Mitochondrial endocrinology Mitochondria as key to hormones and metabolism
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. Petersen, K.F., Dufour, S., Befroy, D., Garcia, R., Shulman, G.I., 2004. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N. Engl. J. Med. 350, 664–671 . Phielix, E., Meex, R., Moonen-Kornips, E., Hesselink, M.K., Schrauwen, P., 2010. Exercise training increases mitochondrial content and ex vivo mitochondrial function similarly in patients with type 2 diabetes and in control individuals. Diabetologia 53, 1714–1721 . Picard, M., Ritchie, D., Wright, K.J., Romestaing, C., Thomas, M.M., Rowan, S.L., Taivassalo, T., Hepple, R.T., 2010. Mitochondrial functional impairment with aging is exaggerated in isolated mitochondria compared to permeabilized myofibers. Aging Cell 9, 1032–1046 . Picard, M., Taivassalo, T., Ritchie, D., Wright, K.J., Thomas, M.M., Romestaing, C., Hepple, R.T., 2011. Mitochondrial structure and function are disrupted by standard isolation methods. PLoS ONE 6, e18317 . Pruchnic, R., Katsiaras, A., He, J., Kelley, D.E., Winters, C., Goodpaster, B.H., 2004. Exercise training increases intramyocellular lipid and oxidative capacity in older adults. Am. J. Physiol. Endocrinol. Metab. 287, E857–E862 . Randle, P.J., Garland, P.B., Hales, C.N., Newsholme, E.A., 1963. The glucose fatty acid cycle: its role in insulin sensitivity and the metabolic didturbances of diabetes mellitus. Lancet 1, 785–789 . Reznick, R.M., Zong, H., Li, J., Morino, K., Moore, I.K., Yu, H.J., Liu, Z.X., Dong, J., Mustard, K.J., Hawley, S.A., Befroy, D., Pypaert, M., Hardie, D.G., Young, L.H., Shulman, G.I., 2007. Aging-associated reductions in AMP-activated protein kinase activity and mitochondrial biogenesis. Cell Metab. 5, 151–156 . Rimbert, V., Boirie, Y., Bedu, M., Hocquette, J.-F., Ritz, P., Morio, B., 2004. Muscle fat oxidative capacity is not impaired by age but by physical inactivity: association with insulin sensitivity. FASEB J. 18, 737–739 . Romanello, V., Guadagnin, E., Gomes, L., Roder, I., Sandri, C., Petersen, Y., Milan, G., Masiero, E., Del Piccolo, P., Foretz, M., Scorrano, L., Rudolf, R., Sandri, M., 2010. Mitochondrial fission and remodelling contributes to muscle atrophy. EMBO J. 29, 1774–1785 . Short, K.R., Vittone, J.L., Bigelow, M.L., Proctor, D.N., Rizza, R.A., Coenen-Schimke, J.M., Nair, K.S., 2003. Impact of aerobic exercise training on age-related changes in insulin sensitivity and muscle oxidative capacity. Diabetes 52, 1888–1896 . Simoneau, J.A., Veerkamp, J.H., Turcotte, L.P., Kelley, D.E., 1999. Markers of capacity to utilize fatty acids in human skeletal muscle: relation to insulin resistance and obesity and effects of weight loss. FASEB J. 13, 2051–2060 . Stump, C.S., Short, K.R., Bigelow, M.L., Schimke, J.M., Nair, K.S., 2003. Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts. Proc. Natl. Acad. Sci. USA 100, 7996–8001 . Toledo, F.G., Watkins, S., Kelley, D.E., 2006. Changes induced by physical activity and weight loss in the morphology of intermyofibrillar mitochondria in obese men and women. J. Clin. Endocrinol. Metab. 91, 3224–3227 . Toledo, F.G., Menshikova, E.V., Ritov, V.B., Azuma, K., Radikova, Z., DeLany, J., Kelley, D.E., 2007. Effects of physical activity and weight loss on skeletal muscle mitochondria and relationship with glucose control in type 2 diabetes. Diabetes 56, 2142–2147 . Toledo, F.G., Menshikova, E.V., Azuma, K., Radikova, Z., Kelley, C.A., Ritov, V.B., Kelley, D.E., 2008. Mitochondrial capacity in skeletal muscle is not stimulated by weight loss despite increases in insulin action and decreases in intramyocellular lipid content. Diabetes 57, 987–994 . Toledo, F.G.S., Menshikova, E.V., Azuma, K., Radikova, Z., Kelley, C.A., Ritov, V.B., Kelley, D.E., 2008. Mitochondrial capacity in skeletal muscle is not stimulated by weight loss despite increases in insulin action and decreases in intramyocellular lipid content. Diabetes 57, 987–994 . Tonkonogi, M., Harris, B., Sahlin, K., 1997. Increased activity of citrate synthase in human skeletal muscle after a single bout of prolonged exercise. Acta Physiol. Scand. 