Endospanin 1 Determines the Balance of Leptin-Regulated Hypothalamic Functions

Roujeau, Clara; Jockers, Ralf; Dam, Julie

doi:10.1159/000494557

Cited by 10 publications

(6 citation statements)

References 91 publications

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“…Fig. 1d), known to impact the amplitude of LepR signaling [46]. oAβ preincubation had no effect on Il-6-induced STAT-3 phosphorylation (Fig.…”

Section: Resultsmentioning

confidence: 99%

Amyloid Beta Peptide Is an Endogenous Negative Allosteric Modulator of Leptin Receptor

Cecon¹,

Lhomme²,

Maurice³

et al. 2020

Neuroendocrinology

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Introduction: Metabolic dysfunction is now recognized as a pivotal component of Alzheimer’s disease (AD), the most common dementia worldwide. However, the precise molecular mechanisms linking metabolic dysfunction to AD remain elusive. Objective: Here, we investigated the direct impact of soluble oligomeric amyloid beta (Aβ) peptides, the main molecular hallmark of AD, on the leptin system, a major component of central energy metabolism regulation. Methods: We developed a new time-resolved fluorescence resonance energy transfer-based Aβ binding assay for the leptin receptor (LepR) and studied the effect of Aβ on LepR function in several in vitro assays. The in vivo effect of Aβ on LepR function was studied in an Aβ-specific AD mouse model and in pro-opiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus. Results: We revealed specific and high-affinity (K_i = 0.1 nM) binding of Aβ to LepR. Pharmacological characterization of this interaction showed that Aβ binds allosterically to the extracellular domain of LepR and negatively affects receptor function. Negative allosteric modulation of LepR by Aβ was detected at the level of signaling pathways (STAT-3, AKT, and ERK) in vitroand in vivo. Importantly, the leptin-induced response of POMC neurons, key players in the regulation of metabolic function, was completely abolished in the presence of Aβ. Conclusion: Our data indicate that Aβ is a negative allosteric modulator of LepR, resulting in impaired leptin action, and qualify LepR as a new and direct target of Aβ oligomers. Preventing the interaction of Aβ with LepR might improve both the metabolic and cognitive dysfunctions in AD condition.

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“…Fig. 1d), known to impact the amplitude of LepR signaling [46]. oAβ preincubation had no effect on Il-6-induced STAT-3 phosphorylation (Fig.…”

Section: Resultsmentioning

confidence: 99%

Amyloid Beta Peptide Is an Endogenous Negative Allosteric Modulator of Leptin Receptor

Cecon¹,

Lhomme²,

Maurice³

et al. 2020

Neuroendocrinology

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“…Leptin resistance, in which the activation of its receptors at the central level no longer occurs correctly, is observed in obesity. Several possible mechanisms have been proposed to contribute to leptin resistance, including impaired leptin transport into the brain [35][36][37][38], a decreased availability of the Ob-R receptor on the cell surface [39][40][41][42][43][44][45][46], or induction of ER stress [3,11].…”

Section: Discussionmentioning

confidence: 99%

Homocysteine causes neuronal leptin resistance and endoplasmic reticulum stress

et al. 2022

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Abnormally high serum homocysteine levels have been associated with several disorders, including obesity, cardiovascular diseases or neurological diseases. Leptin is an anti-obesity protein and its action is mainly mediated by the activation of its Ob-R receptor in neuronal cells. The inability of leptin to induce activation of its specific signaling pathways, especially under endoplasmic reticulum stress, leads to the leptin resistance observed in obesity. The present study examined the effect of homocysteine on leptin signaling in SH-SY5Y neuroblastoma cells expressing the leptin receptor Ob-Rb. Phosphorylation of the signal transducer and activator of transcription (STAT3) and leptin-induced STAT3 transcriptional activity were significantly inhibited by homocysteine treatment. These effects may be specific to homocysteine and to the leptin pathway, as other homocysteine-related compounds, namely methionine and cysteine, have weak effect on leptin-induced inhibition of STAT3 phosphorylation, and homocysteine has no impact on IL-6-induced activation of STAT3. The direct effect of homocysteine on leptin-induced Ob-R activation, analyzed by Ob-R BRET biosensor to monitor Ob-R oligomerization and conformational change, suggested that homocysteine treatment does not affect early events of leptin-induced Ob-R activation. Instead, we found that, unlike methionine or cysteine, homocysteine increases the expression of the endoplasmic reticulum (ER) stress response gene, a homocysteine-sensitive ER resident protein. These results suggest that homocysteine may induce neuronal resistance to leptin by suppressing STAT3 phosphorylation downstream of the leptin receptor via ER stress.

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“…LEPROT, also named Endospanin, is a candidate for regulating LEPTIN sensitivity [ 10 ]. The expression of LEPROT was negatively correlated with LEPTIN receptors and LEPTIN sensitivity [ 46 ]. Schwartz et al (1996) indicated that higher serum and plasma LEPTIN levels contributed to a higher total body fat percentage.…”

Section: Discussionmentioning

confidence: 99%

SINE Insertion May Act as a Repressor to Affect the Expression of Pig LEPROT and Growth Traits

Wang

Chi

et al. 2022

Genes

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Retrotransposon is an important component of the mammalian genome. Previous studies have shown that the expression of protein-coding genes was affected by the insertion of retrotransposon into the proximal genes, and the phenotype variations would be related to the retrotransposon insertion polymorphisms (RIPs). In this study, leptin (LEP), leptin receptor (LEPR), and leptin receptor overlapping transcript (LEPROT), which play important roles in the regulation of fat synthesis and body weight, were screened to search for the RIPs and their effect on phenotype and gene expression, as well as to further study the function of the insertion. The results showed that three RIPs located in intron 1 of LEPROT and intron 2 and 21 of LEPR were identified, and they were all SINEA1, which was one type of retrotransposon. The SINE insertion at the LEPROT was the dominant allele in native pig breeds. The age of 100 kg body weight of SINE+/+ Large White individuals was significantly higher than those of SINE+/− and SINE−/− individuals (p < 0.05). The LEPROT gene expression in the liver and suet of 30-day-old SINE−/− Sujiang piglets were significantly higher than those of SINE+/+ and SINE+/− piglets (p < 0.01). The dual-luciferase reporter gene assay showed that SINE insertion in PK15 and 3T3-L1 cells significantly reduced the promoter activity of the LEPROT gene (p < 0.01). Therefore, SINE insertion can be a repressor to reduce the expression of LEPROT and could be a useful molecular marker for assisted selection of growth traits in pig breeding.

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Endospanin 1 Determines the Balance of Leptin-Regulated Hypothalamic Functions

Cited by 10 publications

References 91 publications

Amyloid Beta Peptide Is an Endogenous Negative Allosteric Modulator of Leptin Receptor

Amyloid Beta Peptide Is an Endogenous Negative Allosteric Modulator of Leptin Receptor

Homocysteine causes neuronal leptin resistance and endoplasmic reticulum stress

SINE Insertion May Act as a Repressor to Affect the Expression of Pig LEPROT and Growth Traits

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