Female-biased upregulation of insulin pathway activity mediates the sex difference in Drosophila body size plasticity

In insects, the rate of growth during development is influenced by environmental factors such as nutrient availability (Boulan et al., 2015; Edgar, 2006; Hietakangas and Cohen, 2009; Nijhout, 2003; Nijhout et al., 2014). When nutrients are abundant, the growth rate is high and body size is large (Beadle et al., 1938; Edgar, 2006; Mirth and Shingleton, 2012; Nijhout, 2003; Robertson, 1963). When nutrients are scarce, the growth rate is lower and body size is smaller (Beadle et al., 1938; Edgar, 2006; Mirth and Riddiford, 2007; Mirth and Shingleton, 2012; Nijhout, 2003; Robertson, 1963). This ability of an organism or genotype to adjust its body size in line with nutrient availability is a form of phenotypic plasticity (Agrawal, 2001; Garland, 2006). While the capacity of individuals to display nutrient-dependent changes to body size depends on many factors, one important factor that affects phenotypic plasticity is whether an animal is male or female (Stillwell et al., 2010; Teder and Tammaru, 2005). For example, in Drosophila the magnitude of changes to wing cell size and cell number in a nutrient-poor diet were larger in females compared with males (Alpatov, 1930). Similarly, the magnitude of protein- and carbohydrate-induced changes to several morphological traits was larger in female flies (Shingleton et al., 2017). While these studies clearly establish a sex difference in nutrient-dependent phenotypic plasticity, the genetic and molecular mechanisms underlying this increased trait size plasticity in females remain unclear.

Clues into potential mechanisms underlying the increased nutrient-dependent phenotypic plasticity in female flies have emerged from over 20 years of studies on nutrient-dependent growth in Drosophila (Andersen et al., 2013; Boulan et al., 2015; Edgar, 2006; Koyama and Mirth, 2018; Mirth and Piper, 2017). In particular, these studies have identified the conserved insulin/insulin-like growth factor signaling pathway (IIS) as a key regulator of nutrient-dependent growth in Drosophila (Böhni et al., 1999; Britton et al., 2002; Chen et al., 1996; Fernandez et al., 1995; Grewal, 2009; Teleman, 2010). In nutrient-rich conditions, insulin-producing cells (IPCs) in the larval brain release Drosophila insulin-like peptides (Dilps) into the circulation (Brogiolo et al., 2001; Géminard et al., 2009; Ikeya et al., 2002; Rulifson et al., 2002). These Dilps bind the Insulin-like Receptor (InR; FBgn0283499) on target cells to induce receptor autophosphorylation and recruitment of adapter proteins (Almudi et al., 2013; Böhni et al., 1999; Chen et al., 1996; Poltilove et al., 2000; Werz et al., 2009). These adapter proteins enable the recruitment of the regulatory and catalytic subunits of the Drosophila homolog of phosphatidylinositol 3-kinase (Pi3K21B; FBgn0020622 and Pi3K92E; FBgn0015279, respectively), which catalyze the production of phosphatidylinositol (3,4,5)-trisphosphate (PIP₃) from phosphatidylinositol (4,5)-bisphosphate (PIP₂) (Leevers et al., 1996). Increased plasma membrane PIP₃ recruits and activates signaling proteins such as phosphoinositide-dependent kinase 1 (Pdk1; FBgn0020386) and Akt (Akt; FBgn0010379), which influence diverse cellular processes to enhance cell, tissue, and organismal size (Cho et al., 2001; Grewal, 2009; Rintelen et al., 2001; Verdu et al., 1999).

