Genetic variation of macronutrient tolerance in Drosophila melanogaster

Abstract

Carbohydrates, proteins and lipids are essential nutrients to all animals; however, closely related species, populations, and individuals can display dramatic variation in diet. Here we explore the variation in macronutrient tolerance in Drosophila melanogaster using the Drosophila genetic reference panel, a collection of ~200 strains derived from a single natural population. Our study demonstrates that D. melanogaster, often considered a “dietary generalist”, displays marked genetic variation in survival on different diets, notably on high-sugar diet. Our genetic analysis and functional validation identify several regulators of macronutrient tolerance, including CG10960/GLUT8, Pkn and Eip75B. We also demonstrate a role for the JNK pathway in sugar tolerance and de novo lipogenesis. Finally, we report a role for tailless, a conserved orphan nuclear hormone receptor, in regulating sugar metabolism via insulin-like peptide secretion and sugar-responsive CCHamide-2 expression. Our study provides support for the use of nutrigenomics in the development of personalized nutrition.

Dietary regulation in health and disease

“…It is crucial to understand how to combine diet with sleep, exercise and other therapeutic interventions to acquire cooperative effects that improve healthspan at the tissue and organismal levels. Considering that gene variants like Pkn involved in nutrition-mediated response, 364 the genetic disparity should be defined in personalized nutrition intervention. The nutritive functions in diverse genotypes also require further exploration.…”

Dietary patterns and cardiometabolic health: Clinical evidence and mechanism

“…For nearly a century, individual response differences to dietary components have been scientifically validated by numerous diet and omics studies, such as the inclusion of genetic variants such as Pkn in nutrient‐mediated responses 328 or how differences in gut microbial community characteristics affect glycemic response. 329 Therefore, providing more precise and dynamic personalized nutritional advice based on gene–diet interactions than is currently available should be a priority and an important direction for future nutritional health policy development.…”

Nutrient responding peptide hormone CCHamide-2 consolidates appetitive memory

“…CCHa is enriched in the endocrine cells in the midgut ( Roller et al, 2008 ; Li et al, 2013 ; Veenstra and Ida, 2014 ; Hung et al, 2020 ; Titos and Rogulja, 2020 ; Zhu et al, 2022 ) or periphery adipose tissue ( Sano et al, 2015 ), suggestive of its role as a part of the enteroendocrine system. The CCHa system affects various physiological functions and related behaviors, including feeding, diuresis, reproduction, and metabolism ( Ida et al, 2012 ; Li et al, 2013 ; Veenstra and Ida, 2014 ; Ren et al, 2015 ; Sano et al, 2015 ; Fujiwara et al, 2018 ; Jayakumar et al, 2018 ; Capriotti et al, 2019 ; Jin et al, 2020 ; Titos and Rogulja, 2020 ; Shahid et al, 2021 ; Havula et al, 2022 ; Zhu et al, 2022 ).…”

“…In fruit flies, Drosophila melanogaster , CCHa2 is one of the two CCHa paralogs and is crucial in regulating energy metabolism ( Ida et al, 2012 ; Li et al, 2013 ; Veenstra and Ida, 2014 ; Ren et al, 2015 ; Jayakumar et al, 2018 ; Jin et al, 2020 ; Havula et al, 2022 ). CCHa2 is preferentially expressed not only in the adipose tissue and the midgut ( Sano et al, 2015 ) but also in the brain ( Ren et al, 2015 ).…”

“…CCHa2-R, the receptor of CCHa2, is enriched in the brain. Secreted CCHa2 binds to CCHa2-R in the pars intercerebralis, promoting insulin signaling to control the growth and pupariation of the flies ultimately ( Sano et al, 2015 ; Havula et al, 2022 ). In agreement with this, the bombesin receptor subtype 3, a mammalian ortholog of the CCHa2-R, also plays a central role in energy and glucose metabolism ( Ohki-Hamazaki et al, 1997 ) via the hypothalamus ( Piñol et al, 2018 ).…”