Hemocytes are the myeloid cells of the fly. In adult flies, 95% of hemocytes are plasmatocytes, which are similar to tissue resident macrophages in mammals. Upon infection or inflammation, hemocytes phagocytose invaders and release different cytokines. However, less is known about the physiological function of hemocytes and how they affect tissue homeostasis and metabolism. Recently, it was shown that resident tissue macrophages in the fly are major regulators of glucose metabolism and lifespan upon metabolic stress. Adult flies on a lipid-enriched diet showed enhanced storage of triglycerides, hyperglycemia, and decreased insulin sensitivity followed by a severe reduction in lifespan. In this context, hemocytes release the Jak/STAT activating cytokine unpaired-3 (upd3) and over-activate the Jak/STAT pathway in various organs including gut and muscles; this is a major driver of shortened lifespan due to high-fat diet. upd3 activation by lipid is dependent on the scavenger receptor croquemort and the Jun-kinase basket. Here, we further investigate the physiological consequences of macrophage cytokine release and dysregulation. We suggest that hemocytes might be a major nutritional sensor regulating tissue homeostasis via release of Jak/STAT-activating cytokines. We and others have observed that several tissues including adult muscle exhibit physiological Jak/STAT signaling in the absence of any overt inflammatory stimuli. As skeletal muscle is the major glucose consuming organ in most multicellular organisms, and lipid-driven upd3 causes changes in glucose homeostasis, we are now exploring the impacts of hemocyte-derived cytokine signals on muscle metabolism and systemic health. Importantly, we suggest that cytokine signaling in this system is important in the response of muscles to nutritional changes, even in the absence of overt inflammatory stimuli.