Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob/ob mice

Thymic atrophy is a prominent feature of malnutrition. Forty-eight hours' s tarvation of normal mice reduced the total thymocyte count to 13% of that o bserved in freely fed controls, predominantly because of a diminution in th e cortical CD4(+)CD8(+) thymocyte subpopulation. Prevention of the fasting- induced fall in the level of the adipocyte-derived hormone leptin by admini stering exogenous recombinant leptin protected mice from these starvation-i nduced thymic changes. The ob/ob mouse, which is unable to produce function al leptin because of a mutation in the obese gene, has impaired cellular im munity together with a marked reduction in the size and cellularity of the thymus. We found that ob/ob mice had a high level of thymocyte apoptosis re sulting in a ratio of CD4(+)CD8(+) (cortical) to CD4(-)CD8(-) (precursor) t hymocytes that was 4-fold lower than that observed in wild-type mice. Perip heral administration of recombinant leptin to ob/ob mice reduced thymocyte apoptosis and substantially increased both thymic cellularity and the CD4()CD8(+)/CD4(-)CD8(-) ratio. In contrast, a comparable weight loss in pair-f ed PBS-treated ob/ob mice had no impact on thymocyte number. In vitro, lept in protected thymocytes from dexamethasone-induced apoptosis. These data in dicate that reduced circulating leptin concentrations are pivotal in the pa thogenesis of starvation-induced lymphoid atrophy.