ABSTRACT
Obesity increases the risk of many cancers in both males and females. This study describes a link between obesity, obesity-associated metabolic alterations, and the risk of developing cancer in male and female mice. The goal of this study was to evaluate the relationship between gender and obesity and to determine the role of estrogen status in obese females and its effect on tumor growth. We examined the susceptibility of C57BL/6 mice to diet-induced obesity, insulin resistance/glucose intolerance, and tumors. Mice were injected sc with one of two tumorigenic cell lines, Lewis lung carcinoma, or mouse colon 38-adenocarcinoma. Results show that tumor growth rate was increased in obese mice vs. control mice irrespective of the tumor cell type. To investigate the effect of estrogen status on tumor development in obese females, we compared metabolic parameters and tumor growth in ovariectomized (ovx) and intact obese female mice. Obese ovx female mice developed insulin resistance and glucose intolerance similar to that observed in obese males. Our results demonstrate that body adiposity increased in ovx females irrespective of the diet administered and that tumor growth correlated positively with body adiposity. Overall, these data point to more rapid tumor growth in obese mice and suggest that endogenous sex steroids, together with diet, affect adiposity, insulin sensitivity, and tumor growth in female mice.
Subject(s)
Diet/adverse effects , Gonadal Hormones/physiology , Neoplasms, Experimental/complications , Neoplasms, Experimental/pathology , Obesity/complications , Obesity/etiology , Adenocarcinoma/pathology , Animals , Cell Movement , Cell Proliferation , Colonic Neoplasms/pathology , Estrogens/blood , Estrogens/physiology , Female , Gonadal Hormones/blood , Humans , Lung Neoplasms/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Obese , Obesity/blood , Ovary/physiology , Tumor Cells, Cultured , Tumor Stem Cell Assay , Xenograft Model Antitumor AssaysABSTRACT
The antiobesity and antidiabetic effects of the beta3-adrenergic agonists were investigated on nonobese type 2 diabetic MKR mice after injection with a beta3-adrenergic agonist, CL-316243. An intact response to acute CL-316243 treatment was observed in MKR mice. Chronic intraperitoneal CL-316243 treatment of MKR mice reduced blood glucose and serum insulin levels. Hyperinsulinemic euglycemic clamps exhibited improvement of the whole body insulin sensitivity and glucose homeostasis concurrently with enhanced insulin action in liver and adipose tissue. Treating MKR mice with CL-316243 significantly lowered serum and hepatic lipid levels, in part due to increased whole body triglyceride clearance and fatty acid oxidation in adipocytes. A significant reduction in total body fat content and epididymal fat weight was observed along with enhanced metabolic rate in both wild-type and MKR mice after treatment. These data demonstrate that beta3-adrenergic activation improves the diabetic state of nonobese diabetic MKR mice by potentiation of free fatty acid oxidation by adipose tissue, suggesting a potential therapeutic role for beta3-adrenergic agonists in nonobese diabetic subjects.
Subject(s)
Adipocytes/metabolism , Adipose Tissue/metabolism , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Dioxoles/pharmacology , Receptors, Adrenergic, beta-3/metabolism , Adrenergic beta-3 Receptor Antagonists , Adrenergic beta-Agonists/pharmacology , Animals , Blood Glucose/metabolism , Body Composition , Glucose/administration & dosage , Glucose/pharmacokinetics , Insulin/metabolism , Lipid Metabolism/drug effects , Liver/metabolism , Mice , Mice, Inbred NOD , Oxidation-ReductionABSTRACT
Thyroid hormone receptors (TRs) are ligand-regulatable transcription factors. Currently, little is known about the expression of TRs or other nuclear hormone receptors during the cell cycle. We thus developed a stable expression system to express green fluorescent protein-TRbeta in HeLa cells under tetracycline regulation, and studied TR expression during the cell cycle by laser scanning cytometry. Only approximately 9-15% of the nonsynchronized cell population expressed TR because the majority of cells were in G(1) phase and did not express detectable amounts of TR. However, when cells were synchronized in early S phase with hydroxyurea and then released, TR expression levels increased in a cell cycle-dependent manner and peaked to 30-40% cells expressing TR at late G(2)/M phase before declining to nonsynchronized levels. Moreover, we observed a direct correlation between transcriptional activity and TR expression during the cell cycle. Similar cell cycle-dependent findings also were observed for endogenous TR in rat pituitary GH(3) cells. Last, cycloheximide studies demonstrated that the increase in TR expression was primarily due to increased translation. These novel observations of cell cycle-dependent expression of TR suggest that differential hormone sensitivity can occur during the cell cycle and may contribute to cell cycle progression during normal development and oncogenesis.
