In particular, a research team has found out how fat cells (adipocytes) enlarge safely to store energy. This process prevents tissue damage and protects against toxic accumulation of fat molecules (lipids) where they shouldn’t be in the body.
The findings, published in Nature Communications, represent a major break in understanding metabolic diseases. But this discovery also creates new grounds for the creation of new therapeutic strategies aimed at combating chronic energetic excess diseases including lipodystrophy, obesity, metabolic syndrome, overweight, and their serious cardiovascular and metabolic complications.
It allows adipocytes to expand and store energy as fat by blocking elevated lipids build up in organs such as the liver and blood vessel wall (particularly in the brain and heart), where such lipids, in excess amounts, can cause irreparable damage. However, this is not a risk-free process. Fat in excess causes the adipocytes to rupture releasing their toxic contents, creating inflammation and metabolic changes.
Adipocytes of the Centro Nacional de Investigaciones Cardiovasculares (CNIC) study underwent expansion and were studied to determine how they adapted to suffering the mechanical stress induced by this expansion to accommodate excess fat. “If we want to understand the aging process and identify treatments to improve health, we need to know how these stresses pace the aging system and what happens to the cells inside our body,” said Miguel Ángel del Pozo Barriuso, head of the Mechanoadaptation and Caveolae Biology group at the CNIC, Spain.
Caveolae flatten when an adipocyte becomes fat and the cell surface is under increased stretching, allowing a ‘reservoir’ of the membrane to be released by the cell, allowing the cell to become bigger without breaking apart. “In contrast, when fat stores wane, these structures reorganize to readapt membrane to reduce surplus and characterize the cell again,” added study first author Dr. María Aboy-Pardal.
In addition to its physical role in protecting adipocytes, caveolae are critical for coordinating cell metabolism. “During adipocyte expansion, ‘molecular components of these membrane structures are relocated to other cell compartments, trafficking signals to modify metabolic activity in ways that reflect energy reserves,’ Prof. del Pozo Barriuso explained. “Caveolae serve as crucial components for effective caveolar function because of their ability to communicate internally. It was a compromising of the body’s metabolic health by an inflammatory reaction,” said Dr. Aboy Pardal.
In male mice in vivo, researchers demonstrate that adipocyte plasma membrane undergoes caveolar reorganization during lipid droplet (LD) expansion. As LDs grow, caveolae disassemble to release membrane reservoirs, increase cell surface area, and transfer caveolar components to the LD surface. Adipose tissue lacking caveolae is stiffer, less deformable, and prone to rupture under mechanical stress. The caveolae protein caveolin 1 (Cav1) tyrosine phosphorylation (Tyr14) is essential for caveolae disassembly, as Tyr14Phe mutants exhibit stiffer, smaller adipocytes with reduced adiposity, impaired Cav1/Eps15 homology domain-containing protein 2 (EHD2) transfer to LDs and converted Cav1 dynamics. These findings highlight Cav1 phosphoregulation as a key modulator of caveolar dynamics and adipocyte mechanoadaptation. Cav-1 has a key role, according to the CNIC study. Cav-1 must be phosphorylated chemically, for caveolae to flatten appropriately when the surrounding cell membrane is subject to mechanical tension on the surface of the cell.
“After these results, we understand better how adipose tissue responds to energetic excess with the mechanical forces,” Dr. del Pozo Barriuso said. In this, obesity and metabolic syndrome, this protective mechanism is essential to minimize organismal damage.
Reference: Aboy-Pardal MCM, Guadamillas MC, Guerrero CR, et al. Plasma membrane remodeling determines adipocyte expansion and mechanical adaptability. Nat Commun. 2024;15(1):10102. doi:10.1038/s41467-024-54224-y
