Study finds how a genetic variant raises diabetes risk through an unexpected mechanism
The variant contributes to a unique form of diabetes by reducing fat cells' ability to store fat and respond to insulin
In normal adipocyte progenitor cells, actin cytoskeleton stress fibers congregate near the center of the cell. As the cell matures, it breaks those fibers down, allowing the cytoskeleton to migrate closer to the cell membrane. This makes room for fat-storing lipid droplets to form and grow, and supports metabolic processes such as insulin responsiveness and lipid metabolism.
Following COBLL1 knockdown, however, the researchers saw that the stress fibers in subcutaneous adipocytes failed to degrade, preventing the cells from remodeling the cytoskeleton, which reduced their fat storage capacity. With the subcutaneous cells unable to store fat efficiently, it is redirected to visceral adipocytes or other tissues like the liver or the muscle, which can lead to severe insulin resistance.
“This COBLL1-downregulating variant renders subcutaneous fat cells insulin resistant and metabolically inactive," Claussnitzer explained. "This strongly suggested to us that a lack of COBLL1 expression was responsible for MONW.”
To validate Claussnitzer and her colleagues' findings, a team led by Nobrega's University of Chicago lab generated a mouse model lacking COBLL1, isolated the adipocyte progenitor cells, and sent cell samples to the Broad. LipocyteProfiler analysis revealed the same defects in actin cytoskeleton remodeling and adipocyte metabolism that Claussnitzer's team had seen in human cells.
“The mice showed what the humans showed: they're lean and they’re insulin resistant," said Claussnitzer. "It was a beautiful recapitulation of the predictions made by the genome-wide association study results we started with.”
Their findings have major therapeutic implications for people with the MONW phenotype, and Claussnitzer and her lab have been approached by pharmaceutical companies interested in developing drugs that modulate COBLL1 expression.
“I find it most exciting that a phenotype that is generally summarized as T2D can be partitioned into a subgroup where subcutaneous adipocyte depletion can be explained by a gene target and an intriguing mechanism of action,” said Claussnitzer. “It introduces a novel and clinically meaningful therapeutic hypothesis.”
Co-first authors on this study were Viktoria Glunk of TUM; Samantha Laber, Nasa Sinnott-Armstrong, and Sophie Strobel of the Broad; and Débora Sobreira of the University of Chicago.
Support for this research was provided in part by the Foundation for the National Institutes of Health; the National Institute of Diabetes and Digestive and Kidney Diseases; the National Heart, Lung, and Blood Institute; the Helmholtz Center Munich; the German Center for Diabetes Research; and the Novo Nordisk Foundation.
Glunk V, Laber S, Sinnott-Armstrong N, Sobreira DR, Strobel SM, et al. A non-coding variant associated with ‘Metabolically Obese Normal Weight’ regulates actin cytoskeleton remodeling in subcutaneous adipocytes via the expression of COBLL1. Nature Metabolism. Online May 30, 2023. DOI: 10.1038/s42255-023-00807-w.
Laber S, Strobel SM, et al. Discovering cellular programs of intrinsic and extrinsic drivers of metabolic traits using LipocyteProfiler. bioRxiv. Online July 19, 2021. DOI: 10.1101/2021.07.17.452050.