In contrast, when nutrients are scarce, Dilp release from the IPCs is reduced (Géminard et al., 2009), and plasma membrane Pi3K recruitment, PIP₃ levels, and Pdk1- and Akt-dependent signaling are all reduced (Britton et al., 2002; Nowak et al., 2013). Together, these changes diminish cell, tissue, and organismal size (Arquier et al., 2008; Britton et al., 2002; Géminard et al., 2009; Honegger et al., 2008; Okamoto et al., 2013; Rulifson et al., 2002; Zhang et al., 2009). Indeed, the potent growth-promoting ability of IIS activation is shown by the fact that increased IIS activity augments body size (Arquier et al., 2008; Goberdhan et al., 1999; Honegger et al., 2008; Ikeya et al., 2002; Nowak et al., 2013; Okamoto et al., 2013; Oldham et al., 2002), whereas reduced IIS activity limits cell, organ, and body size (Böhni et al., 1999; Brogiolo et al., 2001; Chen et al., 1996; Colombani et al., 2003; Gao et al., 2000; Grönke et al., 2010; Leevers et al., 1996; Murillo-Maldonado et al., 2011; Rulifson et al., 2002; Weinkove et al., 1999; Zhang et al., 2009). Because increased IIS activity bypasses the reduction in cell size in low-nutrient conditions (Britton et al., 2002; Géminard et al., 2009; Nowak et al., 2013), and mutations that blunt IIS pathway activity reduce size in nutrient-rich contexts (Böhni et al., 1999; Brogiolo et al., 2001; Chen et al., 1996; Leevers et al., 1996), Drosophila studies have established IIS as one key pathway that promotes organismal growth downstream of nutrient input. While this highlights the impact of Drosophila on our knowledge of how IIS couples nutrient input with growth, it is important to note that most studies used a mixed-sex population of larvae. Given that cell and body size differ significantly between male and female flies (Alpatov, 1930; Brown and King, 1961; Okamoto et al., 2013; Partridge et al., 1994; Rideout et al., 2015; Sawala and Gould, 2017; Testa et al., 2013), more knowledge is needed of nutrient-dependent changes to body size and IIS activity in each sex.

Recent studies have begun to make progress in this area by studying IIS regulation and function in both sexes in a single dietary context (reviewed in Millington and Rideout, 2018). For example, in late third instar larvae, there are sex differences in dilp mRNA levels, IIS activity, and Drosophila insulin-like peptide 2 (Dilp2; FBgn0036046) secretion from the IPCs (Rideout et al., 2015; McDonald et al., 2020). Similarly, transcriptomic studies have detected male-female differences in mRNA levels of genes associated with IIS function (Mathews et al., 2017; Rideout et al., 2015), and revealed links between IIS and the sex determination hierarchy gene regulatory network (Castellanos et al., 2013; Chang et al., 2011; Clough et al., 2014; Fear et al., 2015; Garner et al., 2018; Goldman and Arbeitman, 2007). As increasing evidence of sex-specific IIS regulation accumulates, several reports reveal sex-limited and sex-biased phenotypic effects caused by changes to IIS function. Changes to IIS activity in larvae show sex-biased effects on growth and final body size (Grönke et al., 2010; Rideout et al., 2015; Shingleton et al., 2005; Testa et al., 2013; Millington et al., 2021), and there are widespread sex-specific and sex-biased changes to gene expression in adult flies with altered diet and IIS activity (Camus et al., 2019; Graze et al., 2018). Further, sex differences exist in how changes to diet and IIS activity affect life span (Bjedov et al., 2010; Clancy, 2001; Giannakou et al., 2004; Grönke et al., 2010; Regan et al., 2016; Tatar et al., 2001; Woodling et al., 2020; Wu et al., 2020). Together, these studies illuminate the utility of Drosophila in revealing sex-specific IIS regulation and describing the physiological impact of this regulation. Yet, more studies are needed to discover the molecular mechanisms underlying sex-specific IIS regulation, and to extend these studies beyond a single nutritional context.

Additional insights into male-female differences in the regulation of cell, tissue, and body size arise from studies on sex determination genes. In Drosophila, sex is determined by the number of X chromosomes. In XX females, a functional splicing factor called Sex-lethal (Sxl; FBgn0264270) is produced (Bell et al., 1988; Bridges, 1921; Cline, 1978; Salz and Erickson, 2010). Sxl-dependent splicing of transformer (tra; FBgn0003741) pre-mRNA allows a functional Tra protein to be produced in females (Belote et al., 1989; Boggs et al., 1987; Inoue et al., 1990; Sosnowski et al., 1989). In XY males, the lack of a functional Sxl protein causes the default splicing of tra pre-mRNA, and no functional Tra protein is produced in males (Cline and Meyer, 1996; Salz and Erickson, 2010; Belote et al., 1989; Boggs et al., 1987; Inoue et al., 1990; Sosnowski et al., 1989). The presence of functional Sxl and Tra proteins in females account for most aspects of female sexual development, behavior, and physiology (Anand et al., 2001; Billeter et al., 2006; Brown and King, 1961; Camara et al., 2008; Christiansen et al., 2002; Clough et al., 2014; Dauwalder, 2011; Demir and Dickson, 2005; Goodwin et al., 2000; Hoshijima et al., 1991; Hudry et al., 2016; Hudry et al., 2019; Ito et al., 1996; Millington and Rideout, 2018; Neville et al., 2014; Nojima et al., 2014; Pavlou et al., 2016; Pomatto et al., 2017; Regan et al., 2016; Rezával et al., 2014; Rezával et al., 2016; Rideout et al., 2010; Ryner et al., 1996; Sturtevant, 1945; von Philipsborn et al., 2014). Recently, new roles for Sxl and Tra in regulating body size were also described. While female flies are normally larger than males, females lacking neuronal Sxl were smaller than control females, and not different in size from males (Sawala and Gould, 2017). Similarly, females lacking a functional Tra protein were smaller than control females; however, these tra mutant females were still larger than males (Brown and King, 1961; Mathews et al., 2017; Rideout et al., 2015). Together, these studies indicate that Tra and Sxl are required to promote a larger body size in females; however, much remains to be discovered about the mechanisms by which Sxl and Tra impact body size. Moreover, which sex determination genes contribute to the male-female difference in diet-induced trait size plasticity remains unknown, as studies on sex determination genes used a single diet.

