Leptin Receptor Immunoreactivity Is Present in Ascending Serotonergic and Catecholaminergic Neurons of the Rat

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Abstract

Using double-labelling immunohistochemistry we have studied the localisation of leptin receptor proteins including both long and short forms and their possible presence in serotonergic (5-HT) and catecholaminergic neurons in the rat brain. Leptin receptor immunoreactivity was found to be widely distributed in the central nervous system including cortical areas, amygdala, several hypothalamic and thalamic nuclei, the raphe system, pontine nuclei, locus coeruleus, parabrachial nucleus, tractus solitarus and the medullary reticular formation. Serotonergic cell groups were identified by 5-HT immunocytochemistry and classified according to standard nomenclature. High degrees of co-existence of leptin receptor immunoreactivity with serotonin in the raphe system were observed in B1, B5, B6, B7, B8 and B9. In B3 and B2 less than 50% of the 5-HT cells colocalised leptin receptor immunoreactivity. Brainstem and diencephalic (catecholaminergic) neurons were identified by tyrosine hydroxylase immunocytochemistry and classified according to standard nomenclature. Within the periventricular hypothalamic dopaminergic nuclei A14 and A12, the metencephalic noradrenergic A6, A7, A2, A1, and the adrenergic C3, C2 and C1 cell groups, nearly all tyrosine hydroxylase-positive cells colocalised with leptin receptor immunoreactivity. In contrast, co-existence of tyrosine hydroxylase and leptin receptor immunoreactivities in the dopaminergic A13, A11, A10, A9 and A8 cell was practically non-existent. Thus leptin, the adipose tissue-derived ligand of the leptin receptor, may in some brain areas directly influence serotonergic, dopaminergic, adrenergic and noradrenergic inputs to the periventricular and medial hypothalamic nuclei.

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The ob gene product, leptin, is an important circulating signal for the regulation of body weight. To identify high affinity leptin-binding sites, we generated a series of leptin-alkaline phosphatase (AP) fusion proteins as well as [125I]leptin. After a binding survey of cell lines and tissues, we identified leptin-binding sites in the mouse choroid plexus. A cDNA expression library was prepared from mouse choroid plexus and screened with a leptin-AP fusion protein to identify a leptin receptor (OB-R). OB-R is a single membrane-spanning receptor most related to the gp130 signal-transducing component of the IL-6 receptor, the G-CSF receptor, and the LIF receptor. OB-R mRNA is expressed not only in choroid plexus, but also in several other tissues, including hypothalamus. Genetic mapping of the gene encoding OB-R shows that it is within the 5.1 cM interval of mouse chromosome 4 that contains the db locus.

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Serotonin (5-hydroxytryptamine, 5-HT) is a monoaminergic neurotransmitter that is believed to modulate numerous sensory, motor and behavioural processes in the mammalian nervous system. These diverse responses are elicited through the activation of a large family of receptor subtypes. The complexity of this signalling system and the paucity of selective drugs have made it difficult to define specific roles for 5-HT receptor subtypes, or to determine how serotonergic drugs modulate mood and behaviour. To address these issues, we have generated mutant mice lacking functional 5-HT2C receptors (previously termed 5-HT1C), prominent G-protein-coupled receptors that are widely expressed throughout the brain and spinal cord and which have been proposed to mediate numerous central nervous system (CNS) actions of serotonin. Here we show that 5-HT2C receptor-deficient mice are overweight as a result of abnormal control of feeding behaviour, establishing a role for this receptor in the serotonergic control of appetite. Mutant animals are also prone to spontaneous death from seizures, suggesting that 5-HT2C receptors mediate tonic inhibition of neuronal network excitability.

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Charles A S Banks, Logan Myers, S. Davis … (2000)

The adipocyte-derived hormone leptin signals the status of body energy stores by activating the long form of the leptin receptor (LRb). Activation of LRb results in the activation of the associated Jak2 tyrosine kinase and the transmission of downstream phosphotyrosine-dependent signals. We have investigated the signaling function of mutant LRb intracellular domains under the control of the extracellular erythropoietin (Epo) receptor. By using this system, we confirm that two tyrosine residues in the intracellular domain of murine LRb become phosphorylated to mediate LRb signaling; Tyr(985) controls the tyrosine phosphorylation of SHP-2, and Tyr(1138) controls STAT3 activation. We furthermore investigated the mechanisms by which LRb controls downstream ERK activation and c-fos and SOCS3 message accumulation. Tyr(985)-mediated recruitment of SHP-2 does not alter tyrosine phosphorylation of Jak2 or STAT3 but results in GRB-2 binding to tyrosine-phosphorylated SHP-2 and is required for the majority of ERK activation during LRb signaling. Tyr(985) and ERK activation similarly mediate c-fos mRNA accumulation. In contrast, SOCS3 mRNA accumulation requires Tyr(1138)-mediated STAT3 activation. Thus, the two LRb tyrosine residues that are phosphorylated during receptor activation mediate distinct signaling pathways as follows: SHP-2 binding to Tyr(985) positively regulates the ERK --> c-fos pathway, and STAT3 binding to Tyr(1138) mediates the inhibitory SOCS3 pathway.