ABSTRACT
OBJECTIVE: Based on its role as an energy storage compartment and endocrine organ, white adipose tissue (WAT) fulfills a critical function in the maintenance of whole-body energy homeostasis. Indeed, WAT dysfunction is connected to obesity-related type 2 diabetes triggered at least partly by an inflammatory response in adipocytes. The pseudokinase tribbles (TRB) 3 has been identified by us and others as a critical regulator of hepatic glucose homeostasis in type 2 diabetes and WAT lipid homeostasis. Therefore, this study aimed to test the hypothesis that the TRB gene family fulfills broader functions in the integration of metabolic and inflammatory pathways in various tissues. RESEARCH DESIGN AND METHODS: To determine the role of TRB family members for WAT function, we profiled the expression patterns of TRB13 under healthy and metabolic stress conditions. The differentially expressed TRB1 was functionally characterized in loss-of-function animal and primary adipocyte models. RESULTS: Here, we show that the expression of TRB1 was specifically upregulated during acute and chronic inflammation in WAT of mice. Deficiency of TRB1 was found to impair cytokine gene expression in white adipocytes and to protect against high-fat diet-induced obesity. In adipocytes, TRB1 served as a nuclear transcriptional coactivator for the nuclear factor kappaB subunit RelA, thereby promoting the induction of proinflammatory cytokines in these cells. CONCLUSIONS: As inflammation is typically seen in sepsis, insulin resistance, and obesity-related type 2 diabetes, the dual role of TRB1 as both a target and a (co) activator of inflammatory signaling might provide a molecular rationale for the amplification of proinflammatory responses in WAT in these subjects.
Subject(s)
Adipose Tissue/physiopathology , Inflammation/physiopathology , Protein Serine-Threonine Kinases/genetics , Adipocytes/physiology , Animals , Cell Line , Chromatin/physiology , DNA Primers , Humans , Kidney/embryology , Male , Mice , Mice, Inbred C57BL , Protein Serine-Threonine Kinases/metabolism , RNA/genetics , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction , TransfectionABSTRACT
Obesity results from chronic energy surplus and excess lipid storage in white adipose tissue (WAT). In contrast, brown adipose tissue (BAT) efficiently burns lipids through adaptive thermogenesis. Studying mouse models, we show that cyclooxygenase (COX)-2, a rate-limiting enzyme in prostaglandin (PG) synthesis, is a downstream effector of beta-adrenergic signaling in WAT and is required for the induction of BAT in WAT depots. PG shifted the differentiation of defined mesenchymal progenitors toward a brown adipocyte phenotype. Overexpression of COX-2 in WAT induced de novo BAT recruitment in WAT, increased systemic energy expenditure, and protected mice against high-fat diet-induced obesity. Thus, COX-2 appears integral to de novo BAT recruitment, which suggests that the PG pathway regulates systemic energy homeostasis.
Subject(s)
Adipocytes, Brown/physiology , Adipose Tissue, Brown/physiology , Adipose Tissue, White/physiology , Cyclooxygenase 2/genetics , Cyclooxygenase 2/metabolism , Energy Metabolism , Prostaglandins/metabolism , Thermogenesis , Adipocytes, Brown/cytology , Adipogenesis , Adipose Tissue , Adipose Tissue, Brown/cytology , Adipose Tissue, White/enzymology , Adrenergic beta-3 Receptor Agonists , Adrenergic beta-Agonists/pharmacology , Animals , Body Weight , Dietary Fats/administration & dosage , Dioxoles/pharmacology , Female , Gene Expression Regulation, Enzymologic , Homeostasis , Male , Mesenchymal Stem Cells/cytology , Mice , Mice, Inbred C57BL , Mice, Obese , Mice, Transgenic , Norepinephrine/metabolism , Obesity/etiology , Obesity/prevention & control , Oxygen Consumption , Receptors, Adrenergic, beta-3/metabolism , Signal TransductionABSTRACT
Numerous epidemiological and experimental studies have established a strong connection between type 2 diabetes and the risk of the development of Alzheimer's disease. Indeed, several pathological features have been identified as common denominators of diabetic and Alzheimer's patients, including insulin resistance, dyslipidemia and inflammation, suggesting a close connection between the two disorders. Here we review common metabolic and inflammatory processes implicated in the pathogenesis of both disorders. In particular, the role of critical transcriptional checkpoints in the control of cellular metabolism, insulin sensitivity, and inflammation will be emphasized in this context. These transcriptional regulators hold great promise as new therapeutic targets in the potentially combined treatment of type 2 diabetes and Alzheimer's disease in the future.
