SUMMARY Adipose tissue (AT) has previously been identified as an extra-medullary reservoir for normal hematopoietic stem cells (HSCs) and may promote tumor development. Here, we show a subpopulation of leukemic stem cells (LSCs) can utilize gonadal adipose tissue (GAT) as a niche to support their metabolism and evade chemotherapy. In a mouse model of blast crisis CML, adipose-resident LSCs exhibit a pro-inflammatory phenotype and induce lipolysis in GAT. GAT lipolysis fuels fatty acid oxidation in LSCs, especially within a subpopulation expressing the fatty acid transporter CD36. CD36+ LSCs have unique metabolic properties, are strikingly enriched in AT, and are protected from chemotherapy by the GAT microenvironment. CD36 also marks a fraction of human blast crisis CML and AML cells with similar biological properties. These findings suggest striking interplay between leukemic cells and adipose tissue to create a unique microenvironment that supports the metabolic demands and survival of a distinct LSC subpopulation.

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Obesity is the result of numerous, interacting behavioral, physiological, and biochemical factors. One increasingly important factor is the generation of additional fat cells, or adipocytes, in response to excess feeding and/or large increases in body fat composition. The generation of new adipocytes is controlled by several "adipocyte-specific" transcription factors that regulate preadipocyte proliferation and adipogenesis. Generally these adipocyte-specific factors are expressed only following the induction of adipogenesis. The transcription factor(s) that are involved in initiating adipocyte differentiation have not been identified. Here we demonstrate that the transcription factor, CREB, is constitutively expressed in preadipocytes and throughout the differentiation process and that CREB is stimulated by conventional differentiation-inducing agents such as insulin, dexamethasone, and dibutyryl cAMP. Stably transfected 3T3-L1 preadipocytes were generated in which we could induce the expression of either a constitutively active CREB (VP16-CREB) or a dominantnegative CREB (KCREB). Inducible expression of VP16-CREB alone was sufficient to initiate adipogenesis as determined by triacylglycerol storage, cell morphology, and the expression of two adipocyte marker genes, peroxisome proliferator activated receptor gamma 2, and fatty acid binding protein. Alternatively, KCREB alone blocked adipogenesis in cells treated with conventional differentiation-inducing agents. These data indicate that activation of CREB was necessary and sufficient to induce adipogenesis. Finally, CREB was shown to bind to putative CRE sequences in the promoters of several adipocyte-specific genes. These data firmly establish CREB as a primary regulator of adipogenesis and suggest that CREB may play similar roles in other cells and tissues.Excess body fat, or obesity, is a major health concern in the United States and other developed nations. It has been estimated that 26% of Americans are overweight (2), with 5 to 14% of men and 7 to 24% of women considered obese depending on the definition employed (2,5,6,12,22,45,57). Similar or even higher estimates for the prevalence of obesity have been reported in other countries (42). Obesity contributes to an increased rate of mortality (20) by virtue of its role in the development of cardiovascular disease, diabetes, pulmonary dysfunction, and gallstones (5, 10, 12).Weight gain and obesity occur when energy intake by an individual exceeds the rate of energy expenditure (23). Energy intake and expenditure are in turn determined by multiple, interacting factors ranging from dietary composition and feeding and exercise habits to physiologic factors and biochemical pathways that modulate lipid and overall energy metabolism (58). At the cellular level obesity was originally considered a hypertrophic disease resulting from an increase in fat cell size or volume (30). However, several studies have demonstrated a hyperplastic component to obesity. For example, sequential biopsies in children indicate that f...

In many chronic inflammatory disorders, glucocorticoid (GC) insensitivity is a challenging clinical problem associated with life-threatening disease progression. The molecular basis of GC insensitivity, however, is unknown. Alternative splicing of the GC receptor (R) pre–messenger RNA generates a second GCR, termed GCR-β, which does not bind GCs but antagonizes the transactivating activity of the classic GCR, termed GCR-α. In the current study, we demonstrate that GC-insensitive asthma is associated with a significantly higher number of GCR-β–immunoreactive cells in peripheral blood than GC-sensitive asthmatics or normal controls. Furthermore, we show that patients with GC-insensitive asthma have cytokine-induced abnormalities in the DNA binding capability of the GCR. These abnormalities can be reproduced by transfection of cell lines with the GCR-β gene resulting in significant reduction of their GCR-α DNA binding capacity. We conclude that increased expression of GCR-β is cytokine inducible and may account for GC insensitivity in this common inflammatory condition.