Sex-biased expression of enteroendocrine cell-derived hormones contributes to higher fat storage in Drosophila females

In Drosophila, females store more fat than males (De Groef et al., 2021; Lease and Wolf, 2011; Parisi et al., 2011; Schwasinger-Schmidt et al., 2012; Sieber and Spradling, 2015; Wat et al., 2020; Wat et al., 2021). Greater female fat storage has been observed in both mated and unmated females compared with age-matched males (De Groef et al., 2021; Parisi et al., 2011; Schwasinger-Schmidt et al., 2012; Sieber and Spradling, 2015; Wat et al., 2020; Wat et al., 2021). In flies, as in other animals, triglyceride is the main form of stored fat. Although triglyceride is present in many cell types and organs (e.g., oenocytes, glia, neurons, and gut) (Sieber and Spradling, 2015; Wat et al., 2020; Chao et al., 2024; Gutierrez et al., 2007; Kis et al., 2015; Kühnlein, 2011; Kühnlein, 2012; Sieber and Thummel, 2009; Villanueva et al., 2019), the majority of triglyceride is stored in an organ called the fat body (Parisi et al., 2011; Kühnlein, 2011; Arrese and Soulages, 2010).

In females, high levels of triglyceride in the fat body play a key role in supporting reproduction and physiology (Sieber and Spradling, 2015; Buszczak et al., 2002). Indeed, triglyceride from the fat body is a key energy source for the developing embryo (Matsuoka et al., 2017). Increased fat storage in adult females also supports prolonged survival during nutrient deprivation compared with males (Schwasinger-Schmidt et al., 2012; Wat et al., 2020). Despite these clear benefits of greater fat storage for female fertility, excess fat accumulation in males adversely affects their reproductive output. Specifically, males carrying a mutation that promotes excess triglyceride accumulation show reduced testis size, defects consistent with delays in spermatogenesis, and ultimately a reduction in sperm number (Chao et al., 2024). The sex difference in fat storage therefore likely reflects the fact that males and females differ in how much whole-body triglyceride storage supports optimal fertility.

Recent studies have identified genes and pathways that contribute to sex differences in fat storage (Sieber and Spradling, 2015; Wat et al., 2020; Wat et al., 2021; Biswas et al., 2025). In mated females, the steroid hormone ecdysone acts on neurons to promote food intake, which is associated with increased body fat (Sieber and Spradling, 2015). In unmated adult females, the insulin/insulin-like growth factor signaling pathway (IIS) plays a key role in maintaining an elevated level of triglyceride storage compared with adult males (Biswas et al., 2025). Specifically, adult females have higher production of Drosophila insulin-like peptide 3 (Dilp3) and greater insulin sensitivity, leading to higher IIS activity. This elevated IIS activity is important for females to store more triglyceride than males, as adult-specific ablation of the insulin-producing cells (IPCs) reduces body fat in females but not males (Biswas et al., 2025).

In males, body fat levels are maintained by higher expression and activity of two catabolic pathways that promote fat breakdown. One pathway is regulated by triglyceride lipase brummer (bmm), where males show higher bmm mRNA levels compared with females (Wat et al., 2020). This elevated bmm expression contributes to the sex difference in fat storage by restricting triglyceride accumulation in males. Similarly, males have higher production and secretion of Adipokinetic hormone (Akh), a key lipolytic hormone in insects (Wat et al., 2021). As with bmm, high levels of Akh in males contribute to the sex difference in fat storage by limiting fat accumulation in males (Wat et al., 2021). Together, these studies have defined a model of the sex difference in fat storage in which females maintain higher levels of fat storage in part due to a higher relative activity level for anabolic pathway IIS, whereas males have lower fat storage due to higher relative activity of catabolic effectors such as bmm and Akh. While some progress has been made in revealing the mechanisms underlying the sex-specific regulation of Akh and IIS (Wat et al., 2021; Biswas et al., 2025), we do not have a complete understanding of the factors that determine the sex-biased regulation and function of these key metabolic factors.

