Fat body phospholipid state dictates hunger-driven feeding behavior

Abstract

Diet-induced obesity leads to dysfunctional feeding behavior. However, the precise molecular nodes underlying diet-induced feeding motivation dysregulation are poorly understood. The fruit fly is a simple genetic model system yet displays significant evolutionary conservation to mammalian nutrient sensing and energy balance. Using a longitudinal high sugar regime in Drosophila, we sought to address how diet-induced changes in adipocyte lipid composition regulate feeding behavior. We observed that subjecting adult Drosophila to a prolonged high-sugar diet degrades the hunger-driven feeding response. Lipidomics analysis reveals that longitudinal exposure to high-sugar diets significantly alters whole-body phospholipid profiles. By performing a systematic genetic screen for phospholipid enzymes in adult fly adipocytes, we identify Pect as a critical regulator of hunger-driven feeding. Pect is a rate-limiting enzyme in the phosphatidylethanolamine (PE) biosynthesis pathway and the fly ortholog of human PCYT2. We show that disrupting Pect activity only in the Drosophila fat cells causes insulin resistance, dysregulated lipoprotein delivery to the brain, and a loss of hunger-driven feeding. Previously human studies have noted a correlation between PCYT2/Pect levels and clinical obesity. Now, our unbiased studies in Drosophila provide causative evidence for adipocyte Pect function in metabolic homeostasis. Altogether, we have uncovered that PE phospholipid homeostasis regulates hunger response.

The fat body cortical actin network regulates Drosophila inter-organ nutrient trafficking, signaling, and adipose cell size

“…Since our observations support a model where Act5C is required for FB Lpp secretion, perturbation of this process may explain (at least in part) the reduced LD and TG storage defects observed in Act5C-depleted FB tissues. This may also account for the reduced insulin signaling in Act5C-deficient FBs, as Lpp trafficking to the brain and insulin secretion from brain IPCs have been shown to directly correlate in other studies ( Brankatschk et al, 2014 ; Kelly et al, 2022 ).…”

“…Past work has shown that Lpp particles accumulate at neurons that harbor insulin-like peptides and influence their release ( Brankatschk and Eaton, 2010 ). More recent studies reveal that high sugar Drosophila feeding promotes Lpp-mediated crosstalk with the brain and ultimately influences insulin signaling and feeding behavior ( Kelly et al, 2022 ). A key emerging question is how Lpp lipid trafficking influences inter-organ insulin signaling and feeding, and how this impacts organismal homeostasis and development.…”

Phosphatidylethanolamine homeostasis under conditions of impaired CDP-ethanolamine pathway or phosphatidylserine decarboxylation

“…This relationship likely involves PC as well because a decrease in the ratio of PC:PE has been shown to increase insulin signaling ( 130 ). Additionally, Drosophila with Pect deficiency (the analog of PCYT2 ), develop insulin resistance and have a disrupted hunger response ( 131 ). This impact of PE on insulin signaling has also been demonstrated by our studies on Pcyt2 knockout mice.…”

CRUMB: a shiny-based app to analyze rhythmic feeding in Drosophila using the FLIC system

“…22 Since then, several other groups have adopted the system and used it to address different biological questions including rhythmic feeding and metabolic homeostasis. 18,[23][24][25][26][27][28][29][30][31][32] Available options of software to analyze locomotor activity from DAMS have multiplied over the years, offering different user interphases and developed in different coding languages [33][34][35][36][37] (summarized in Cai et al 15 ). In contrast, due to its recent implementation, user-friendly tools to analyze FLIC data are still scarce, 23 and available scripts require the user to understand and use R coding syntax.…”