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

Abstract

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-/ob-and db-/db-mice, 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.Key words: apolipoprotein D • leptin • leptin receptor • obesity • diabetes • signal transduction. polipoprotein D (Apo D) was originally purified from blood as a minor apoprotein component of the high-density lipoprotein particles and was thus designated as apolipoprotein (1). However, Apo D does not show sequence similarity to other apolipoproteins (2). Instead, it is a member of the lipocalin family of proteins that are characterized by a conserved eight-stranded, beta-barrel tertiary structure and function in the binding and transporting of small hydrophobic ligands (3). The physiological function of Apo D, as well as the identity of its putative ligand, remains to be characterized. It has been proposed that Apo D is a transporter for an unknown ligand that is structurally similar to heme-related molecules, such as biliverdin and porphyrins (4). In addition, Apo D might bind and transport other ligands, including arachidonic acid, cholesterol, and steroid hormones such as progesterone and pregnenolone (2,5). This ability of Apo D to associate with a variety of ligands suggests that it might have multiple, tissue-specific functions. For example, Apo D binds progesterone in breast A cyst fluid (6), and it also binds and transports an axilliary odorant when it is secreted from apocrine glands (7).Although it is present in a wide range of peripheral tissues in primates and rabbits (8), Apo D is highly concentrated in brain and is almost undetectable in most peripheral tissues in rodents (9). It is reported that, in brain, Apo D is expressed in the parenchyma, as well as in the subarachnoid space and pia matter, and it is synthesized in a number of cell types, including neurons, neuroglial cells, astrocytes, fibroblasts, and perivascular cells (10, 11). There is evidence...

Clusterin and LRP2 are critical components of the hypothalamic feeding regulatory pathway

“…Expression of Apo-AIV, known as a gastrointestinal satiety protein, is also found in hypothalamic neurons 7,8 . Apolipoprotein D, a lipocalin highly expressed in the brain, is coexpressed with LepRb in hypothalamic neurons 9 . Hypothalamic expression levels of these apolipoproteins are increased by leptin administration and reduced in several mice models of obesity 7,9,10 .…”

“…Apolipoprotein D, a lipocalin highly expressed in the brain, is coexpressed with LepRb in hypothalamic neurons 9 . Hypothalamic expression levels of these apolipoproteins are increased by leptin administration and reduced in several mice models of obesity 7,9,10 . Furthermore, ICV administration of those apolipoproteins induces a significant anorexia 7,9,10 .…”

“…Hypothalamic expression levels of these apolipoproteins are increased by leptin administration and reduced in several mice models of obesity 7,9,10 . Furthermore, ICV administration of those apolipoproteins induces a significant anorexia 7,9,10 . Despite apparent appetite-regulating effects of these apolipoproteins, their receptors and signalling pathways in the hypothalamus remain elusive.…”

“…Previous studies have demonstrated an involvement of apolipoproteins in hypothalamic appetite-regulatory pathways. Apolipoprotein AIV, D and E are produced in the hypothalamus and their expression levels are controlled by leptin [7][8][9][10] . Moreover, central administration of these apolipoproteins causes anorexia and weight loss in rodents 7,9,10 , indicating that hypothalamic apolipoproteins function as an intrinsic anorexigenic factor.…”

Apolipoprotein D mediates autocrine protection of astrocytes and controls their reactivity level, contributing to the functional maintenance of paraquat-challenged dopaminergic systems

“…Exogenously administered ApoD has been described to be internalized by various cell lines and located in different subcellular compartments, including the nucleus and the cytoplasm (Do Carmo et al, 2007;Liu et al, 2001;Sarjeant et al, 2003;Thomas et al, 2003). The protective effect of hApoD reported in PQ-challenged astrocytes led us to test the internalization of hApoD by primary murine astrocytes, and whether there are differences between ApoD-KO and WT astrocytes.…”