161, 435–436 . Waters, D.L., Brooks, W.M., Qualls, C.R., Baumgartner, R.N., 2003. Skeletal muscle mitochondrial function and lean body mass in healthy exercising elderly. Mech. Ageing Dev. 124, 301–309 . Wenz, T., Rossi, S.G., Rotundo, R.L., Spiegelman, B.M., Moraes, C.T., 2009. Increased muscle PGC-1alpha expression protects from sarcopenia and metabolic disease during aging. Proc. Natl. Acad. Sci. USA 106, 20405–20410 . 34
Review Hepatic energy metabolism in human diabetes mellitus, obesity and non-alcoholic fatty liver disease Chrysi Koliaki a , Michael Roden a , b , ⇑ a Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany b Division of Endocrinology and Diabetology and Metabolic Diseases, University Clinics Düsseldorf, Düsseldorf, Germany a r t i c l e i n f o Article history: Available online 12 June 2013 Keywords: Mitochondrion Steatosis Non-alcoholic steatohepatitis (NASH) Lipotoxicity a b s t r a c t Alterations of hepatic mitochondrial function have been observed in states of insulin resistance and non- alcoholic fatty liver disease (NAFLD). Patients with overt type 2 diabetes mellitus (T2DM) can exhibit reduction in hepatic adenosine triphosphate (ATP) synthesis and impaired repletion of their hepatic ATP stores upon ATP depletion by fructose. Obesity and NAFLD may also associate with impaired ATP recovery after ATP-depleting challenges and augmented oxidative stress in the liver. On the other hand, patients with obesity or NAFLD can present with upregulated hepatic anaplerotic and oxidative fluxes, including b-oxidation and tricarboxylic cycle activity. The present review focuses on the methods and data on hepatic energy metabolism in various states of human insulin resistance. We propose that the liver can adapt to increased lipid exposition by greater lipid storing and oxidative capacity, resulting in increased oxidative stress, which in turn could deteriorate hepatic mitochondrial function in chronic insulin resistance and NAFLD. Ó 2013 Elsevier Ireland Ltd. All rights reserved. Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 2. Literature search. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 3. Assessment of hepatic energy metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 3.1. In vitro methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 3.2. In vivo methods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 3.3. Ex vivo methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 4. The physiological role of liver energy metabolism and mitochondrial function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 5. Liver mitochondrial function in healthy humans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 6. Liver mitochondrial function in T2DM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 7. Liver mitochondrial function in obesity and steatosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 8. Liver mitochondrial function in advanced NAFLD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 9. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 1. Introduction Non-alcoholic fatty liver disease (NAFLD) comprises a broad spectrum of chronic liver diseases, ranging from uncomplicated hepatic steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, and finally liver cirrhosis and hepatocellular carcinoma ( Angulo,
