INAUGURAL ARTICLE by a Recently Elected Academy Member:Enhancement of hematopoiesis and lymphopoiesis in diet-induced obese mice

The bone marrow, which is located throughout the skeletal mass, is one of the largest and most active tissues of the body. Through complex differentiation pathways originating with hematopoietic stem cells, the marrow produces billions of new leukocytes and erythrocytes each day (1–4). Osteoblasts, chondrocytes, myocytes, adipocytes, etc., also arise daily from marrow mesenchymal stem cells. Because it is a highly vascular tissue, the marrow provides a highway for the constant transport of newly produced cells to the systemic circulation. Thus, the breadth of divergent events occurring daily in the marrow is remarkable. Given the complex operations occurring in the bone marrow each day, it would seem logical to assume that it would be altered by disease states, changes in metabolism and metabolic diseases. However, the roles that the marrow might play in the etiology of disease have been largely overlooked. It is known, however, that increased proliferation of granulocyte percursors is observed in mice in response to inflammation and infection (5, 6). Malnutrition, including zinc deficiency and protein calorie deficiencies, profoundly alters the primary immune tissues, especially the bone marrow (7, 8). Stress, which may create elevated levels of endogenous glucocorticoids, initiates marked apoptosis among pre-B and pre-T cells while enhancing myelopoiesis in the marrow (9, 10). In dextran sodium sulfate-induced colitis, the marrow exhibits marked declines in erythropoiesis and accelerated production of monocytes and granulocytes, thereby exacerbating the anemia and inflammation of the gut that accompanies this disease. These examples make clear that hematopoietic processes in the marrow are actively responding to new and diverse physiological processes and not simply maintaining homeostasis. In addition to metabolic changes, obesity is also associated with chronic low-grade inflammation that leads to the increased production of adipokines, proinflammatory cytokines, leptin, etc., in blood (11). These factors play a role in the development of several comorbidities associated with obesity, such as cardiovascular disease, diabetes, hypertension, arthritis, and stroke (12, 13). Inflammation, along with documented changes in T-cell and macrophage function, indicates that immune dysregulation has occurred in the obese (14, 15). Considering the system-wide changes occurring during obesity, it is possible that immune cell development in the primary immune tissues would be affected by obesity-associated inflammation, increased adiposity, and/or hormonal changes. Indeed, leptin-deficient obese ob/ob mice have a 40% reduction in the number of bone marrow cells and smaller thymuses compared with lean mice (16). These same mice also have reduced lymphocyte numbers in peripheral blood (17). Similarly, obese db/db mice, which have an inactive leptin receptor, have a deficit in lymphocyte progenitors as well as reduced B- and CD4+ T-cell numbers in peripheral blood (18). Provision of recombinant leptin to ob/ob mice promoted both lymphopoiesis and myelopoiesis (16). Thus, it seemed that leptin, which is substantially elevated in the obese, might alter hematopoiesis. Comparatively little was known about the effects of diet-induced obesity (DIO) on hematopoiesis. It is known that adipose tissue in DIO mice contains increased numbers of proinflammatory macrophages (adipose tissue macrophages) that are bone marrow-derived as well as a large number of stem cells (19–22). Similarly, obesity in humans has been associated with increased white blood cell counts (23–25), but the role of the marrow in these changes was unclear. Considering all of the aforementioned issues, it seemed plausible to assume that other obesity-related changes would occur in hematopoietic and lymphopoietic processes in bone marrow and the thymus. In this study, we investigated the effects of diet-induced obesity in young mice on hematopoietic and lymphopoietic function. Profound changes in the primary immune tissues were noted in the obese mice that persisted throughout 180 d of this study.