived upd3 Cytokine Causes Impaired Glucose Homeostasis and Reduced Lifespan in Drosophila Fed a Lipid-Rich Diet

Abstract

SummaryLong-term consumption of fatty foods is associated with obesity, macrophage activation and inflammation, metabolic imbalance, and a reduced lifespan. We took advantage of Drosophila genetics to investigate the role of macrophages and the pathway(s) that govern their response to dietary stress. Flies fed a lipid-rich diet presented with increased fat storage, systemic activation of JAK-STAT signaling, reduced insulin sensitivity, hyperglycemia, and a shorter lifespan. Drosophila macrophages produced the JAK-STAT-activating cytokine upd3, in a scavenger-receptor (crq) and JNK-dependent manner. Genetic depletion of macrophages or macrophage-specific silencing of upd3 decreased JAK-STAT activation and rescued insulin sensitivity and the lifespan of Drosophila, but did not decrease fat storage. NF-κB signaling made no contribution to the phenotype observed. These results identify an evolutionarily conserved “scavenger receptor-JNK-type 1 cytokine” cassette in macrophages, which controls glucose metabolism and reduces lifespan in Drosophila maintained on a lipid-rich diet via activation of the JAK-STAT pathway.

Retinal Axon Guidance Requires Integration of Eya and the Jak/Stat Pathway into Phosphotyrosine-Based Signaling Circuitries in Drosophila

“…Lnk negatively feeds back on Jak/Stat signaling in mammalian cells, although in Drosophila it has been studied as a positive regulator of insulin/insulin-like growth factor signaling (Werz et al 2009;Oh et al 2010;Slack et al 2010;Almudi et al 2013). The Jak/Stat ligands unpaired (Upd) 2 and 3 influence insulin signaling in Drosophila (Rajan and Perrimon 2012; Woodcock et al 2015), thus potentially implicating Lnk in Jak/Stat signaling in flies.…”

“…Intriguingly, the Jak/Stat pathway is relevant to innate immunity in both Drosophila and mammals (reviewed in Perrimon 2004 andO'Shea andPlenge 2012). In Drosophila, Jak/Stat signaling regulates hemocyte (blood cell) development and release of Upd cytokines in response to infection (Agaisse et al 2003;Copf et al 2011;Minakhina et al 2011;Woodcock et al 2015). The tyrosine kinases from our short list of candidates also have potential links to immunity.…”

Drosophilaas a model to study obesity and metabolic disease

“…For high-carbohydrate feeding, high-sucrose diets are the most common (Buescher et al, 2013;Garrido et al, 2015;Havula et al, 2013;Navrotskaya et al, 2016;Musselman et al, 2011;Pasco and Léopold, 2012;Reis, 2016;Rovenko et al, 2015a); however, highglucose and high-fructose diets have also been used (Rovenko et al, 2015b). For high-fat feeding, coconut oil supplementation is the most common way to elicit diet-induced obesity in flies (Birse et al, 2010;Heinrichsen et al, 2014;Hong et al, 2016;Reed et al, 2010), although lard and the hydrogenated soybean and palm oil product known as Crisco have also been used (Lee et al, 2017;Musselman et al, 2011;Woodcock et al, 2015). The formulation of these diets can be tricky and care must be taken to avoid reduced survival owing to unusually sticky or dry food conditions.…”

Purple sweet potato anthocyanin attenuates fat-induced mortality in Drosophila melanogaster

“…A high-fat diet has been associated with a shorter lifespan from Drosophila to mammals (Baur et al, 2006;Driver and Cosopodiotis, 1979;Silberberg and Silberberg, 1954;Woodcock et al, 2015). In humans, long consumption of high fat diets could induce obesity which facilitates the development of cardiovascular diseases, type 2 diabetes, hypertension, some types of cancers, and inflammationmediated diseases (Hariri and Thibault, 2010;Xia et al, 2010;Zhou and Pan, 2015).…”