In the present study, we aimed to improve knowledge of the genetic and molecular mechanisms that contribute to male-female differences in nutrient-dependent phenotypic plasticity in Drosophila. Our detailed examination of body size revealed increased phenotypic plasticity in females in response to a protein-rich diet, in line with studies on plasticity in other traits (Shingleton et al., 2017). We discovered that a female-biased upregulation of IIS activity was responsible for the larger body size of females raised on a protein-rich diet. Mechanistically, we show that the nutrient-dependent upregulation of stunted (sun; FBgn0014391) mRNA levels by transcriptional coactivator Spargel (Srl; FBgn0037248) in females triggers the diet-induced increase in IIS activity, as females with reduced sun do not augment IIS activity or body size in a protein-rich diet. Importantly, we show that sex determination gene tra is required for the nutrient-dependent increase in sun mRNA, IIS activity, and phenotypic plasticity in females, and that Srl represents a key link between Tra and regulation of sun mRNA levels. In males, ectopic Tra expression confers nutrient-dependent body size plasticity via Srl-mediated regulation of sun mRNA levels and IIS activity. Together, these results provide new insight into the molecular mechanisms that govern male-female differences in body size plasticity, and identify a previously unrecognized role for sex determination gene tra in regulating nutrient-dependent phenotypic plasticity.

In many animals, body size plasticity in response to environmental factors such as nutrition differs between the sexes (Fairbairn, 1997). While past studies have identified mechanisms underlying nutrient-dependent growth in a mixed-sex population, and revealed factors that promote sex-specific growth in a single nutritional context, the mechanisms underlying the sex difference in nutrient-dependent body size plasticity remain unknown. In this study, we showed that females have higher phenotypic plasticity compared with males when reared on a protein-rich diet, and elucidated the molecular mechanisms underlying the sex difference in nutrient-dependent body size plasticity in this context. Our data suggests a model in which high levels of dietary protein augment female body size by stimulating an increase in IIS activity, where we identified a requirement for dilp2 and sun in promoting this nutrient-dependent increase in IIS activity. Importantly, we discovered tra as the factor responsible for stimulating sun mRNA levels and IIS activity in a protein-rich context, revealing a novel role for sex determination gene tra in regulating phenotypic plasticity. Mechanistically, tra enhanced sun mRNA levels and body size in protein-rich conditions via transcriptional coactivator Srl, identifying Srl as one link between tra and the nutrient-dependent regulation of gene expression. Together, these findings provide new insight into how Drosophila females achieve increased nutrient-dependent body size plasticity compared with males.

One key feature of this increased phenotypic plasticity in females was a female-biased increase in IIS activity in a protein-rich context. This reveals a previously unrecognized sex difference in the coupling between IIS activity and dietary protein. In females, there was tight coupling between increased nutrient input and enhanced IIS activity across a wide protein concentration range in all control genotypes. In males, this close coordination between dietary protein and IIS activity was weaker in a protein-rich context. Our data shows that sex-biased nutrient-dependent change to IIS activity during development is physiologically significant, as it supports an increased rate of growth and consequently larger body size in females but not in males raised on a protein-rich diet. In future studies, it will be important to determine whether the sex difference in coupling between nutrients and IIS activity exists in other contexts. For example, previous studies on the extension of life span by dietary restriction have shown that male and female flies differ in the concentration of nutrients that produces the maximum life span extension, and in the magnitude of life span extension produced by dietary restriction (Magwere et al., 2004; Regan et al., 2016). Similar sex-specific effects of dietary restriction and reduced IIS on life span have also been observed in mice (Holzenberger et al., 2003; Kane et al., 2018; reviewed in Regan and Partridge, 2013; Selman et al., 2008) and humans (Van Heemst et al., 2005). Future studies will be needed to determine whether a male-female difference in coupling between nutrients and IIS activity account for these sex-specific life span responses to dietary restriction. Indeed, given that sex differences have been reported in the risk of developing diseases associated with overnutrition and dysregulation of IIS activity such as obesity and type 2 diabetes (Kautzky-Willer et al., 2016; Mauvais-Jarvis, 2018; Tramunt et al., 2020), more detailed knowledge of the male-female difference in coupling between nutrients and IIS activity in other models may provide insights into this sex-biased risk of disease.