2002; Smith and Adams, 2011 ). Hepatic steatosis is defined as intrahepatic fat content above 5.5% ( Browning et al., 2004; Roden, 2006 ) and represents a clinical finding typically coexisting with obesity, while NASH and other forms of advanced NAFLD are char- acterized by histological signs of inflammation and fibrosis ( Roden, 2006; Smith and Adams, 2011 ). As liver biopsies are not routinely performed, only rough estimates of the prevalence of NAFLD are 0303-7207/$ - see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mce.2013.06.002 ⇑ Corresponding author. Address: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Auf’m Hennekamp 65, 40225 Düsseldorf, Germany. Tel.: +49 211 3382 201. E-mail addresses: Chryssi.Koliaki@ddz.uni-duesseldorf.de (C. Koliaki), Michael.- Roden@ddz.uni-duesseldorf.de (M. Roden). Molecular and Cellular Endocrinology 379 (2013) 35–42 Contents lists available at SciVerse ScienceDirect Molecular and Cellular Endocrinology j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / m c e
available, which range from 3% to 30%, with NASH being present in approximately one third of all cases ( Clark, 2006; Smith and Adams, 2011 ). Even higher estimates are suggested for insulin resistant cohorts such as patients with type 2 diabetes mellitus (T2DM) or severe obesity, suggesting that these entities and NAFLD share common pathogenic mechanisms ( Roden, 2006 ). NAFLD re- sults from the dynamic interplay of increased lipid influx into the liver, increased de novo hepatic lipogenesis and defective lipid uti- lization, which will stimulate hepatic lipid accumulation. Chronic dietary overload with fructose and saturated fatty acids, will also enhance accumulation of lipid metabolites along with oxidative and endoplasmic reticulum stress and release of cytokines, and thereby foster NAFLD progression ( Krebs and Roden, 2004; Roden, 2006; Smith and Adams, 2011 ). Insulin resistance is tightly associated with ectopic fat accumu- lation in peripheral tissues, including skeletal muscle and liver as the most important sites ( Roden, 2005; Szendroedi and Roden, 2009
). For skeletal muscle, increased intramyocellular fat content, specifically increased lipid availability, promotes insulin resistance through several mechanisms including diacylglycerol (DAG) acti- vation of novel protein kinase C (PKC) isoforms, leading to im- paired insulin-stimulated glucose transport and muscle glycogen synthesis ( Roden, 2004 ). Insulin resistant humans such as patients with T2DM and first-degree relatives of T2DM patients, may fur- ther show impaired mitochondrial function in muscle, character- ized by lower flux through adenosine triphosphate (ATP) synthase under basal and insulin-stimulated conditions ( Petersen et al., 2005; Szendroedi et al., 2007 ). These abnormalities have been mainly attributed to decreased mitochondrial content rather than to an inherent impairment of mitochondrial functionality ( Boushel et al., 2007; Morino et al., 2005 ). Whether impaired mito- chondrial function is causally associated with insulin resistance and how intramyocellular lipids modulate mitochondrial substrate oxidation remains a matter of debate, because recent data support a dissociation of muscle mitochondrial function from insulin sensi- tivity (
Asmann et al., 2006; Boushel et al., 2007; De Feyter et al., 2008; Holloszy, 2009 ). Elevated hepatocellular lipid content can promote hepatic insu- lin resistance in the setting of NAFLD, through mechanisms similar to those involved in lipid-induced muscle insulin resistance, such as hepatic accumulation of DAG and DAG-induced activation of PKC
e ( Jornayvaz and Shulman, 2012; Kumashiro et al., 2011; Sam- uel et al., 2004 ). Although alterations in mitochondrial function could contribute to hepatic insulin resistance and NAFLD, the exact nature of this relationship remains a hot topic of metabolic re- search. Recent data from both humans and animal models showed either decreased, unchanged or even increased hepatic mitochon- drial function and oxidative phosphorylation capacity in insulin resistant states such as T2DM, obesity and NAFLD ( Lockman and Nyirenda, 2010; Vial et al., 2010 ). It cannot be precluded that tis- sue-specific differences exist in the association between mitochon- drial function and insulin resistance or intracellular lipid content, but this requires confirmation by adequately controlled human studies, examining both liver and muscle mitochondrial function in these metabolic states. The present review aims to provide a concise update of the available data on hepatic energy metabolism in several phenotypes of insulin resistance (T2DM, obesity, NAFLD), and analyzes patho- genetic concepts possibly underlying alterations of energy homeo- stasis in human liver. 