Mitochondrial dysfunction in obesity

aDepartments of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
Current opinion in endocrinology, diabetes, and obesity (Impact Factor: 3.37). 10/2010; 17(5):446-52. DOI: 10.1097/MED.0b013e32833c3026
Source: PubMed

ABSTRACT The review highlights recent findings regarding the functions of mitochondria in adipocytes, providing an understanding of their central roles in regulating substrate metabolism, energy expenditure, disposal of reactive oxygen species (ROS), and in the pathophysiology of obesity and insulin resistance, as well as roles in the mechanisms that affect adipogenesis and mature adipocyte function.
Nutrient excess leads to mitochondrial dysfunction, which in turn leads to obesity-related pathologies, in part due to the harmful effects of ROS. The recent recognition of 'ectopic' brown adipose in humans suggests that this tissue may play an underappreciated role in the control of energy expenditure. Transcription factors, PGC-1alpha and PRDM16, which regulate brown adipogenesis, and members of the TGF-beta superfamily that modulate this process may be important new targets for antiobesity drugs.
Mitochondria play central roles in ATP production, energy expenditure, and disposal of ROS. Excessive energy substrates lead to mitochondrial dysfunction with consequential effects on lipid and glucose metabolism. Adipocytes help to maintain the appropriate balance between energy storage and expenditure and maintaining this balance requires normal mitochondrial function. Many adipokines, including members of the TGF-beta superfamily, and transcriptional coactivators, PGC-1alpha and PRDM16, are important regulators of this process.

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Available from: Juan C Bournat, Nov 14, 2014
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    • "This newly discovered ''plasticity'' of adipocytes has intensified efforts to identify novel methods to treat obesity and insulin resistance by increasing browning and peripheral energy expenditure (Boss and Farmer, 2012; Cypess and Kahn, 2010). Mitochondrial dysfunction has been shown to be associated with the development of obesity and insulin resistance (Bournat and Brown, 2010; Patti and Corvera, 2010). The peroxisome proliferator-activated receptor g coactivator-1a (PGC-1a) is a central transcriptional regulator of mitochondrial and peroxisomal remodeling and biogenesis (Wu et al., 1999; Bagattin et al., 2010). "
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    ABSTRACT: Altering the balance between energy intake and expenditure is a potential strategy for treating obesity and metabolic syndrome. Nonetheless, despite years of progress in identifying diverse molecular targets, biological-based therapies are limited. Here we demonstrate that heat shock factor 1 (HSF1) regulates energy expenditure through activation of a PGC1α-dependent metabolic program in adipose tissues and muscle. Genetic modulation of HSF1 levels altered white fat remodeling and thermogenesis, and pharmacological activation of HSF1 via celastrol was associated with enhanced energy expenditure, increased mitochondrial function in fat and muscle and protection against obesity, insulin resistance, and hepatic steatosis during high-fat diet regimens. The beneficial metabolic changes elicited by celastrol were abrogated in HSF1 knockout mice. Overall, our findings identify the temperature sensor HSF1 as a regulator of energy metabolism and demonstrate that augmenting HSF1 via celastrol represents a possible therapeutic strategy to treat obesity and its myriad metabolic consequences.
    Cell metabolism 09/2015; DOI:10.1016/j.cmet.2015.08.005 · 17.57 Impact Factor
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    • "Mitochondrial structure and functions are constantly adjusted to maintain cellular metabolic homeostasis. Defects in mitochondrial functions have been associated to different pathologies, including obesity, type-2 diabetes, and neurodegenerative diseases [1–4]. In peripheral tissues, insulin-resistance is associated with mitochondrial dysfunctions in myocytes, hepatocytes, adipocytes, and islets β-cells [2,5]. "
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    ABSTRACT: Brain mitochondrial activity is centrally involved in the central control of energy balance. When studying mitochondrial functions in the brain, however, discrepant results might be obtained, depending on the experimental approaches. For instance, immunostaining experiments and biochemical isolation of organelles expose investigators to risks of false-positive and/or false-negative results. As an example, the functional presence of cannabinoid type 1 (CB1) receptors on brain mitochondrial membranes (mtCB1) was recently reported and rapidly challenged, claiming that the original observation was likely due to artifact results. Here, we addressed this issue by directly comparing the procedures used in the two studies. Our results show that the use of appropriate controls and quantifications allows detecting mtCB1 receptor with CB1 receptor antibodies, and that, if mitochondrial fractions are enriched and purified, CB1 receptor agonists reliably decrease respiration in brain mitochondria. These data further underline the importance of adapted experimental procedures to study brain mitochondrial functions.
    Molecular Metabolism 07/2014; 3(4). DOI:10.1016/j.molmet.2014.03.007
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    • "Brown adipose tissue has a high mitochondrial density [8] and MnSOD mRNA was about 10-fold more abundant when compared to white fat depots with similar MnSOD mRNA levels (Fig. 1A–D). MnSOD protein was equally abundant in subcutaneous and visceral fat of mice kept on a SD (Fig. 3A, Table S2, 2.). "
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    ABSTRACT: Excess fat storage in adipocytes is associated with increased generation of reactive oxygen species (ROS) and impaired activity of antioxidant mechanisms. Manganese superoxide dismutase (MnSOD) is a mitochondrial enzyme involved in detoxification of ROS, and objective of the current study is to analyze expression and regulation of MnSOD in obesity. MnSOD is increased in visceral but not subcutaneous fat depots of rodents kept on high fat diets (HFD) and ob/ob mice. MnSOD is elevated in visceral adipocytes of fat fed mice and exposure of differentiating 3T3-L1 cells to lipopolysaccharide, IL-1α, saturated, monounsaturated and polyunsaturated free fatty acids (FFA) upregulates its level. FFA do not alter cytochrome oxidase 4 arguing against overall induction of mitochondrial enzymes. Upregulation of MnSOD in fat loaded cells is not mediated by IL-6, TNF or sterol regulatory element binding protein 2 which are induced in these cells. MnSOD is similarly abundant in perirenal fat of Zucker diabetic rats and non-diabetic animals with similar body weight and glucose has no effect on MnSOD in 3T3-L1 cells. To evaluate whether MnSOD affects adipocyte fat storage, MnSOD was knocked-down in adipocytes for the last three days of differentiation and in mature adipocytes. Knock-down of MnSOD does neither alter lipid storage nor viability of these cells. Heme oxygenase-1 which is induced upon oxidative stress is not altered while antioxidative capacity of the cells is modestly reduced. Current data show that inflammation and excess triglyceride storage raise adipocyte MnSOD which is induced in epididymal adipocytes in obesity.
    PLoS ONE 01/2014; 9(1):e86866. DOI:10.1371/journal.pone.0086866 · 3.23 Impact Factor
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