Delta-Like 1 Homologue (DLK1) Protein in Neurons of the Arcuate Nucleus That Control Weight Homeostasis and Effect of Fasting on Hypothalamic DLK1 mRNA

Delta-like 1 homologue (DLK1; also called preadipocyte factor 1) is an epidermal growth factor repeat-containing transmembrane protein that is cleaved by tumor necrosis factor-α-converting enzyme to generate a biologically active soluble form. DLK1 is involved in the differentiation of several cell types, including adipocytes. Lack of the dlk1 gene results in adiposity, and polymorphism within the gene encoding DLK1 is associated with human obesity. The dlk1 gene is expressed in restricted areas of the adult brain, with an enrichment of cell bodies expressing DLK1 mRNA in the hypothalamus. Antibodies to DLK1 were used to study the cellular localization and chemical identity of DLK1-immunoreactive neuronal cell bodies in rat hypothalamus. DLK1 immunoreactivity was demonstrated in the cell soma and dendrites of cell bodies in the suprachiasmatic, supraoptic, paraventricular, dorsomedial, arcuate nuclei and in the perifornical/lateral hypothalamic area. In the arcuate nucleus (Arc), DLK1 immunoreactivity was mainly seen in many neurons of the ventromedial and to a lesser extent in its ventrolateral division. Double labeling showed that 93.7% of orexigenic agouti-related peptide (AgRP) and 94.1% of neuropeptide Y (NPY) neurons located in the ventromedial part of the Arc were DLK1 positive, whereas 36.1% of anorexigenic pro-opiomelanocortin and 34.6% of cocaine- and amphetamine-regulated transcript neurons of the Arc contained DLK1 immunoreactivity. DLK1 mRNA was downregulated in the hypothalamus of fasted animals. Presence of DLK1 in the majority of orexigenic Arc NPY/AgRP neurons and regulation of DLK1 mRNA by nutritional challenge suggest that DLK1 has a role in hypothalamic regulation of body weight control.