Recent clues into the regulation of Akh, bmm, and IIS have emerged from studies on peptide hormone function (Birse et al., 2011; Hentze et al., 2015; Kapan et al., 2012; Kubrak et al., 2022; Kubrak et al., 2024; Kubrak et al., 2016; Nässel et al., 2008; Oh et al., 2019; Sano et al., 2015; Scopelliti et al., 2019; Yoshinari et al., 2021; Zandawala et al., 2018), as several hormones influence physiology via effects on Akh- and Dilp-producing cells (Birse et al., 2011; Hentze et al., 2015; Kapan et al., 2012; Kubrak et al., 2022; Kubrak et al., 2016; Nässel et al., 2008; Oh et al., 2019; Sano et al., 2015; Scopelliti et al., 2019; Yoshinari et al., 2021; Zandawala et al., 2018; Nässel and Vanden Broeck, 2016; Nässel and Zandawala, 2019; Toprak, 2020). In particular, recent studies have illuminated an important role for hormones produced by the enteroendocrine (EE) cells of the gut (Nässel and Zandawala, 2019; Miguel-Aliaga et al., 2018; Wegener and Veenstra, 2015; Zhou et al., 2020). Adult Drosophila EE cells produce and release hormones such as Allatostatin A (AstA), Allatostatin C (AstC), neuropeptide F (NPF), tachykinin (Tk), Diuretic hormone 31 (Dh31), Bursicon, CCHamide 1 (CCHa1), and CCHamide 2 (CCHa2), and short neuropeptide F (sNPF) (Chen et al., 2016; Hung et al., 2020; Reiher et al., 2011; Veenstra, 2009; Veenstra et al., 2008).

EE cells are identified by expression of the homeodomain protein Prospero in adults (Micchelli and Perrimon, 2006; Ohlstein and Spradling, 2006), where EE cells that produce distinct hormones are present in anatomically defined regions of the adult gut (Ohlstein and Spradling, 2006). For example, AstA- and Dh31-producing EE cells are located in the posterior midgut, whereas EE cells that produce AstC and Tk are found along the entire length of the midgut (Chen et al., 2016). NPF-producing cells are found in the anterior and middle midgut (Veenstra et al., 2008). Supporting a role for EE cell-derived hormones in regulating Akh/IIS, in fed conditions studies show EE cell-derived hormones such as Bursicon inhibit Akh secretion (Scopelliti et al., 2019), whereas NPF enhances Dilp secretion from the IPCs (Yoshinari et al., 2021). During starvation, AstC promotes Akh release from Akh-producing cells (APCs) to enable lipid mobilization (Kubrak et al., 2022). While some EE cell-derived hormones have been shown to have sex-biased effects on food intake and energy mobilization (Kubrak et al., 2022; Malita et al., 2022; Kubrak et al., 2026), sex differences in the regulation and function of most of these hormones remain unclear. Defining potential differences in EE cells is an important task, as prior studies have revealed profound differences in gut biology between males and females.

For example, males and females differ in overall gut size and shape (Ahmed et al., 2020; Blackie et al., 2024) and in the number of intestinal stem cell divisions (Ahmed et al., 2020; Hudry et al., 2016; Regan et al., 2016; Zipper et al., 2020). The absorptive lining of the gut also shows sex differences during aging (Regan et al., 2016; Regan et al., 2022). After mating, females also show pronounced changes to gut size, function, and gene expression (Ahmed et al., 2020; Cognigni et al., 2011; Hadjieconomou et al., 2020; Reiff et al., 2015; White et al., 2021). While sex differences in intestinal stem cells and enterocytes play a key role in mediating these differences in gut biology, we know less about male–female differences in EE cells. We therefore aimed to perform a detailed characterization of EE cell-derived hormones in males and females, and to determine the contribution of these hormones to physiology in each sex. We reveal profound sex-biased regulation of EE cell-expressed hormones AstC, Tk, and NPF: females show higher mRNA levels of these hormones in the gut than males. For at least one EE cell-derived hormone, this sex-biased regulation was physiologically significant, as knock-down of AstC in the gut reduced fat storage in females with no effect in males. Knock-down of Tk in the gut produced a trend toward reduced female fat storage. Female-specific fat storage defects were also observed following knock-down of AstC and Tk receptors in neurons and/or neuropeptide-producing cells. While the specific cell type targeted by these EE cell-derived hormones to influence fat storage remains unclear, this reveals a female-specific contribution of one EE cell-derived hormone in regulating body fat.

