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

Mitochondrial dysfunction in adipocytes: the culprit in type 2 diabetes?

“…When the db/db mice were treated with the thiazolidinedione (TZD)-derivative rosiglitazone, mitochondrial morphology and levels of respiratory chain proteins were restored in adipocytes, fatty acid oxidation was improved, and hyperglycaemia was reduced. These data are in line with recent studies by Bogacka et al and Wilson-Fritch et al, which showed that TZDs induce mitochondrial biogenesis, both in human and mouse adipocytes, with concomitant upregulation of genes involved in fatty acid beta-oxidation [11,12].…”

“…Although these studies suggest a direct role for mitochondria [10][11][12], they do not exclude the alternative possibility that TZD-induced improvements in mitochondrial function in adipocytes are an indirect consequence of improved glycaemic control, which was also a feature of these studies. Hyperglycaemia may itself switch cellular metabolism to a glycolytic state, leading to the reduced expression of mitochondrial genes, as observed, for example, in the study of insulin-regulated vs diabetesregulated gene expression in MIRKO mice [13].…”

“…The recent discovery of adipokines has placed adipocytes back in the centre of the metabolic stage. The recent publications by Choo et al, Bogacka et al and Wilson-Fritsch et al [10][11][12] have introduced another exciting possibility into adipocyte research: that mitochondria in adipocytes may shield against the development of type 2 diabetes.…”

R-α-Lipoic acid and acetyl-l-carnitine complementarily promote mitochondrial biogenesis in murine 3T3-L1 adipocytes

“…Promoting mitochondrial biogenesis by upregulation of the Ppargc1a pathway has been suggested as a strategy for preventing and reversing insulin resistance, obesity and diabetes [3,9,10]. In this regard, several drugs have been tested, such as metformin and 5-aminoimidazole-4-carboxamide ribonucleoside [11], the Pparg agonist pioglitazone/rosiglitazone and Ppara agonist WY-14,643 [12][13][14], as well as beta 3-adrenergic receptors agonist CL-316,243 [15] and oestrogen-related receptor α [16].…”

Augmenting energy expenditure by mitochondrial uncoupling: a role of AMP-activated protein kinase

“…Thus, treatment using leptin (Orci et al 2004), PPARa agonists (Ribet et al 2010), adrenoreceptor agonists and lipolytic agents (Granneman et al 2003;Yehuda-Shnaidman et al 2010), dietary n-3 polyunsaturated fatty acids (Jelenik et al 2010;Kopecky et al 2009;Flachs et al 2005), and thiazolidinediones acting as specific agonists of PPARc [TZD; (Tiraby et al 2003;Wilson-Fritch et al 2004;Petrovic et al 2010)] resulted in reduced adiposity and metabolic disturbances related to obesity, observed mostly under the conditions of high-fat feeding in obesity-prone C57BL/6 mice. Importantly, lipid catabolism in WAT was always up-regulated, and in situ lipogenesis in WAT was suppressed (Orci et al 2004;Ribet et al 2010;Flachs et al 2005;Tiraby et al 2003;Wilson-Fritch et al 2004), suggesting activation of AMPK Genes Nutr (2012) 7:369-386 381 in response to decreased energy status in WAT. Indeed, when studied under the conditions of the above treatments, AMPK in WAT and other tissues was found to be activated (Jelenik et al 2010;Kopecky et al 2009;Orci et al 2004;Ye et al 2006).…”