Extracellular vesicles (EVs) have emerged as a novel messaging system of the organism, mediating cell-cell and interorgan communication. Through their content of proteins and nucleic acids, as well ...as membrane proteins and lipid species, EVs can interact with and modulate the function of their target cells. The regulation of whole-body metabolism requires cross-talk between key metabolic tissues including adipose tissue (AT), the liver and skeletal muscle. Furthermore, the regulation of nutrient/energy allocation during pregnancy requires co-ordinated communication between the foetus and metabolic organs of the mother. A growing body of evidence is suggesting that EVs play a role in communication between and within key metabolic organs, both physiologically during metabolic homoeostasis but also contributing to pathophysiology during metabolic dysregulation observed in metabolic diseases such as obesity and diabetes. As obesity and its associated metabolic complications are reaching epidemic proportions, characterization of EV-mediated communication between key metabolic tissues may offer important insights into the regulation of metabolic functions during disease and offer global therapeutic opportunities. Here, we focus on the role of EVs in metabolic regulation and, in particular, EV-mediated cross-talk between cells of the AT.
This review focuses on adipose tissue biology and introduces the concept of adipose tissue plasticity and expandability as key determinants of obesity-associated metabolic dysregulation. This concept ...is fundamental to our understanding of adipose tissue as a dynamic organ at the center of nutritional adaptation. Here, we summarize the current knowledge of the mechanisms by which adipose tissue can affect peripheral energy homeostasis, particularly in the context of overnutrition. Two mechanisms emerge that provide a molecular understanding for obesity-associated insulin resistance. These are a) the dysregulation of adipose tissue expandability and b) the abnormal production of adipokines. This knowledge has the potential to pave the way for novel therapeutic concepts and strategies for managing and/or correcting complications associated with obesity and the metabolic syndrome.
Adipose tissue expands to accommodate increased lipid through hypertrophy of existing adipocytes and by initiating differentiation of preadipocytes. The capacity of adipose tissue to expand is ...critical for accommodating changes in energy availability, but this capacity is not an unlimited process and likely varies between individuals. We suggest that it is not the absolute amount of adipose tissue but rather the capacity of adipose tissue to expand that affects metabolic homeostasis. Here we highlight examples of disease states and transgenic animal models with altered adipose tissue function that support this hypothesis and discuss possible mechanisms by which altered adipose tissue expandability impairs metabolic homeostasis.
The safest place to store lipids is the white adipose tissue, but its storage capacity may become saturated resulting in excess of fat "overspilled" to non-adipose tissues. This overspill of fat ...occurs in apparently opposite pathological states such as lipodistrophy or obesity. When the excess of energy is redirected towards peripheral organs, their initial response is to facilitate the storage of the surplus in the form of triacylglycerol, but the limited triacylglycerol buffer capacity becomes saturated soon. Under these conditions excess of lipids enter alternative non-oxidative pathways that result in production of toxic reactive lipid species that induce organ-specific toxic responses leading to apoptosis. Reactive lipids can accumulate in non-adipose tissues of metabolically relevant organs such as pancreatic beta-cells, liver, heart and skeletal muscle leading to lipotoxicity, a process that contributes substantially to the pathophysiology of insulin resistance, type 2 diabetes, steatotic liver disease and heart failure. The effects of this lipotoxic insult can be minimised by several strategies: (a) decreased incorporation of energy, (b) a less orthodox approach such as increased adipose tissue expandability and/or (c) increased oxidation of fat in peripheral organs. Aging should be considered as physiological degenerative process potentially accelerated by concomitant lipotoxic insults. Conversely, the process of aging can sensitise cells to effects of lipid toxicity.
Oxidative stress and mitochondrial dysfunction are associated with disease and aging. Oxidative stress results from overproduction of reactive oxygen species (ROS), often leading to peroxidation of ...membrane phospholipids and production of reactive aldehydes, particularly 4‐hydroxy‐2‐nonenal. Mild uncoupling of oxidative phosphorylation protects by decreasing mitochondrial ROS production. We find that hydroxynonenal and structurally related compounds (such as trans‐retinoic acid, trans‐retinal and other 2‐alkenals) specifically induce uncoupling of mitochondria through the uncoupling proteins UCP1, UCP2 and UCP3 and the adenine nucleotide translocase (ANT). Hydroxynonenal‐induced uncoupling was inhibited by potent inhibitors of ANT (carboxyatractylate and bongkrekate) and UCP (GDP). The GDP‐sensitive proton conductance induced by hydroxynonenal correlated with tissue expression of UCPs, appeared in yeast mitochondria expressing UCP1 and was absent in skeletal muscle mitochondria from UCP3 knockout mice. The carboxyatractylate‐sensitive hydroxynonenal stimulation correlated with ANT content in mitochondria from Drosophila melanogaster expressing different amounts of ANT. Our findings indicate that hydroxynonenal is not merely toxic, but may be a biological signal to induce uncoupling through UCPs and ANT and thus decrease mitochondrial ROS production.
Peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1α) is a transcriptional coactivator able to up-regulate mitochondria! biogenesis, respiratory capacity, oxidative phosphorylation, ...and fatty acid β-oxidation with the final aim of providing a more efficient pathway for aerobic energy production. In the continuously renewed intestinal epithelium, proliferative cells in the crypts migrate along the villus axis and differentiate into mature enterocytes, increasing their respiratory capacity and finally undergoing apoptosis. Here we show that in the intestinal epithelial surface, PGC1α drives mitochondrial biogenesis and respiration in the presence of reduced antioxidant enzyme activities, thus determining the accumulation of reactive oxygen species and fostering the fate of enterocytes toward apoptosis. Combining gain-and loss-offunction genetic approaches in human cells and mouse models of intestinal cancer, we present an intriguing scenario whereby PGCIα regulates enterocyte cell fate and protects against tumorigenesis.
Tamoxifen-Induced Anorexia Is Associated With Fatty Acid Synthase Inhibition in the Ventromedial Nucleus of the Hypothalamus
and Accumulation of Malonyl-CoA
Miguel López 1 ,
Christopher J. Lelliott 1 ...,
Sulay Tovar 2 ,
Wendy Kimber 1 ,
Rosalía Gallego 3 ,
Sam Virtue 1 ,
Margaret Blount 1 ,
Maria J. Vázquez 2 ,
Nick Finer 1 ,
Trevor J. Powles 4 ,
Stephen O’Rahilly 1 ,
Asish K. Saha 5 ,
Carlos Diéguez 2 and
Antonio J. Vidal-Puig 1
1 Department of Clinical Biochemistry, University of Cambridge, Addenbrooke’s Hospital, Cambridge, U.K
2 Department of Physiology, School of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain
3 Department of Morphological Sciences, School of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain
4 Parkside Oncology Clinic, London, U.K
5 Diabetes Research Unit, EBRC-827, Boston Medical Centre, Boston, Massachusetts
Address correspondence and reprint requests to Antonio J. Vidal-Puig, PhD, MD, Department of Clinical Biochemistry, University
of Cambridge, Addenbrooke’s Hospital, Hills Road Cambridge, CB2 2QR, U.K. E-mail: ajv22{at}cam.ac.uk
Abstract
Fatty acid metabolism in the hypothalamus has recently been shown to regulate feeding. The selective estrogen receptor modulator
tamoxifen (TMX) exerts a potent anorectic effect. Here, we show that the anorectic effect of TMX is associated with the accumulation
of malonyl-CoA in the hypothalamus and inhibition of fatty acid synthase (FAS) expression specifically in the ventromedial
nucleus of the hypothalamus (VMN). Furthermore, we demonstrate that FAS mRNA expression is physiologically regulated by fasting
and refeeding in the VMN but not in other hypothalamic nuclei. Thus, the VMN appears to be the hypothalamic site where regulation
of FAS and feeding converge. Supporting the potential clinical relevance of these observations, reanalysis of a primary breast
cancer prevention study showed that obese women treated with TMX gained significantly less body weight over a 6-year period
than obese women given placebo. The finding that TMX can modulate appetite through alterations in FAS expression and malonyl-CoA
levels suggests a link between hypothalamic sex steroid receptors, fatty acid metabolism, and feeding behavior.
ACC, acetyl-CoA carboxylase
AMPK, AMP-activated protein kinase
ARC, arcuate nucleus of the hypothalamus
CART, cocaine- and amphetamine-regulated transcript
FAS, fatty acid synthase
LHA, lateral hypothalamic area
POMC, proopiomelanocortin
PVN, paraventricular nucleus of the hypothalamus
RMH, Royal Marsden Hospital
TMX, tamoxifen
TOFA, 5-(tetradecyloxy)-2-furoic acid
VMN, ventromedial nucleus of the hypothalamus
Footnotes
M.L. and C.J.L. contributed equally to this work.
Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org .
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted February 1, 2006.
Received October 18, 2005.
DIABETES
Energy Metabolism in Uncoupling Protein 3 Gene Knockout Mice Vidal-Puig, Antonio J.; Grujic, Danica; Zhang, Chen-Yu ...
