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' starvation of normal mice reduced the total thymocyte count to 13% of that observed in freely fed controls, predominantly because of a diminution in the cortical CD4(+)CD8(+) thymocyte subpopulation. Prevention of the fasting-induced fall in the level of the adipocyte-derived hormone leptin by administering exogenous recombinant leptin protected mice from these starvation-induced thymic changes. The ob/ob mouse, which is unable to produce functional leptin because of a mutation in the obese gene, has impaired cellular immunity 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 resulting in a ratio of CD4(+)CD8(+) (cortical) to CD4(-)CD8(-) (precursor) thymocytes that was 4-fold lower than that observed in wild-type mice. Peripheral 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-fed PBS-treated ob/ob mice had no impact on thymocyte number. In vitro, leptin protected thymocytes from dexamethasone-induced apoptosis. These data indicate that reduced circulating leptin concentrations are pivotal in the pathogenesis of starvation-induced lymphoid atrophy.
Howard
J K
JK
Endocrine Unit and Department of Immunology, Imperial College School of Medicine, Hammersmith Hospital, London W12 ONN, United Kingdom.
Lord
G M
GM
Matarese
G
G
Vendetti
S
S
Ghatei
M A
MA
Ritter
M A
MA
Lechler
R I
RI
Bloom
S R
SR
D000818:Animals; D017304:Annexin A5 / Q000032:analysis; D017209:Apoptosis / Q000187:drug effects; D001284:Atrophy; D003907:Dexamethasone / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000494:pharmacology*; D008221:Lymphoid Tissue / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D013217:Starvation / Q000473:pathology*; D013950:Thymus Gland / Q000473:pathology*
D017304:Annexin A5; D007328:Insulin; D020738:Leptin; D003907:Dexamethasone