Skip the Shake and Mind the Marrow

Epidemiologic studies conducted in many industrialized countries have shown a correlation between rising rates of obesity and an increasing incidence of endocrine and cardiovascular diseases, and obese individuals have been reported to be at greater than normal risk for developing cancer in general and leukemia in particular. Further, atopic and immune disorders appear to occur at a greater than normal rate in obese children. Until recently, however, little research has been directed toward understanding how Western diets and adiposity impact the function of hematopoietic stem and progenitor cells, which, after all, give rise to the immune system. Now, a study by Dr. Benjamin Adler and coworkers from Stony Brook University, Stony Brook, New York, is among several th<pat are aimed at rigorously exploring these relationships.

Using a validated murine model, the authors investigated the effects of a high-fat diet (HFD) (60% calories from fat) on hematopoiesis at three time points (2 days, 1 week, and 6 weeks). Along with an increase in bone marrow adipocytes, they observed an early influx of macrophages and immature myeloid cells into the expanding fat deposits. The HFD cohorts were found to have an early, transient increase in lymphocytes and a transient gain in the bone marrow progenitor cells that gave way subsequently to a sustained net loss of both B- and T-cell populations and an expansion of myelopoiesis while peripheral blood counts and leukocyte subset distribution in the peripheral blood remained largely unaffected. Studies that focused on the lymphopoiesis showed that the B-cell population was reduced by 10 percent after one week and 25 percent after six weeks in the HFD-fed animals compared with those fed a normal diet. IL-7 secreted by supportive cells of the BM niche is a critical factor in early B-cell lineage development and is necessary for B-cell commitment. By one week, IL-7 expression fell by 19 percent in the HFD-cohort, and by week six, expression had fallen by 23 percent, at which time a 363 percent increase in adipose encroachment within the marrow space was observed.

The processes that mediate the effects of marrow adiposity on myeloid skewing and lymphopenia are incompletely understood, but an earlier report from the laboratory of Dr. George Daley¹  suggested that local bone marrow adipocytes suppress hematopoiesis through release of paracrine factors. This hypothesis was supported by experiments that showed that pharmacologic or genetic interference with marrow adiposity improved several measures of hematopoietic function, and compelling studies by others implicate adipocytes as predominantly negative regulators of the bone marrow microenvironment.