Steroid Signaling Establishes a Female Metabolic State and Regulates SREBP to Control Oocyte Lipid Accumulation

Abstract

Disruptions in energy homeostasis severely affect reproduction in many organisms and are linked to several reproductive disorders in humans. As a result, understanding the mechanisms that control nutrient accumulation in the oocyte will provide valuable insights into the links between metabolic disease and reproductive dysfunction. We show that the steroid hormone ecdysone functions in Drosophila to control lipid metabolism and support oocyte production. First, local EcR-mediated signaling induces a stage-specific accumulation of lipids in stage-10 oocytes. EcR induces lipid accumulation by promoting the activation of the lipogenic transcription factor SREBP and by controlling the expression of the low-density lipoprotein (LDL) receptor homolog, LpR2. Second, global signaling via the ecdysone receptor, EcR, establishes a female metabolic state and promotes whole-body triglyceride and glycogen storage at high levels. EcR acts in the CNS to mediate these effects, in part by promoting higher levels of feeding in females. Thus, ecdysone functions at two levels to support reproduction: first by inducing lipid accumulation in the late stages of oocyte development and second by providing a signal that coordinates lipid metabolism in the germline with whole-animal lipid homeostasis. Ecdysone regulation allows females to assess the demands of oogenesis and alter their behavior and metabolic state to support the biosynthetic requirements of oocyte production.

Incompatibility between mitochondrial and nuclear genomes during oogenesis results in ovarian failure and embryonic lethality

“…It is likely, therefore, that this mito-nuclear incompatibility impairs mitochondrial quality, consistent with previous evidence that (simw 501 ); OreR mitochondria have reduced oxidative phosphorylation complex activity and an aberrant morphology in muscle (Holmbeck et al, 2015;Meiklejohn et al, 2013). Thus, temperature-sensitive events during early oogenesis in (simw 501 ); OreR mothers may result in persistent sub-functional mitochondria that cannot support energy-demanding processes during later oogenesis and early embryogenesis (Sieber and Spradling, 2015;Sieber et al, 2016).…”

Drosophilaas a model to study obesity and metabolic disease

“…Reproduction also requires tight control of lipid homeostasis. Although females must increase oocyte and whole-animal lipogenesis to support the production of offspring (Sieber and Spradling, 2015), morbid maternal obesity adversely affects egg size, glycogen and TAG content, adult mass and gene expression in offspring and even in the F2 generation (Buescher et al, 2013;Dew-Budd et al, 2016;Matzkin et al, 2013). Highly obesogenic diets reduce fecundity (Brookheart et al, 2017;Matzkin et al, 2013Matzkin et al, , 2011 as does genetically induced obesity (Palu et al, 2017).…”

As the fat flies: The dynamic lipid droplets of Drosophila embryos

“…During mid-oogenesis (starting with stage 9), the nurse cells also generate massive amounts of lipid droplets [43]. Lipid accumulation is under hormonal control: the steroid hormone ecdysone activates, via the SREBP transcription factor, genes involved in lipid metabolism [44]. Like in other insects, the lipids needed for this massive droplet assembly are ultimately derived from lipoproteins (here called lipophorins) circulating in the hemolymph, the insect blood [45, 46]; lipophorins shuttle lipids between the gut, the fat body (the fly adipose tissue), and peripheral tissues, including the ovary [47].…”