Immunohistochemical localization of leptin receptor in the rat brain

Shioda, Seiji; Funahashi, Hiroomi; Nakajo, Shigeo; Yada, Toshihiko; Maruta, Osamu; Nakai, Yasumitsu

doi:10.1016/s0304-3940(98)00082-2

Cited by 207 publications

(137 citation statements)

References 21 publications

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“…It has been shown that the endogenous long isoform of the leptin receptor is found predominantly within the cell bodies of rat neurons, not at the cell surface (35,36). In addition, immunohistochemical localization studies using an antibody that recognizes all leptin receptor isoforms showed intracellular immunoreactivity in brain, including intense intracellular staining of the choroid plexus epithelium, where it is thought that most of the receptor is the shortest isoform (HLR-5) (36,37). Electron microscopic examination of the distribution of the endogenous long isoform in hypothalamic neurons revealed that most of the intracellular receptors were in the Golgi (38).…”

Section: Resultsmentioning

confidence: 99%

Subcellular Localization and Internalization of the Four Human Leptin Receptor Isoforms

Barr¹,

Lane²,

Taylor³

1999

Journal of Biological Chemistry

125

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There are four known isoforms of the human leptin receptor (HLR) with different C-terminal cytoplasmic domains (designated by the number of unique C-terminal amino acids). In cells expressing HLR-5, -15, or -274, 15-25% of the leptin binding sites were located at the plasma membrane. In contrast, in cells expressing HLR-67, only 5% of the total binding sites were at the plasma membrane. Immunofluorescent microscopy showed that all four isoforms partially co-localized with calnexin and ␤-COP, markers of the endoplasmic reticulum and the Golgi, respectively. All isoforms were also detected in an unidentified punctate compartment. All isoforms were internalized via clathrin-mediated endocytosis, but at different rates. After 20 min at 37°C, 45% of a bound cohort of labeled ligand had been internalized by HLR-15, 30% by HLR-67, 25% by HLR-274, and 15% by HLR-5. Degradation of internalized leptin occurred in lysosomes. Overnight exposure to leptin down-regulated all isoforms, but to a variable extent. HLR-274 displayed the greatest down-regulation and also appeared to reach lysosomes more quickly than the other isoforms. The faster degradation of HLR-274 may help to terminate leptin signaling.Leptin is a peptide secreted primarily by adipose cells that regulates appetite, energy metabolism, and neuroendocrine function. Leptin acts both centrally, presumably in the hypothalamus, and directly on peripheral tissues (1-3). Leptin binding activates its receptor, a member of the cytokine receptor superfamily, which includes receptors for interleukins, prolactin, growth hormone, and erythropoietin (4, 5). As a result of differential mRNA splicing, there are several isoforms of the leptin receptor with different lengths and C-terminal sequences. The regions that are identical in all the receptor isoforms include the extracellular ligand binding domain, the transmembrane domain, and the first 29 amino acids in the cytoplasmic domain. (4, 6 -11).Some cytokine receptors (e.g. receptors for growth hormone, erythropoietin, and prolactin) form homodimers when activated by ligand, while others form hetero-oligomers (12)(13)(14). Recent studies have shown that leptin receptors form homodimers, both in the presence and absence of ligand (15, 16). Each leptin receptor binds one molecule of leptin, resulting in a tetrameric complex composed of two receptors and two leptin molecules. However, activation of the receptor is thought to result from a ligand induced conformational change rather than dimerization of the receptor (15, 17). All the leptin receptor isoforms contain a "box 1" Janus kinase binding site in the cytoplasmic domain. The longest form also contains a "box 2" motif and putative STAT 1 binding sites (5, 10, 11, 18) and thus only the long form is able to activate STAT proteins (18 -20).Receptor-mediated endocytosis is a well characterized mechanism for selectively transporting nutrients, hormones, and growth factors into cells. Often receptors are concentrated in clathrin-coated pits and then internalized in clathrin-coate...

