CLSTN3β enforces adipocyte multilocularity to facilitate lipid utilization

Area of Science:

• Cell Biology
• Metabolic Regulation
• Adipose Tissue Biology

Background:

• Multilocular adipocytes are characteristic of thermogenic adipose tissue, but the molecular mechanisms controlling this phenotype are not fully understood.
• Lipid droplet (LD) morphology and expansion are critical for adipocyte function, particularly in energy metabolism.

Purpose of the Study:

• To identify factors that regulate lipid droplet morphology and function in thermogenic adipocytes.
• To elucidate the role of CLASTININ-3 beta (CLSTN3β) in controlling lipid droplet expansion and lipid utilization.

Main Methods:

• Investigated the function of CLSTN3β using mouse models lacking the protein and cell culture systems.
• Utilized techniques including immunofluorescence microscopy, biochemical assays, and analysis of substrate utilization in adipose tissue.
• Examined the localization and interactions of CLSTN3β at endoplasmic reticulum-lipid droplet contact sites.

Main Results:

• CLSTN3β, an endoplasmic reticulum membrane protein, limits lipid droplet expansion by localizing to ER-LD contact sites.
• Mice lacking CLSTN3β exhibit abnormal LD morphology, altered substrate use in brown adipose tissue, and increased susceptibility to cold-induced hypothermia.
• Forced expression of CLSTN3β induces a multilocular LD phenotype and enhances fatty acid oxidation in adipocytes.
• CLSTN3B is identified as a specific marker for multilocular adipocytes in human adipose tissue.

Conclusions:

• CLSTN3β is a key regulator of lipid droplet size and function, essential for efficient lipid utilization in thermogenic adipocytes.
• This study defines a molecular mechanism involving CLSTN3β that controls LD morphology to support fatty acid oxidation and thermogenesis.
• CLSTN3β represents a potential target for modulating energy expenditure and metabolic health.