Insect metamorphosis promotes the exploration of different ecological niches, as well as exposure to different parasites, across life stages. Adaptation should favour immune responses that are tailored to specific microbial threats, with the potential for metamorphosis to decouple the underlying genetic or physiological basis of immune responses in each stage. However, we do not have a good understanding of how early-life exposure to parasites influences immune responses in subsequent life stages. Is there a developmental legacy of larval infection in holometabolous insect hosts? To address this question, we exposed flour beetle ( Tribolium castaneum ) larvae to a protozoan parasite that inhabits the midgut of larvae and adults despite clearance during metamorphosis. We quantified the expression of relevant immune genes in the gut and whole body of exposed and unexposed individuals during the larval, pupal and adult stages. Our results suggest that parasite exposure induces the differential expression of several immune genes in the larval stage that persist into subsequent stages. We also demonstrate that immune gene expression covariance is partially decoupled among tissues and life stages. These results suggest that larval infection can leave a lasting imprint on immune phenotypes, with implications for the evolution of metamorphosis and immune systems. This article is part of the theme issue ‘The evolution of complete metamorphosis'.

Type IV P‐type ATPases (P4‐ATPases) are enzymes that catalyze the translocation of lipids across plasma membranes. Our lab recently discovered that Atp10a, a mammalian P4‐ATPase, can translocate glucosylceramide, a sphingolipid. Both Atp10a and glucosylceramide have been independently implicated in metabolic dysfunction. To explore the role of Atp10a in metabolic dysfunction and sphingolipid metabolism, we created a novel Atp10a knockout (KO) mouse model. Atp10a KO mice display a female‐specific excess weight gain on standard chow that is exacerbated by 12 weeks of high fat feeding and this is attributable to increased adiposity. Additionally, they display an accumulation of neutral lipids and altered ceramide metabolism in their livers. After a 5 hour fast, these mice exhibit elevated blood glucose levels that are not coupled to a proportional elevation in insulin levels. Atp10a KO mice also exhibit elevated plasma free fatty acids, cholesterol, and triglycerides. Thus far, our studies have shown that knocking out Atp10a in a mouse results in sex‐specific perturbations to body weight and composition, glucose homeostasis, plasma lipid levels, and liver metabolism.

Genetic predisposition and environment play substantial roles in obesity, type 2 diabetes and cardiovascular disease (CVD). Genetic association studies have linked ATP10A, encoding a type IV P‐type ATPase (P4‐ATPase), to human metabolic disease. ATP10A is a lipid flippase that catalyzes the membrane translocation of phosphatidylcholine and glucosylceramide. These lipids and their respective metabolites have been independently implicated in metabolic dysfunction. To explore the role of this flippase in metabolism, we created a novel Atp10aknockout (KO) mouse model. Atp10a KO mice display a female‐specific weight gain during high‐fat diet feeding and this is attributable to increased adiposity. Female Atp10a KO mice also exhibit elevated plasma free fatty acids, cholesterol, and triglycerides, as well as a depletion in eicosanoid species compared to the wild type (WT) littermates. Additionally, female Atp10a KO mice exhibit elevated fasting blood glucose levels without compensatory elevation of insulin. We also found that the liver of female Atp10aKO mice displays larger lipid droplets, which was associated with increased diacylglycerol acyltransferase‐2 (DGAT2) expression and an attenuation of the insulin signaling pathway compared to the WT littermates. Thus far, our studies have shown that knocking out Atp10a in mice on a high fat diet results in sex‐specific perturbations to body composition, plasma lipid levels, glucose homeostasis, and liver metabolism. We have recently found that ATP10A is specifically expressed in the endothelial cells of multiple tissues. We are now exploring these metabolic phenotypes through the lens of endothelial cell dysfunction. These studies suggest mechanisms by which this flippase contributes to the development of CVD with obesity.

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