Journal of biological chemistry/The Journal of biological chemistry,
05/2000, Letnik:
275, Številka:
21
Journal Article
Recenzirano
Odprti dostop
Uncoupling protein 3 (UCP3) is a member of the mitochondrial anion carrier superfamily. Based upon its high homology with UCP1 and its restricted tissue distribution to skeletal muscle and brown ...adipose tissue, UCP3 has been suggested to play important roles in regulating energy expenditure, body weight, and thermoregulation. Other postulated roles for UCP3 include regulation of fatty acid metabolism, adaptive responses to acute exercise and starvation, and prevention of reactive oxygen species (ROS) formation. To address these questions, we have generated mice lacking UCP3 (UCP3 knockout (KO) mice). Here, we provide evidence that skeletal muscle mitochondria lacking UCP3 are more coupled (i.e. increased state 3/state 4 ratio), indicating that UCP3 has uncoupling activity. In addition, production of ROS is increased in mitochondria lacking UCP3. This study demonstrates that UCP3 has uncoupling activity and that its absence may lead to increased production of ROS. Despite these effects on mitochondrial function, UCP3 does not seem to be required for body weight regulation, exercise tolerance, fatty acid oxidation, or cold-induced thermogenesis. The absence of such phenotypes in UCP3 KO mice could not be attributed to up-regulation of other UCP mRNAs. However, alternative compensatory mechanisms cannot be excluded. The consequence of increased mitochondrial coupling in UCP3 KO mice on metabolism and the possible role of yet unidentified compensatory mechanisms, remains to be determined.
Dact1 , a Nutritionally Regulated Preadipocyte Gene, Controls Adipogenesis by Coordinating the Wnt/β-Catenin Signaling Network
Claire Lagathu 1 ,
Constantinos Christodoulides 1 ,
Sam Virtue 1 ,
...William P. Cawthorn 1 ,
Chiara Franzin 1 ,
Wendy A. Kimber 1 ,
Edoardo Dalla Nora 1 ,
Mark Campbell 1 ,
Gema Medina-Gomez 1 ,
Benjamin N.R. Cheyette 2 ,
Antonio J. Vidal-Puig 1 and
Jaswinder K. Sethi 1
1 Institute of Metabolic Science–Metabolic Research Laboratories and Department of Clinical Biochemistry, University of Cambridge,
Addenbrooke's Hospital, Cambridge, U.K
2 Department of Psychiatry and Graduate Programs in Developmental Biology and Neuroscience, University of California, San Francisco,
California
Corresponding author: Jaswinder K. Sethi, jks30{at}cam.ac.uk , or Antonio J. Vidal-Puig, ajv22{at}cam.ac.uk
Abstract
OBJECTIVE— Wnt signaling inhibits adipogenesis, but its regulation, physiological relevance, and molecular effectors are poorly understood.
Here, we identify the Wnt modulator Dapper1/Frodo1 ( Dact1 ) as a new preadipocyte gene involved in the regulation of murine and human adipogenesis.
RESEARCH DESIGN AND METHODS— Changes in Dact1 expression were investigated in three in vitro models of adipogenesis. In vitro gain- and loss-of-function studies were used
to investigate the mechanism of Dact1 action during adipogenesis. The in vivo regulation of Dact1 and Wnt/β-catenin signaling were investigated in murine models of altered nutritional status, of pharmacological stimulation
of in vivo adipogenesis, and during the development of dietary and genetic obesity.
RESULTS— Dact1 is a preadipocyte gene that decreases during adipogenesis. However, Dact1 knockdown impairs adipogenesis through activation
of the Wnt/β-catenin signaling pathway, and this is reversed by treatment with the secreted Wnt antagonist, secreted Frizzled-related
protein 1 (Sfrp1). In contrast, constitutive Dact1 overexpression promotes adipogenesis and confers resistance to Wnt ligand-induced
antiadipogenesis through increased expression of endogenous Sfrps and reduced expression of Wnts. In vivo, in white adipose
tissue, Dact1 and Wnt/β-catenin signaling also exhibit coordinated expression profiles in response to altered nutritional status, in response
to pharmacological stimulation of in vivo adipogenesis, and during the development of dietary and genetic obesity.
CONCLUSIONS— Dact1 regulates adipogenesis through coordinated effects on gene expression that selectively alter intracellular and paracrine/autocrine
components of the Wnt/β-catenin signaling pathway. These novel insights into the molecular mechanisms controlling adipose
tissue plasticity provide a functional network with therapeutic potential against diseases, such as obesity and associated
metabolic disorders.
Footnotes
C.C. is currently affiliated with the Department of Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, U.K.
Published ahead of print at http://diabetes.diabetesjournals.org on 10 December 2008.
C.L. and C.C. contributed equally to this work
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted November 26, 2008.
Received August 27, 2008.
DIABETES
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