2. Literature search The PubMed electronic database was searched repeatedly over three months for all types of articles published in English language until January 2013, using the following search terms: ‘‘hepatic en- ergy metabolism and insulin resistance’’, ‘‘hepatic energy metabo- lism and NAFLD’’, ‘‘hepatic energy metabolism and T2DM’’, ‘‘hepatic energy metabolism and obesity’’, ‘‘hepatic energy metab- olism and liver steatosis’’, ‘‘hepatic mitochondrial function and insulin resistance’’, ‘‘hepatic mitochondrial function and NAFLD’’. Full-text articles and reference lists of selected review papers were critically reviewed. Our literature search strategy was restricted to studies in humans, but a limited number of mechanistic studies using animal models of insulin resistance and NAFLD were also re- viewed and are briefly discussed herein. 3. Assessment of hepatic energy metabolism Liver mitochondrial function can be evaluated directly or indi- rectly by in vitro, in vivo and ex vivo techniques. 3.1. In vitro methods The in vitro methods include measurements of mitochondrial mass and functionality in biopsy-derived liver samples. They com- prise mitochondrial membrane potential and proton leak kinetics, assessment of mitochondrial content by ultrastructural observa- tions, citrate synthase activity and ratio of mitochondrial relative to nuclear DNA, polarographic determination of oxygen consump- tion rates, enzyme activities of mitochondrial respiratory com- plexes I–V, markers of oxidative stress such as mitochondrial production of superoxide anion and lipid peroxidation products, and anti-oxidant capacity such as superoxide dismutase specific activity and reduced to oxidized glutathione ratio ( Bouderba et al., 2012; García-Ruiz et al., 1995; Pérez-Carreras et al., 2003; Raffaella et al., 2008; Vendemiale et al., 2001; Vial et al., 2011 ). 3.2. In vivo methods Most studies assessed hepatic energy metabolism in vivo by using non-invasive, phosphorous magnetic resonance spectros- copy ( 31
thesis in human liver ( Bourdel-Marchasson et al., 1996; Chmelík et al., 2008; Cortez-Pinto et al., 1999; Nair et al., 2003; Schmid et al., 2008; Sharma et al., 2009; Szendroedi et al., 2009 ). 31
MRS allows for quantification of hepatic phosphorous metabolites such as gamma nucleotide triphosphate ( c -NTP), alpha NTP ( a - NTP), beta NTP (b-NTP), inorganic phosphate (Pi), phosphomono- esters and phosphodiesters. Fig. 1
depicts a typical liver 31 P MRS spectrum of one healthy subject with all the peaks corresponding to hepatocellular phosphorous metabolites that are resolved with this technique. This technique can now be also applied on clinical scanners ( Laufs et al., 2013 ). High resolution three dimensional (3D) magnetic spectroscopy imaging is the most recent develop- ment providing absolute concentrations of phosphorus com- pounds, corrected for hepatocellular fat content, as well as their regional distribution within the liver ( Chmelík et al., 2008 ). 31 P MRS can also allow for assessing hepatic ATP synthesis, yielding a direct estimate of the unidirectional flux through ATP synthase ( Schmid et al., 2008 ). Intravenous fructose challenge with monitor- ing of the degree of ATP depletion and the extent of ATP recovery yields a measure of the flexibility of hepatic energy homeostasis ( Abdelmalek et al., 2012 ). Fructose induces transient decrease of hepatic ATP as a result of its rapid phosphorylation by fructokinase after entering hepatocytes. Since hepatic fructose metabolism also causes a rapid intracellular uric acid elevation, serum uric acid con- centrations have been proposed as a surrogate marker of hepatic ATP repletion upon ATP-depleting challenges ( Abdelmalek et al., 2012
