Fluctuating nutritional stress triggers bone marrow fit-memory immune cells to constrain weight regain. Mus musculus

Weight regain after appreciable weight loss is a major challenge in the successful treatment of obesity. The immune cells adapt to fluctuating nutritional stress but their roles in regulating weight regain remain unclear. Here, we identify a stem cell-like CD7+ monocyte subpopulation that accumulates in the bone marrow of mice and humans that have experienced dieting-induced weight loss. Inducible depletion of CD7+ monocytes via dual recombinase-mediated genetic targeting accelerates weight regain. These immune cells, accumulating fit memories during fluctuating nutritional stress via epigenetic adaptions, preferentially migrate to the subcutaneous white adipose tissue to promote energy expenditure. Mechanistically, CD7+ monocytes secret fibrinogen-like protein 2, which displays increased chromatin accessibility after weight loss, to activate PKA signaling via functional receptor Transmembrane Protein 120A, thus facilitating beige fat thermogenesis. Nevertheless, the bone marrow CD7+ monocytes gradually enter a quiescent state after weight loss, accompanied by increased susceptibility to weight regain. Notably, administration of FLT3 ligand remarkably rejuvenates CD7+ monocytes, thus ameliorating rapid weight regain. Together, our findings identify a unique bone marrow-derived fit-memory immune cell population and provide a potential strategy to combat weight regain.