In addition to revealing a sex difference in the nutrient-dependent upregulation of IIS activity, our data identified a female-specific requirement for dilp2 and sun in mediating the diet-induced increase in IIS activity in a protein-rich context. While previous studies have shown that both dilp2 and sun positively regulate body size (Ikeya et al., 2002; Grönke et al., 2010; Delanoue et al., 2016), we describe new sex-specific roles for dilp2 and sun in nutrient-dependent phenotypic plasticity. Elegant studies have shown that sun is a secreted factor that stimulates Dilp2 release from the IPCs (Delanoue et al., 2016). Together with our data, this suggests a model in which females are able to achieve a larger body size in a protein-rich diet because they have the ability to upregulate sun mRNA levels, whereas males do not. Indeed, we show that higher sun mRNA levels are sufficient to augment body size. This model aligns well with findings from two previous studies on Dilp2 secretion in male and female larvae. The first study, which raised larvae on a protein-rich diet equivalent to the 2Y diet, found increased Dilp2 secretion in females compared to males (Rideout et al., 2015). The second study, which raised larvae on a diet equivalent to the 1Y diet, found no sex difference in Dilp2 secretion and no effects of dilp2 loss on body size (Sawala and Gould, 2017). Thus, while these previous studies differed in their initial findings on a sex difference in Dilp2 secretion, our data reconcile these minor differences by identifying context-dependent effects of dilp2 on body size. It is important to note that absolute confirmation of a sex difference in hemolymph Dilp2 levels will be needed in future studies because the body size plasticity defects in the dilp2-HF strain precluded its use as a tool to quantify circulating Dilp2 levels in our study. Future studies will also need to determine whether these sex-specific and context-dependent effects of dilp2 are observed in other phenotypes regulated by dilp2 and other dilp genes. For example, flies carrying mutations in dilp genes show changes to aging, metabolism, sleep, and immunity, among other phenotypes (Bai et al., 2012; Brown et al., 2020; Cong et al., 2015; Grönke et al., 2010; Liu et al., 2016; Nässel and Vanden Broeck, 2016; Okamoto et al., 2009; Okamoto and Nishimura, 2015; Post et al., 2018; Post et al., 2019; Slaidina et al., 2009; Stafford et al., 2012; Zhang et al., 2009; Brogiolo et al., 2001; Cognigni et al., 2011; Linneweber et al., 2014; Semaniuk et al., 2018; Suzawa et al., 2019; Ugrankar et al., 2018). Further, it will be interesting to determine whether the sex-specific regulation of sun is observed in any other contexts, and whether it will influence sex differences in phenotypes associated with altered IIS activity, such as life span.

While our findings on sun and dilp2 provide mechanistic insight into the molecular basis for the larger body size of females reared on a protein-rich diet, a key finding from our study was the identification of sex determination gene tra as the factor that confers plasticity to females. Normally, nutrient-dependent body size plasticity is higher in females than in males in a protein-rich context. In females lacking a functional Tra protein, however, this increased nutrient-dependent body size plasticity was abolished. In males, which normally lack a functional Tra protein, ectopic Tra expression conferred increased nutrient-dependent body size plasticity. While a previous study showed that on the 2Y diet Tra promotes Dilp2 secretion (Rideout et al., 2015), our current study extends this finding in two ways: by identifying sun as one link between Tra, Dilp2, and changes to IIS activity; and by showing that Tra regulates sun mRNA via conserved transcriptional coactivator Srl. While previous studies discovered Srl as the factor that promotes sun mRNA levels in response to dietary protein in a mixed-sex larval population (Delanoue et al., 2016), our findings reveal a previously unrecognized sex-specific role for Srl in regulating transcription. Because loss of Tra reduces Srl transcriptional activity, this new link between Tra and Srl suggests an additional way in which Tra may impact gene expression beyond its canonical downstream targets dsx and fru. While this builds on recent studies that reveal a number of additional Tra-regulated genes (Clough et al., 2014; Hudry et al., 2016; Hudry et al., 2019), it will be important to determine whether these additional Tra-regulated genes including sun represent direct targets of Tra/Srl. Future studies will also be needed to elucidate how Tra impacts Srl transcriptional activity in a context-dependent manner. However, uncovering a connection between a sex determination gene and a key regulator of genes involved in mitochondrial function suggests an additional mechanism that may contribute to sex differences in phenotypes affected by mitochondrial function (e.g. lifespan) (Tiefenböck et al., 2010; Cho et al., 2011; Tower, 2015; Tower, 2017). In addition, it will be critical to explore how the presence of Tra allows an individual to couple dietary protein with body size. Because the tra locus is regulated both by alternative splicing and transcription (Belote et al., 1989; Boggs et al., 1987; Grmai et al., 2018; Inoue et al., 1990; Sosnowski et al., 1989), and Tra protein is regulated by phosphorylation (Du et al., 1998), our study highlights the importance of additional studies on the regulation of the tra genomic locus and Tra protein throughout development to gain mechanistic insight into its effects on nutrient-dependent body size plasticity.

