Homocysteine causes neuronal leptin resistance and endoplasmic reticulum stress

Abstract

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.

A new framework for exploratory network mediator analysis in omics data

“…Additionally, PLP acts as a vital mediator in the homocysteine degradation pathway, which involves breaking down homocysteine, an amino acid derived from methionine metabolism. It is essential for maintaining normal homocysteine levels in the body, as elevated levels have been associated with various health issues, including obesity ( Preninka et al 2022 ). Furthermore, excessive consumption of sweets, desserts, and unhealthy fats, particularly those high in refined sugars, often lacks essential nutrients like vitamins B6, thiamin, and folate.…”

Gene expression of cardiovascular risk markers in mononuclear cells of pregnant woman in relation to plasma leptin and homocysteine levels: A cross sectional study

“…9,10 Although the role of Hcy in gestational leptin resistance has not been investigated, results from in vitro models have shown that increased Hcy levels reduce the response to leptin signaling in individuals with obesity. 11 These findings suggest that Hcy could regulate leptin resistance during pregnancy. The relationship between Hcy and leptin has been widely investigated under obstetric conditions with a greater cardiovascular risk; 12 however, contributions of biochemical and hematologic factors in the early modulation of leptin and Hcy levels is not completely understood under physiologic conditions.…”

“…Epidemiological studies have indicated that changes in folic acid and methionine metabolism are closely associated with increased levels of homocysteine (Hcy), which induces a proatherogenic response and significantly increases the risk of cardiovascular diseases 9,10 . Although the role of Hcy in gestational leptin resistance has not been investigated, results from in vitro models have shown that increased Hcy levels reduce the response to leptin signaling in individuals with obesity 11 . These findings suggest that Hcy could regulate leptin resistance during pregnancy.…”