A systemic role of macrophage-derived BMP2/4 homolog Dpp in inhibiting sterol hormone synthesis under dietary stress.

Western dietary patterns are commonly characterized by high intakes of refined sugars, processed foods, and saturated fats.1 This dietary paradigm is correlated with an increased susceptibility to numerous chronic diseases, including type 2 diabetes mellitus, obesity, cardiovascular pathologies, chronic systemic inflammation, and adverse developmental outcomes.2,3 Of particular concern is the observed phenomenon of delayed pubertal onset (developmental timing) in obese children,4,5 potentially attributable to impaired synthesis of puberty-driving steroid hormones.6 Animal models exhibit human-like pubertal delay, inflammation, and insulin resistance when fed high-calorie diets.7,8,9 Systemic physiology is modulated by signaling from sensing organs such as adipose tissue,10,11 the gut,12 and macrophages.13 This inter-organ communication maintains homeostasis under metabolic stress. Specifically, macrophages sense dietary changes to tune tissue states.13,14,15 In Drosophila, high-sugar diets (HSDs) trigger inflammation and delay the larval-to-pupal transition16-a puberty analog. Moreover, macrophages sense nutritional status to regulate ecdysone synthesis and developmental timing.17 In this study, we show that macrophages respond to an HSD by increasing the production of Decapentaplegic (Dpp), a homolog of human bone morphogenetic protein (BMP)2/4. Dpp then signals to the endocrine system to inhibit the synthesis of ecdysone, a steroid hormone that triggers the larval-to-pupal transition. By reducing ecdysone synthesis, the larval stage is prolonged. This extended developmental period provides larvae exposed to an HSD with more time to reach an optimal size. These results underscore a pivotal role of macrophages in the regulation of steroid hormone synthesis under high-calorie dietary regimens, thus positioning these cells as potential therapeutic targets for the management of metabolic disorders that impact development.