Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone

Abstract

Adipose tissue plays a central role in the control of energy homeostasis through the storage and turnover of triglycerides and through the secretion of factors that affect satiety and fuel utilization. Agents that enhance insulin sensitivity, such as rosiglitazone, appear to exert their therapeutic effect through adipose tissue, but the precise mechanisms of their actions are unclear. Rosiglitazone changes the morphological features and protein profiles of mitochondria in 3T3-L1 adipocytes. To examine the relevance of these effects in vivo, we studied white adipocytes from ob/ob mice during the development of obesity and after treatment with rosiglitazone. The levels of approximately 50% of gene transcripts encoding mitochondrial proteins were decreased with the onset of obesity. About half of those genes were upregulated after treatment with rosiglitazone, and this was accompanied by an increase in mitochondrial mass and changes in mitochondrial structure. Functionally, adipocytes from rosiglitazone-treated mice displayed markedly enhanced oxygen consumption and significantly increased palmitate oxidation. These data reveal mitochondrial remodeling and increased energy expenditure in white fat in response to rosiglitazone treatment in vivo and suggest that enhanced lipid utilization in this tissue may affect whole-body energy homeostasis and insulin sensitivity. IntroductionThe ability of brown adipose tissue to affect whole-body metabolism upon thermogenic stress has been known for many years (1, 2). More recently, the important contribution of white adipose tissue (WAT) to the control of energy homeostasis has been recognized with the study of tissue-specific knockout models and the discovery of adipocyte-specific secreted factors that have powerful effects on fuel metabolism (3, 4). These observations have raised many as-yetunanswered questions about the mechanisms by which adipocytes maintain their energy homeostasis as well as sense and respond to the metabolic requirements of the organism.Brown adipocytes contain a large complement of mitochondria that serve as a source of heat generated as a consequence of flow through the electron transport chain under uncoupled conditions elicited by uncoupling protein 1 (UCP-1). Recently we reported that adipogenesis of the 3T3-L1 cell line, representative of white adipocytes, is also accompanied by a stimulation of mitochondrial biogenesis (5). The need for a large mitochondrial mass in white fat can be linked to key functions of the adipocyte that require mitochondrial function. For example, adipocytes must generate glycerol 3-phosphate at a rate sufficient to sustain triglyceride synthesis, and for this the glyceroneogenic pathway and

CCR2 modulates inflammatory and metabolic effects of high-fat feeding

“…Concomitant with an increase in inflammatory gene expression, obesity leads to decreased expression of genes required for mitochondrial function, TG metabolism, and adipocyte differentiation (8,(31)(32)(33). Recent studies suggested that CCL2 directly effects similar changes in adipocyte gene expression (21).…”

Suppression of oxidative metabolism and mitochondrial biogenesis by the transcriptional corepressor RIP140 in mouse adipocytes

“…Lipogenesis in adipocytes in turn is thought to be 1 pathway whereby fatty acids are sequestered away from other tissues such as muscle, reducing insulin resistance (33). Interestingly, obesity and insulin resistance in ob/ob mice are accompanied by a decrease in mitochondrial gene expression in white adipose tissue (12).…”

“…RIP140 appears to interact with multiple nuclear receptors through its LXXLL motifs, including PPARγ (37), which promotes and maintains the adipocyte phenotype (53). Both RIP140 depletion and the treatment of 3T3-L1 adipocytes or obese ob/ob mice with the PPARγ agonist rosiglitazone cause an increase in the expression of genes encoding mitochondrial proteins (12). We therefore tested whether RIP140 might act by a mechanism involving direct repression of PPARγ to regulate glucose uptake and GLUT4 expression.…”

“…Furthermore, the insulin sensitizer rosiglitazone, a ligand for the transcription factor PPARγ, enhances mitochondrial mass and alters mitochondrial morphology in cultured adipocytes (10) and in the white adipose tissue of dogs and rats (11). Conversely, the onset of obesity and insulin resistance in ob/ob mice is accompanied by a decrease in the expression of mitochondrial genes in fat cells that is reversed by rosiglitazone treatment (12). Interestingly, microarray analysis of gene expression in human skeletal muscle revealed small decreases throughout a subset of mitochondrial genes in diabetic subjects (13,14).…”

PPARγ regulates adipocyte cholesterol metabolism via oxidized LDL receptor 1

“…TZDs cause the differentiation of new, small adipocytes and promote apoptosis of older, larger adipocytes (30). In addition, TZDs induce PGC-1 and mitochondrial biogenesis in adipocytes, increasing lipid oxidation (82).…”