While the main outcome of our work was to reveal the molecular mechanisms that regulate the sex difference in nutrient-dependent body size plasticity, we also provide some insight into how genes that contribute to nutrient-dependent body size plasticity affect female fecundity and male fertility. Our findings align well with previous studies demonstrating that increased nutrient availability during development and a larger female body size confers increased ovariole number and fertility (Green and Extavour, 2014; Klepsatel et al., 2020; Mendes and Mirth, 2016; Robertson, 1957a; Robertson, 1957b), as females lacking either dilp2 or fat body-derived sun were unable to augment egg production in a protein-rich context. Given that previous studies demonstrate IIS activity influences germline stem cells in the ovary in adult flies (Hsu et al., 2008; Hsu and Drummond-Barbosa, 2009; Kao et al., 2015; LaFever and Drummond-Barbosa, 2005; Lin and Hsu, 2020; Su et al., 2018), there is a clear reproductive benefit that arises from the tight coupling between nutrient availability, IIS activity, and body size in females. In males, however, the relationship between fertility and body size remains less clear. While larger males are more reproductively successful both in the wild and in laboratory conditions (Ewing, 1961; Partridge and Farquhar, 1983), other studies revealed that medium-sized males were more fertile than both larger and smaller males (Lefranc and Bundgaard, 2000). Given that our study revealed no significant increase in the number of progeny produced by larger males, the fertility benefits that accompany a larger body size in males may be context-dependent. For example, a larger body size increases the ability of males to outcompete smaller males (Flatt, 2020; Partridge et al., 1987; Partridge and Farquhar, 1983). Thus, in crowded situations, a bigger body may provide significant fertility gains. On the other hand, in conditions where nutrients are limiting, an imbalance in the allocation of energy from food to growth rather than to reproduction may decrease fertility (Bass et al., 2007; Camus et al., 2017; Jensen et al., 2015; Wood et al., 2018). Future studies will need to resolve the relationship between body size and fertility in males, as this will suggest the ultimate reason(s) for the sex difference in nutrient-dependent body size plasticity.

All data generated in this study are provided in Supplementary file 2. All statistical tests and p-values are listed in Supplementary file 1. Exact diets used in this study are described in Supplementary file 3 for ease of replication. All genotypes used in this study are listed in Supplementary file 4. A complete list of primers used in this study is provided in Supplementary file 5.

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Author details

1. Jason W Millington

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

   Contribution

   Conceptualization, Formal analysis, Investigation, Visualization, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4330-2431

2. George P Brownrigg

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

   Contribution

   Formal analysis, Investigation

   Competing interests

   No competing interests declared

3. Charlotte Chao

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

   Contribution

   Formal analysis, Investigation

   Competing interests

   No competing interests declared

4. Ziwei Sun

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

   Contribution

   Investigation

   Competing interests

   No competing interests declared

5. Paige J Basner-Collins

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

   Contribution

   Investigation

   Competing interests

   No competing interests declared

6. Lianna W Wat

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

   Contribution

   Investigation

   Competing interests

   No competing interests declared

7. Bruno Hudry

   MRC London Institute of Medical Sciences, and Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom

   Present address

   Institut de Biologie Valrose, Centre de Biochimie, Faculte des Sciences, Universite Nice Sophia Antipolis, Nice, France

   Contribution

   Resources

   Competing interests

   No competing interests declared

8. Irene Miguel-Aliaga

   MRC London Institute of Medical Sciences, and Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom

   Contribution

   Resources

   Competing interests

   No competing interests declared

9. Elizabeth J Rideout

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

   Contribution

   Conceptualization, Supervision, Funding acquisition, Validation, Writing - original draft, Project administration, Writing - review and editing

   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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