Lack of cardiolipin linked to obesity and type 2 diabetes

Large amounts of cardiolipin produced in the fat cells' mitochondria result in stronger calorie-burning, while low amounts of the molecule are related to obesity and type 2 diabetes, according to a study conducted at the University of Copenhagen. Brown fat is a unique type of fat tissue that burns calories rather than stores them and this latest study has shown that cardiolipin functions almost like an ‘on-off switch’ for the activity of brown fat.

Switching off production of cardiolipin in mice led to insulin resistance, which is the cornerstone of diabetes, explained Associate Professor, Zach Gerhart-Hines from the Novo Nordisk Foundation Center for Basic Metabolic Research, and senior author of the study. The research was featured in the paper, ‘Fat Mitochondria Is Essential for Systemic Energy Homeostasis,’ published in Cell Metabolism

A brown fat cell functions as a microscopic biological furnace that warms the body. The study examined what happens in the fat cells of mice that are exposed to cold temperature, where brown fat is pushed to burn energy at full throttle. The researchers found that the mitochondria produced a lot of the molecule, cardiolipin. However, in order to understand how this could affect energy balance and health, they had to develop new tools.

They generated mouse models in which they could switch off cardiolipin production in brown fat. After decreasing cardiolipin levels, the mice became insulin resistant and thus provided a clear link to diabetes.

“What really surprised us was that when we turned up the production of cardiolipin in both mouse and human fat cells, we increased the amount of calories the fat cells were able to burn,” added Gerhart-Hines.

The researchers further uncovered promising evidence that strongly suggests the scientific findings are relevant to humans. When the researchers investigated the genetics of metabolic disease, they found that people with a gene mutation linked to low cardiolipin production have a higher risk of being overweight and developing type 2 diabetes than others.

The researchers also examined the levels of the enzyme that makes cardiolipin in fat cells from healthy and diabetic patients. They found that fat cells from healthy, insulin-sensitive people had significantly more cardiolipin-producing enzyme.

"We're excited that what we find in the petri dish and animal models seems to also be true in humans. This could open up new approaches to improve metabolic health by finding ways to boost the amount of cardiolipin in the body's fat cells,” said Elahu Sustarsic, the postdoctoral researcher at the University of Copenhagen who led the studies.

This work has revealed for the first time that a single fat molecule in the powerhouse of fat cells can have a profound influence on the health of the whole body. The researchers now hope to uncover ways to boost cardiolipin in fat cells to increase insulin sensitivity and combat metabolic disease.

The highly collaborative effort is the result of several research groups' cross-disciplinary exploration of the brown fat cells' production of cardiolipin. Researchers from Harvard Medical School in the US, the Helmholtz Diabetes Center in Germany, and several Danish institutions including the University of Southern Denmark and University of Copenhagen have contributed to the project.