Adipocytes cause leukemia cell resistance to daunorubicin via oxidative stress response.

Adipocytes promote cancer progression and impair treatment, and have been shown to protect acute lymphoblastic leukemia (ALL) cells from chemotherapies. Here we investigate whether this protection is mediated by changes in oxidative stress. Co-culture experiments showed that adipocytes protect ALL cells from oxidative stress induced by drugs or irradiation. We demonstrated that ALL cells induce intracellular ROS and an oxidative stress response in adipocytes. This adipocyte oxidative stress response leads to the secretion of soluble factors which protect ALL cells from daunorubicin (DNR). Collectively, our investigation shows that ALL cells elicit an oxidative stress response in adipocytes, leading to adipocyte protection of ALL cells against DNR

Salsalate treatment improves glycemia without altering adipose tissue in nondiabetic obese hispanics.

ObjectiveSalsalate treatment has well-known effects on improving glycemia, and the objective of this study was to examine whether the mechanism of this effect was related to changes in adipose tissue.MethodsA randomized double-blind and placebo-controlled trial in obese Hispanics (18-35 years) was conducted. The intervention consisted of 4 g day(-1) of salsalate (n = 11) versus placebo (n = 13) for 4 weeks. Outcome measures included glycemia, adiposity, ectopic fat, and adipose tissue gene expression and inflammation.ResultsIn those receiving salsalate, plasma fasting glucose decreased by 3.4% (P < 0.01), free fatty acids decreased by 42.5% (P = 0.06), and adiponectin increased by 27.7% (P < 0.01). Salsalate increased insulin AUC by 38% (P = 0.01) and HOMA-B by 47.2% (P < 0.01) while estimates of insulin sensitivity/resistance were unaffected. These metabolic improvements occurred without changes in total, abdominal, visceral, or liver fat. Plasma markers of inflammation/immune activation were unchanged following salsalate. Salsalate had no effects on adipose tissue including adipocyte size, presence of crown-like structures, or gene expression of adipokines, immune cell markers, or cytokines downstream of NF-κB with the exception of downregulation of IL-1β (P < 0.01).ConclusionsFindings suggest that metabolic improvements in response to salsalate occurred without alterations in adiposity, ectopic fat, or adipose tissue gene expression and inflammation

Abnormalities in autonomic function in obese boys at-risk for insulin resistance and obstructive sleep apnea.

Study objectivesCurrent evidence in adults suggests that, independent of obesity, obstructive sleep apnea (OSA) can lead to autonomic dysfunction and impaired glucose metabolism, but these relationships are less clear in children. The purpose of this study was to investigate the associations among OSA, glucose metabolism, and daytime autonomic function in obese pediatric subjects.MethodsTwenty-three obese boys participated in: overnight polysomnography; a frequently sampled intravenous glucose tolerance test; and recordings of spontaneous cardiorespiratory data in both the supine (baseline) and standing (sympathetic stimulus) postures.ResultsBaseline systolic blood pressure and reactivity of low-frequency heart rate variability to postural stress correlated with insulin resistance, increased fasting glucose, and reduced beta-cell function, but not OSA severity. Baroreflex sensitivity reactivity was reduced with sleep fragmentation, but only for subjects with low insulin sensitivity and/or low first-phase insulin response to glucose.ConclusionsThese findings suggest that vascular sympathetic activity impairment is more strongly affected by metabolic dysfunction than by OSA severity, while blunted vagal autonomic function associated with sleep fragmentation in OSA is enhanced when metabolic dysfunction is also present

The role of adipose tissue and obesity in causing treatment resistance of acute lymphoblastic leukemia