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Section: Resultsmentioning

confidence: 99%

Subcellular Localization and Internalization of the Four Human Leptin Receptor Isoforms

Barr¹,

Lane²,

Taylor³

1999

Journal of Biological Chemistry

125

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“…One important question that needs to be addressed is whether leptin modulates monoamine neurotransmission. A high percentage of 5-HT neurons in the raphe nuclei and dopamine neurons in the ventral tegmental area (VTA) express the leptin receptor [33][34][35], which supports the possibility of interactions. However, evidence supporting a functional interaction between leptin and monoamines remains ambiguous.…”

Section: Interaction Of Leptin With Monoaminesmentioning

confidence: 88%

The leptin hypothesis of depression: a potential link between mood disorders and obesity?

Lü

2007

Current Opinion in Pharmacology

259

198

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SummaryThe adipose-derived hormone leptin is well known for its function in the control of energy homeostasis. Recent studies suggest a novel role for this adipokine in the regulation of mood and emotion. Low levels of leptin have been found to be associated with depressive behaviors in rodents and humans. Pharmacological studies indicate that leptin has antidepressant-like efficacy. Both leptin insufficiency and leptin resistance may contribute to alterations of affective status. Identifying the key brain regions that mediate leptin's antidepressant activity and dissecting its intracellular signal transduction pathways may provide new insights into the pathogenesis of depression and facilitate the development of novel therapeutic strategies for the treatment of this illness.

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“…Cerebrums at 0 h (sham-operated) and 4 and 8 h after MCAO were removed from decapitated animals and divided into the ipsilateral and contralateral hemispheres. The samples were then homogenized in lysis buffer as described (48) before being centrifuged at 12,000 ϫ g for 30 min at 4°C. Supernatant was collected as total cell lysate for the detection of phospho-specific antibodies.…”

Section: Methodsmentioning

confidence: 99%

Pituitary adenylate cyclase-activating polypeptide (PACAP) decreases ischemic neuronal cell death in association with IL-6

Ohtaki

Nakamachi

Dohi

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

182

192

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Pituitary adenylate cyclase-activating polypeptide (PACAP) has been reported to decrease ischemic neuronal damage and increase IL-6 secretion in rats. However, the mechanisms underlying neuroprotection are still to be fully elucidated. The present study was designed to investigate the role played by PACAP and IL-6 in mediating neuroprotection after ischemia in a null mouse. Infarct volume, neurological deficits, and cytochrome c in cytoplasm were higher in PACAP ؉/؊ and PACAP ؊/؊ mice than in PACAP ؉/؉ animals after focal ischemia, although the severity of response was ameliorated by the injection of PACAP38. A decrease in mitochondrial bcl-2 was also accentuated in PACAP ؉/؊ and PACAP ؊/؊ mice, but the decrease could be prevented by PACAP38 injection. PACAP receptor 1 (PAC1R) immunoreactivity was colocalized with IL-6 immunoreactivity in neurons, although the intensity of IL-6 immunoreactivity in PACAP ؉/؊ mice was less than that in PACAP ؉/؉ animals. IL-6 levels increased in response to PACAP38 injection, an effect that was canceled by cotreatment with the PAC1R antagonist. However, unlike in wild-type controls, PACAP38 treatment did not reduce the infarction in IL-6 null mice. To clarify the signaling pathway associated with the activity of PACAP and IL-6, phosphorylated STAT (signal transducer and activator of transcription) 3, ERK (extracellular signal-regulated kinase), and AKT levels were examined in PACAP ؉/؊ and IL-6 null mice after ischemia. Lower levels of pSTAT3 and pERK were observed in the PACAP ؉/؊ mice, whereas a reduction in pSTAT3 was recorded in the IL-6 null mice. These results suggest that PACAP prevents neuronal cell death after ischemia via a signaling mechanism involving IL-6.bcl-2 ͉ extracellular signal-regulated kinase ͉ ischemia ͉ pituitary adenylate cyclase-activating polypeptide-specific receptor ͉ signal transducer and activator of transcription 3

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Immunohistochemical localization of leptin receptor in the rat brain

Cited by 207 publications

References 21 publications

Subcellular Localization and Internalization of the Four Human Leptin Receptor Isoforms

Subcellular Localization and Internalization of the Four Human Leptin Receptor Isoforms

The leptin hypothesis of depression: a potential link between mood disorders and obesity?

Pituitary adenylate cyclase-activating polypeptide (PACAP) decreases ischemic neuronal cell death in association with IL-6

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