Jason Millington

All Publications

• A low sugar diet enhances Drosophila body size in males and females via sex-specific mechanisms. Development (Cambridge, England) Millington, J. W., Biswas, P., Chao, C., Xia, Y. H., Wat, L. W., Brownrigg, G. P., Sun, Z., Basner-Collins, P. J., Geltink, R. I., Rideout, E. J. 2022

  Abstract

  In Drosophila, changes to dietary protein elicit different body size responses between the sexes. Whether these differential body size effects extend to other macronutrients remains unclear. Here, we show that lowering dietary sugar (0S diet) enhanced body size in male and female larvae. Despite an equivalent phenotypic effect between the sexes, we detected sex-specific changes to signaling pathways, transcription, and whole-body glycogen and protein. In males, the low sugar diet augmented insulin/insulin-like growth factor signaling pathway (IIS) activity by increasing insulin sensitivity, where increased IIS was required for male metabolic and body size responses in 0S. In females reared on low sugar, IIS activity and insulin sensitivity were unaffected, and IIS function did not fully account for metabolic and body size responses. Instead, we identified a female-biased requirement for the target of rapamycin pathway in regulating metabolic and body size responses. Together, our data suggest the mechanisms underlying the low sugar-induced increase in body size are not fully shared between the sexes, highlighting the importance of including males and females in larval studies even when similar phenotypic outcomes are observed.

  View details for DOI 10.1242/dev.200491

  View details for PubMedID 35195254

• Sex determination gene transformer regulates the male-female difference in Drosophila fat storage via the adipokinetic hormone pathway ELIFE Wat, L. W., Chowdhury, Z. S., Millington, J. W., Biswas, P., Rideout, E. J. 2021; 10

  Abstract

  Sex differences in whole-body fat storage exist in many species. For example, Drosophila females store more fat than males. Yet, the mechanisms underlying this sex difference in fat storage remain incompletely understood. Here, we identify a key role for sex determination gene transformer (tra) in regulating the male-female difference in fat storage. Normally, a functional Tra protein is present only in females, where it promotes female sexual development. We show that loss of Tra in females reduced whole-body fat storage, whereas gain of Tra in males augmented fat storage. Tra's role in promoting fat storage was largely due to its function in neurons, specifically the Adipokinetic hormone (Akh)-producing cells (APCs). Our analysis of Akh pathway regulation revealed a male bias in APC activity and Akh pathway function, where this sex-biased regulation influenced the sex difference in fat storage by limiting triglyceride accumulation in males. Importantly, Tra loss in females increased Akh pathway activity, and genetically manipulating the Akh pathway rescued Tra-dependent effects on fat storage. This identifies sex-specific regulation of Akh as one mechanism underlying the male-female difference in whole-body triglyceride levels, and provides important insight into the conserved mechanisms underlying sexual dimorphism in whole-body fat storage.

  View details for DOI 10.7554/eLife.72350.sa2

  View details for Web of Science ID 000720132300001

  View details for PubMedID 34672260

  View details for PubMedCentralID PMC8594944

• Female-biased upregulation of insulin pathway activity mediates the sex difference in Drosophila body size plasticity ELIFE Millington, J. W., Brownrigg, G. P., Chao, C., Sun, Z., Basner-Collins, P. J., Wat, L. W., Hudry, B., Miguel-Aliaga, I., Rideout, E. J. 2021; 10

  Abstract

  Nutrient-dependent body size plasticity differs between the sexes in most species, including mammals. Previous work in Drosophila showed that body size plasticity was higher in females, yet the mechanisms underlying increased female body size plasticity remain unclear. Here, we discover that a protein-rich diet augments body size in females and not males because of a female-biased increase in activity of the conserved insulin/insulin-like growth factor signaling pathway (IIS). This sex-biased upregulation of IIS activity was triggered by a diet-induced increase in stunted mRNA in females, and required Drosophila insulin-like peptide 2, illuminating new sex-specific roles for these genes. Importantly, we show that sex determination gene transformer promotes the diet-induced increase in stunted mRNA via transcriptional coactivator Spargel to regulate the male-female difference in body size plasticity. Together, these findings provide vital insight into conserved mechanisms underlying the sex difference in nutrient-dependent body size plasticity.