EE cell-derived hormones regulate body fat in single- and mixed-sex animal groups; however, it has been unclear whether the regulation and function of these peptides differ between the sexes. The goal of our study was to perform a detailed comparison of EE cell-derived hormones between the sexes, and to test if these hormones contribute to the sex difference in fat storage. Our assessment revealed profound female-biased expression of EE cell-expressed hormones within the gut. For one hormone, AstC, this differential expression was physiologically significant, as we showed that EE cell-derived AstC promotes female fat storage. Interestingly, these effects were not mediated by the IPC or APC, cells that we have previously shown contribute to the sex difference in fat storage. Taken together, our data provide additional insight into the highly complex mechanism(s) by which unmated female flies achieve higher fat storage than male flies (Figure 5).

Figure 5

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While it was not the main goal of our study, our survey of EE cell-expressed hormones in Drosophila revealed that the sex bias in expression was not uniform across tissues. In the gut, mRNA levels of AstC, Tk, and NPF were higher in females than in males. In the brain, mRNA levels of these hormones showed a significant male bias, in line with data from previous reports on Tk (Asahina et al., 2014) and NPF (Lee et al., 2006). While it remains unclear whether the tissue-specific sex bias in expression is physiologically significant, peptides derived from the gut and the brain have been shown to mediate distinct effects on physiology and/or behavior. For example, EE cell-derived AstC regulates energy homeostasis and food-seeking behaviors in adult females (Kubrak et al., 2022), whereas neuron-derived AstC is involved in regulating locomotion in adult males (Díaz et al., 2019) and the circadian regulation of oogenesis in adult females (Zhang et al., 2021). Neuron-derived Tk similarly regulates locomotion (Lee et al., 2021; Winther et al., 2006), food consumption (Qi et al., 2021), Dilp secretion (Birse et al., 2011), and aggression (Asahina et al., 2014), whereas gut-derived Tk regulates intestinal lipogenesis (Song et al., 2014) and stem cell divisions in the midgut (Amcheslavsky et al., 2014; Foronda et al., 2014; O’Brien et al., 2011). Supporting a potential sex-specific role for peptides derived from different anatomical sites in regulating physiology, gut-derived AstC stimulates fat breakdown during starvation through the Akh pathway in mated females with no effect in males (Kubrak et al., 2022). Future studies are therefore needed to determine whether there are sex differences in whether the effects of EE cell-derived hormones are primarily mediated by local or systemic mechanisms.

Another important task for future studies will be to elucidate how sex differences in neuropeptide expression are established. The first step in understanding these mechanisms will be to determine which factors specify the sex bias in neuropeptide mRNA levels. Because our data show that sex determination gene tra does not regulate the sex bias in neuropeptide expression in either the brain or the gut, the role of other factors that influence sexual identity and sexual differentiation must be assessed. One strong candidate is the steroid hormone ecdysone, as virgin females have higher ecdysone titers than males (Bownes et al., 1984; Harshman et al., 1999; Schwedes and Carney, 2012). Ecdysone plays a role in regulating sexual differentiation and development (Sieber and Spradling, 2015; Li et al., 2014; Riddiford et al., 2000), and contributes to male–female differences in multiple aspects of intestinal physiology (e.g., intestinal stem cell proliferation) (Ahmed et al., 2020; Zipper et al., 2020) and brain development (Dalton et al., 2009; Zhang et al., 2018). Another candidate is juvenile hormone, which has been shown to regulate sexual maturation in Drosophila and other insects (Argue et al., 2013; Barth and Lester, 1973; Bilen et al., 2013; Flatt et al., 2005; Raikhel et al., 2005; Wijesekera et al., 2016; Wyatt and Davey, 1996). While it remains unclear whether juvenile hormone titers differ between virgin males and females, juvenile hormone regulates many aspects of gut physiology in mated females (e.g., intestinal lipid accumulation, intestinal stem cell proliferation) (Reiff et al., 2015; Rahman et al., 2017) and influences brain development (Liu et al., 2024). Other than hormones, it is possible that the sex determination gene Sex-lethal plays a role in regulating the sex difference in mRNA levels of EE cell-derived hormones, as tra-independent effects of Sex-lethal have been described in the brain (Evans and Cline, 2013). While sex differences in the expression of EE cell-derived hormones do not involve tra, and are therefore unlikely to involve known tra targets such as fruitless (Heinrichs et al., 1998; Ryner et al., 1996), without further experiments we cannot fully rule out these additional sex determination pathway members.