Obesity is responsible for ~90,000 cancer deaths per year, increasing cancer incidence and impairing its treatment. Obesity has also been shown to impact hematological malignancies, through as yet unknown mechanisms. Adipocytes are present in bone marrow and the microenvironments of many types of cancer, and have been found to promote cancer cell survival. In this review, we explore several ways in which obesity might cause leukemia treatment resistance. Obese patients may be at a treatment disadvantage due to altered pharmacokinetics of chemotherapy and dosage capping based on ideal body weight. The adipose tissue provides fuel to cancer cells in the form of amino acids and free fatty acids. Adipocytes have been shown to cause cancer cells to resist chemotherapy-induced apoptosis. In addition, obese adipose tissue is phenotypically altered, producing a milieu of pro-inflammatory adipokines and cytokines, some of which have been linked to cancer progression. Given the prevalence of obesity, understanding its role and adipose tissue in ALL treatment is necessary for evaluating current treatment regimen and revealing new therapeutic targets

The role of adipose tissue and obesity in causing treatment resistance of acute lymphoblastic leukemia.

Obesity is responsible for ~90,000 cancer deaths/year, increasing cancer incidence and impairing its treatment. Obesity has also been shown to impact hematological malignancies, through as yet unknown mechanisms. Adipocytes are present in bone marrow and the microenvironments of many types of cancer, and have been found to promote cancer cell survival. In this review, we explore several ways in which obesity might cause leukemia treatment resistance. Obese patients may be at a treatment disadvantage due to altered pharmacokinetics of chemotherapy and dosage "capping" based on ideal body weight. The adipose tissue provides fuel to cancer cells in the form of amino acids and free fatty acids. Adipocytes have been shown to cause cancer cells to resist chemotherapy-induced apoptosis. In addition, obese adipose tissue is phenotypically altered, producing a milieu of pro-inflammatory adipokines and cytokines, some of which have been linked to cancer progression. Given the prevalence of obesity, understanding its role and adipose tissue in acute lymphoblastic leukemia treatment is necessary for evaluating current treatment regimen and revealing new therapeutic targets

Gilsanz V. Differential effect of marrow adiposity and visceral and subcutaneous fat on cardiovascular risk in young, healthy adults

Background—Adipose tissue is an endocrine organ that influences many metabolic processes and accumulates in different depots, including the bone marrow. While the negative associations between visceral fat (VF) or subcutaneous fat (SF) and cardiovascular disease (CVD) risks are well known, the relation between marrow fat (MF) and metabolic risk is unexplored. Objectives—We examined the relations between these three fat depots and whether CVD risks are associated to marrow adiposity. Design—observational cross sectional study Subjects and Methods—Computed tomography was used to measure VF, SF and MF depots in 131 healthy young adults (60 females, 71 males; 16-25 years of age). Weight, body mass index (BMI), waist and hip circumferences, blood pressure (BP), carotid intima media thickness (CIMT) and serum levels of lipids, glucose and insulin were also measured. Results—Regardless of gender, MF was not associated to values of VF or SF, anthropometric measures, or lipid or carbohydrate serum levels (P>0.05 for all). In contrast, VF was associated to SF (r’s = 0.74 for females, 0.78 for males; both P’s <0.0001) and these depots were related to anthropometric parameters (r’s between.69 and.87; all P’s <0.0001) and to most measures of lipids, glucose or insulin (r’s between.25 and.62). Conclusions—Marrow adiposity in young men and women is independent of visceral and subcutaneous fat, and is not associated to CVD risk. These findings do not support the concept that marrow adiposity is involved in the comorbidities related to fat accumulation in other compartments. Keywords marrow fat; visceral fat; subcutaneous fat; cardiovascular risk; computed tomograph

Mechanisms by Which Obesity Impacts Survival from Acute Lymphoblastic Leukemia.

The prevalence of obesity has steadily risen over the past decades, even doubling in more than 70 countries. High levels of body fat (adiposity) and obesity are associated with endocrine and hormonal dysregulation, cardiovascular compromise, hepatic dysfunction, pancreatitis, changes in drug metabolism and clearance, inflammation, and metabolic stress. It is thus unsurprising that obesity can affect the development of and survival from a wide variety of malignancies. This review focuses on acute lymphoblastic leukemia, the most common malignancy in children, to explore the multiple mechanisms connecting acute lymphoblastic leukemia, obesity, and adipocytes, and the implications for leukemia therapy