  View details for DOI 10.7554/eLife.58341

  View details for Web of Science ID 000618526800001

  View details for PubMedID 33448263

  View details for PubMedCentralID PMC7864645

• Genetic manipulation of insulin/insulin-like growth factor signaling pathway activity has sex-biased effects on Drosophila body size G3-GENES GENOMES GENETICS Millington, J. W., Brownrigg, G. P., Basner-Collins, P. J., Sun, Z., Rideout, E. J. 2021; 11 (3)

  Abstract

  In Drosophila raised in nutrient-rich conditions, female body size is approximately 30% larger than male body size due to an increased rate of growth and differential weight loss during the larval period. While the mechanisms that control this sex difference in body size remain incompletely understood, recent studies suggest that the insulin/insulin-like growth factor signaling pathway (IIS) plays a role in the sex-specific regulation of processes that influence body size during development. In larvae, IIS activity differs between the sexes, and there is evidence of sex-specific regulation of IIS ligands. Yet, we lack knowledge of how changes to IIS activity impact body size in each sex, as the majority of studies on IIS and body size use single- or mixed-sex groups of larvae and/or adult flies. The goal of our current study was to clarify the body size requirement for IIS activity in each sex. To achieve this goal, we used established genetic approaches to enhance, or inhibit, IIS activity, and quantified pupal size in males and females. Overall, genotypes that inhibited IIS activity caused a female-biased decrease in body size, whereas genotypes that augmented IIS activity caused a male-specific increase in body size. These data extend our current understanding of body size regulation by showing that most changes to IIS pathway activity have sex-biased effects, and highlights the importance of analyzing body size data according to sex.

  View details for DOI 10.1093/g3journal/jkaa067

  View details for Web of Science ID 000697752600005

  View details for PubMedID 33793746

  View details for PubMedCentralID PMC8063079

• Sexual Dimorphism: Ecdysone Modulates Sex Differences in the Gut CURRENT BIOLOGY Millington, J. W., Rideout, E. J. 2020; 30 (21): R1327-R1330

  Abstract

  Sex differences in the Drosophila gut were discovered only recently. Recent work significantly extends our understanding of how steroid hormones specify these male-female differences by revealing a key role for ecdysone in regulating intestinal stem cell proliferation.

  View details for DOI 10.1016/j.cub.2020.08.088

  View details for Web of Science ID 000585930500018

  View details for PubMedID 33142105

• A role for triglyceride lipase brummer in the regulation of sex differences in Drosophila fat storage and breakdown PLOS BIOLOGY Wat, L. W., Chao, C., Bartlett, R., Buchanan, J. L., Millington, J. W., Chih, H., Chowdhury, Z. S., Biswas, P., Huang, V., Shin, L. J., Wang, L., Gauthier, M. L., Barone, M. C., Montooth, K. L., Welte, M. A., Rideout, E. J. 2020; 18 (1): e3000595

  Abstract

  Triglycerides are the major form of stored fat in all animals. One important determinant of whole-body fat storage is whether an animal is male or female. Here, we use Drosophila, an established model for studies on triglyceride metabolism, to gain insight into the genes and physiological mechanisms that contribute to sex differences in fat storage. Our analysis of triglyceride storage and breakdown in both sexes identified a role for triglyceride lipase brummer (bmm) in the regulation of sex differences in triglyceride homeostasis. Normally, male flies have higher levels of bmm mRNA both under normal culture conditions and in response to starvation, a lipolytic stimulus. We find that loss of bmm largely eliminates the sex difference in triglyceride storage and abolishes the sex difference in triglyceride breakdown via strongly male-biased effects. Although we show that bmm function in the fat body affects whole-body triglyceride levels in both sexes, in males, we identify an additional role for bmm function in the somatic cells of the gonad and in neurons in the regulation of whole-body triglyceride homeostasis. Furthermore, we demonstrate that lipid droplets are normally present in both the somatic cells of the male gonad and in neurons, revealing a previously unrecognized role for bmm function, and possibly lipid droplets, in these cell types in the regulation of whole-body triglyceride homeostasis. Taken together, our data reveal a role for bmm function in the somatic cells of the gonad and in neurons in the regulation of male-female differences in fat storage and breakdown and identify bmm as a link between the regulation of triglyceride homeostasis and biological sex.

  View details for DOI 10.1371/journal.pbio.3000595

  View details for Web of Science ID 000510743800011

  View details for PubMedID 31961851

  View details for PubMedCentralID PMC6994176

• Sex differences in Drosophila development and physiology CURRENT OPINION IN PHYSIOLOGY Millington, J. W., Rideout, E. J. 2018; 6: 46-56

  View details for DOI 10.1016/j.cophys.2018.04.002

  View details for Web of Science ID 000471292800008