Ling Qi, PhD
Researchers from the Ling Qi Laboratory in the UVA Department of Molecular Physiology and Biological Physics have identified the SEL1L-HRD1 protein complex as a key player in regulating leptin receptor turnover, providing a deeper understanding of the molecular mechanisms that contribute to metabolic disorders. They published a study in Nature Communications that revealed significant insights into the role of endoplasmic reticulum (ER)-associated protein degradation (ERAD) in the hypothalamus and its critical implications for diet-induced obesity (DIO) and type 2 diabetes.
Obesity and type 2 diabetes have become major global health challenges, often linked to dysregulated leptin signaling in the brain. The research team discovered that SEL1L, a component of the highly conserved ER-associated protein degradation (ERAD) machinery, plays a vital role in POMC-expressing neurons, which are crucial for energy balance and appetite regulation.
The study demonstrates that the absence of SEL1L in these neurons leads to impaired leptin signaling, resulting in increased susceptibility to high-fat diet-induced complications, including fatty liver disease, glucose intolerance, and insulin and leptin resistance.
“Our findings highlight the essential function of the SEL1L-HRD1 complex in maintaining leptin receptor integrity,” said Ling Qi, PhD, the Andrew P. Somlyo Distinguished Professor in Physiology and chair of the Department ofof Molecular Physiology and Biological Physics.
“When SEL1L is lost, misfolded leptin receptors accumulate in the ER, disrupting critical signaling pathways necessary for maintaining energy homeostasis.”
The researchers further elucidated that both the wild-type and the disease-associated Cys604Ser variant of the leptin receptor are prone to misfolding and are direct substrates of the SEL1L-HRD1 ERAD system. This misfolding results in a significant retention of the receptors in the ER, independent of ER stress, which exacerbates the impairment of leptin signaling and contributes to central leptin resistance.
This study not only uncovers a pivotal mechanism underlying the pathogenesis of central leptin resistance but also suggests potential therapeutic targets for the prevention and treatment of obesity and type 2 diabetes. By targeting the SEL1L-HRD1 ERAD pathway, new strategies could be developed to restore leptin signaling and improve metabolic health.
Filed Under: Research