High-Fat Diets Trigger Inflammatory Monocyte Production in Bone Marrow

Researchers in Toronto have found that high-fat diets in mice boost production of inflammatory immune cells in the bone marrow, triggering an imbalance of monocytes in the rest of the body. The findings help explain how such diets contribute to the development of insulin resistance, type 2 diabetes, and other complications in individuals with obesity.

The bone marrow produces many immune cells, including monocytes, and is very sensitive to environmental changes. An invasion of monocytes into fat tissue is a hallmark of obesity, but what leads to this harmful phenomenon is unclear.

Scientists have previously shown that fat cells in the bone marrow rapidly expand in response to a high-fat diet. Senior author Amira Klip, Senior Scientist in Cell Biology at SickKids, and Professor in the Departments of Paediatrics, Biochemistry, and Physiology at the University of Toronto, Canada, together with colleagues, set out to find if high-fat diet-induced changes in the bone marrow led to the production of the inflammatory monocytes that invade fat tissue in people with obesity.

They found that mice fed a high-fat diet begin to experience metabolic disturbances throughout their body and in the bone marrow within three weeks. Fat cells in the bone marrow multiply and take on white fat cell characteristics. Metabolic changes in the monocytes at the bone marrow cells also occur; they use less oxygen to break down sugar into energy, and lactic acid builds up in the cells and surrounding fluid.

The team also found that mitochondria—the cellular factories that break down sugar into energy—break apart into fragments within the monocytes and become less efficient. Such mitochondrial fragmentation is associated with insulin resistance.

Over several weeks, the number of monocytes in the bone marrow shifts to include less of a monocyte called Ly6Clow to more of a monocyte called Ly6Chigh, the same type of monocyte that invades fat tissue in people with obesity. This accumulation of Ly6Chigh monocytes in the bone marrow starts before monocytes build up in fat tissue in the rest of the body to become inflammatory macrophages, the mature form of monocytes. 

“These results show that high-fat diets can cause remodeling in bone marrow fat cells that disrupt the normal balance of monocytes and can subsequently lead to invasive Ly6Chigh monocytes spilling into the body,” says Klip.

The team further demonstrated that white fat tissue can spur these changes in experiments using cell samples from mice fed a high-fat diet. They also found that brown fat tissue, which is more abundant in leaner people, can cause a shift towards the non-invasive Ly6Clow monocytes.

“Our study reveals how high-fat diets trigger a cascade of inflammation in the body that involves the bone marrow,” says Klip. “More research is needed to understand this process further and find out if there are ways to prevent or reverse this process. It will also be important to know if the bone marrow is also an early responder to obesity in humans. Learning more could lead to new therapies for treating obesity and preventing complications such as diabetes.”

The findings were published recently in the journal eLife.