In parallel to identifying the factor(s) responsible for establishing the sex difference in EE cell-expressed hormones, it will be important to reveal the cellular basis for this differential expression. For example, a sex difference in the number of EE cells and neuropeptide-expressing cells in the brain could explain the differences in expression. Supporting this, gut length, overall brain size, and neuron number have been shown to differ between males and females (Miguel-Aliaga et al., 2018; Hudry et al., 2016; Asahina, 2018; Cachero et al., 2010; Jiao et al., 2022; Kimura et al., 2005; Nojima et al., 2021; Ren et al., 2016; Sanders and Arbeitman, 2008; Sato and Yamamoto, 2023). In the gut, the difference in length is at least partially due to a sex difference in the proliferation of intestinal stem cells (Ahmed et al., 2020; Hudry et al., 2016; Regan et al., 2016), which undergo asymmetric divisions and subsequent differentiation to generate all gut cell types, including EE cells (Miguel-Aliaga et al., 2018; Micchelli and Perrimon, 2006; Buchon and Osman, 2015; Driver and Ohlstein, 2014; Jiang and Edgar, 2011; Lemaitre and Miguel-Aliaga, 2013; Schonhoff et al., 2004).

In the brain, males and females differ in the number of neurons found within many identified clusters (Asahina, 2018; Cachero et al., 2010; Kimura et al., 2005; Nojima et al., 2021; Ren et al., 2016; Sanders and Arbeitman, 2008; Sato and Yamamoto, 2023; Kimura, 2011), including the cells that produce NPF (Lee et al., 2006) and Tk (Asahina et al., 2014). Differences in neuron number have been primarily attributed to sex-specific programmed cell death (Sanders and Arbeitman, 2008; Kimura, 2011; Garner et al., 2018; Kimura et al., 2008; Nojima et al., 2010); however, sex differences in neuroblast cell death and/or proliferation may also play a role (Ren et al., 2016; Ghosh et al., 2019; Taylor and Truman, 1992; Truman and Bate, 1988).

Beyond the effects of cell number, sex differences in EE cell-derived hormone mRNA levels may also be due to differential gene and/or protein expression of these factors, which have been reported for other peptide hormones (Wat et al., 2021; Biswas et al., 2025; Lee et al., 2006). Because sex differences in the activity of peptide hormone-producing cells have also been previously described (Wat et al., 2021), it is clear that a detailed examination of sex differences in EE cells, and more generally in neuropeptide-producing cells, is needed to gain a comprehensive picture of how these cells differ between males and females. Benefits of such a detailed study include gaining insight into potential mechanisms underlying sex differences in other aspects of physiology and behavior. For example, EE cells regulate ISC homeostasis (Amcheslavsky et al., 2014; Scopelliti et al., 2014), and EE cell-derived hormones act locally and systemically to regulate appetite, food ingestion, food digestion, gut motility, and immune responses (Wegener and Veenstra, 2015; Guo et al., 2022; Kamareddine et al., 2018; Ren et al., 2015). Importantly, male–female differences in many of these phenotypes have been reported (Cognigni et al., 2011; Hadjieconomou et al., 2020; Belmonte et al., 2019; Duneau et al., 2017; Peng et al., 2025; Shahrestani et al., 2018).

Overall, our findings identify EE cell-derived hormones AstC as an important factor that promotes higher fat storage in Drosophila adult virgin females. This builds on a recent paper identifying a key role for IIS in promoting higher levels of fat storage in unmated females but not males (Biswas et al., 2025), advancing knowledge of the factors that establish an optimal level of stored fat in each sex.

Source data 1 contains raw data with calculations. Source data 2 contains the statistics for all data.

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Author details

1. Puja Biswas

   Department of Cellular and Physiological Sciences, Life Sciences Institute, The University of British Columbia, Vancouver, Canada

   Present address

   Department of Pediatrics, BC Children’s Hospital Research Institute, The University of British Columbia, Vancouver, Canada

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Visualization, Methodology, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-6808-6662

2. Elizabeth J Rideout

   Department of Cellular and Physiological Sciences, Life Sciences Institute, The University of British Columbia, Vancouver, Canada

   Contribution

   Conceptualization, Resources, Supervision, Funding acquisition, Methodology, Writing – original draft, Writing – review and editing, Project administration

   For correspondence

   elizabeth.rideout@ubc.ca

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-0012-2828

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