Leptin induced GRP78 expression through the PI3K-mTOR pathway in neuronal cells

Area of Science:

• Endocrinology
• Molecular Biology
• Cellular Stress Response

Background:

• Obesity is linked to endoplasmic reticulum (ER) stress, a condition cells manage via the unfolded protein response (UPR).
• The ER chaperone GRP78 (78 kDa glucose-regulated protein) plays a key role in mitigating ER stress by promoting protein folding.

Purpose of the Study:

• To investigate whether leptin, a key regulator of energy balance, can activate the UPR and confer protection against ER stress in obesity.
• To elucidate the molecular pathways mediating leptin's effect on ER stress response.

Main Methods:

• Utilized SH-SY5Y neuroblastoma cells expressing the leptin receptor (SH-SY5Y-ObRb).
• Treated cells with leptin and assessed GRP78 and CHOP (an ER-apoptotic marker) expression.
• Investigated the involvement of the IRE1-XBP1 pathway and the PI3K-mTOR pathway using specific inhibitors (LY294002, rapamycin).

Main Results:

• Leptin treatment significantly induced GRP78 expression in SH-SY5Y-ObRb cells.
• Leptin-induced GRP78 expression was independent of the IRE1-XBP1 pathway.
• Inhibition of PI3K (with LY294002) and mTOR (with rapamycin) blocked leptin-induced GRP78 expression, indicating PI3K-mTOR pathway involvement.
• Leptin did not induce CHOP, suggesting a protective rather than apoptotic effect.

Conclusions:

• Leptin upregulates GRP78 expression through the PI3K-mTOR signaling pathway.
• This leptin-induced GRP78 upregulation may serve as a protective mechanism against ER stress implicated in obesity.
• Leptin's action appears to enhance cellular defense against ER stress without triggering apoptosis.