New mechanism of fat breakdown discovered by NCNP — Obesity and diabetes improvement confirmed in mice

A research group led by Section Chief Tomohiro Kabuta and Researcher Ryohei Sakai from the Department of Degenerative Neurological Diseases, Institute for Medical Science at the National Center of Neurology and Psychiatry (NCNP) has discovered a new intracellular mechanism for breaking down fat and demonstrated in mice that this mechanism improves obesity and insulin resistance. This discovery could lead to the development of new treatments and prevention methods for obesity and diabetes. Their findings were published in Cell Reports.

Obesity is caused by the accumulation of lipids such as neutral fats as lipid droplets within cells and is known to increase the risk of various diseases, including type 2 diabetes, stroke, dementia, and cancer.

Previously, two main pathways for breaking down fat were known. One is degradation in the cytoplasm, and the other is degradation through macroautophagy. In addition to these, a mechanism called "microlipophagy" was recently reported in mammalian liver cells, where lysosomes directly take up and degrade lipid droplets. However, the molecular mechanisms and regulatory proteins that bridge lysosomes and lipid droplets remained unclear.

The research group focused on the lysosomal membrane protein LAMP2B and clarified the molecular mechanism and pathophysiological significance of "microlipophagy," where lysosomal membranes directly take up lipid droplets. They demonstrated that overexpression of the LAMP2B protein promotes intracellular lipid degradation. Since this effect depends on the lysosomal lipid degradation enzyme (LIPA), it became clear that LAMP2B is involved in the lysosomal degradation system.

Furthermore, the binding between the cytoplasmic domain of LAMP2B and phosphatidic acid, a membrane component of the phospholipid monolayer of lipid droplets, is important for promoting lipid degradation, suggesting that LAMP2B plays a bridging role. Moreover, using correlative light and electron microscopy (CLEM), the group successfully captured for the first time the direct uptake of lipid droplets into lysosomes. When LAMP2B protein expression was suppressed, the uptake of lipid droplets into lysosomes was inhibited, resulting in the suppression of lipid degradation.

In experiments using mice, LAMP2B overexpression resulted in suppression of lipid accumulation caused by high-fat diet, improvement of insulin resistance, and suppression of inflammation in adipose tissue. Furthermore, lipid analysis of the liver suggested that hydrolysis of triacylglycerol was promoted.

These results revealed that LAMP2B plays an important role in suppressing excessive lipid accumulation and regulating lipid metabolism balance by promoting the degradation of lipid droplets.

This is expected to serve as an important foundation for developing new treatments for obesity and related diseases. In particular, it was suggested that this could lead to the control of chronic inflammation caused by obesity and the resulting cytokine storm.

Journal Information
Publication: Cell Reports
Title: The lysosomal membrane protein LAMP2B mediates microlipophagy to target obesity-related disorders
DOI: 10.1016/j.celrep.2025.115829