Apolipoprotein D interacts with the long-form leptin receptor: a hypothalamic function in the control of energy homeostasis.

Leptin and its long form receptor, Ob-Rb, in the hypothalamus play a key function in regulating food intake and body weight. We demonstrate here that apolipoprotein D (Apo D), a lipocalin that is heavily expressed in brain, interacts specifically with the cytoplasmic portion of Ob-Rb but not the short form receptor, Ob-Ra. This finding is detected in yeast two-hybrid systems as well as in protein precipitation experiments in vitro and in vivo. Apo D and Ob-Rb are coexpressed in neurons of the hypothalamic arcuate and paraventricular nuclei that are known to be involved in eating and body weight regulation. Moreover, hypothalamic level of Apo D mRNA is stimulated by dietary fat. It is also significantly elevated in rats and inbred mice that become obese on a highfat diet, compared with their lean controls, and is strongly, positively correlated with body fat mass and circulating leptin levels. This positive association with body fat, however, is lost in obese ob/oband db-/dbmice, which exhibit markedly reduced levels of hypothalamic Apo D mRNA compared with that of wild-type mice. These results suggest that Apo D in the hypothalamus is involved in the leptin/Ob-Rb signal transduction pathway that controls body fat accumulation on a high-fat diet.