). Another non-invasive molecular imaging tool is positron emission tomography (PET) combined with intravenous adminis- 36 C. Koliaki, M. Roden / Molecular and Cellular Endocrinology 379 (2013) 35–42 tration of lipid radiotracers such as 18-fluoro-6-thia-heptadeca- noic acid and 11 C-palmitate, which enables the quantification of hepatic fatty acid uptake, oxidation and esterification ( Iozzo
et al., 2010; Viljanen et al., 2009 ). Additional in vivo methods in- clude stable isotope tracer techniques, such as the oral administra- tion of [U- 13 C]propionate and deuterated water ( 2 H 2 O), and the intravenous infusion of [3,4- 13 C
]glucose, [1,2- 13 C 2 ]b-hydroxybu- tyrate, [3,4- 13 C 2 ]acetoacetate and [ 13 C
]palmitate, which help pro- file hepatic glucose and mitochondrial metabolism and assess various systemic and hepatic pathways including lipolysis, gluco- neogenesis, tricarboxylic acid cycle function (TCA), non-oxidative pathways replenishing TCA cycle intermediates (anaplerosis) and ketogenesis ( Sunny et al., 2011 ). Stable isotopes, such as 13 C-octa-
noate, 13 C-methionine and 13 C-ketoisocaproate, have been also ap- plied in non-invasive carbon-labeled breath tests, to assess hepatic mitochondrial b-oxidation and the severity of NAFLD, by measur- ing the cumulative percentage of isotope exhalation or the 13 CO 2 enrichment in exhaled air ( Banasch et al., 2011; Miele et al., 2003; Portincasa et al., 2006 ). Finally, plasma concentrations of 3-hydroxybutyrate have been used as a simple and less informa- tive, but organ-specific biochemical surrogate marker of hepatic li- pid oxidation ( Kotronen et al., 2009 ). 3.3. Ex vivo methods High resolution respirometry by oxygraphs has been frequently applied to skeletal muscle, but could also be performed in liver tis- sue and isolated mitochondria. This method will provide useful information on coupled and uncoupled maximal respiratory capac- ity of liver tissue or hepatic mitochondria after addition of various mitochondrial substrates such as octanoyl-coenzyme A, malate, pyruvate, glutamate, succinate. To our knowledge, there are no published data with this technique in humans so far, but prelimin- ary data in mice are promising and lay the ground for applying high resolution respirometry to quantify human liver mitochon- drial function in several disease states ( Benard et al., 2006; Kozlov et al., 2006; Kuznetsov et al., 2002 ). 4. The physiological role of liver energy metabolism and mitochondrial function The human liver plays a critical role in regulating glucose and lipid metabolism and whole-body energy homeostasis. Liver main- tains blood glucose within a narrow concentration range, by its ability to store glucose as glycogen and produce glucose after either glycogen breakdown (glycogenolysis) or de novo glucose production from gluconeogenic precursors (gluconeogenesis) ( Ro-
den and Bernroider, 2003 ). In healthy humans, hepatic glycogenol- ysis and gluconeogenesis are stimulated in the fasted state and immediately inhibited in the postprandial state as a result of rapid insulin action ( Tappy, 1995 ). On the contrary, patients with T2DM exhibit reduced postprandial hepatic glycogen synthesis and in- creased hepatic glucose output in both fasting and postprandial conditions, mainly driven by enhanced hepatic gluconeogenesis ( Krssak et al., 2004 ). The rise in the portal glucagon:insulin ratio and the increased hepatic free fatty acid oxidation are held mainly responsible for enhanced gluconeogenesis in T2DM ( Roden and Bernroider, 2003 ). Liver mitochondria represent the major orchestrator of hepato- cellular energy metabolism, since they are the site of fatty acid oxi- dation and ATP synthesis ( Pessayre et al., 2002 ). Three different sources contribute to the hepatic levels of free fatty acids: de novo lipogenesis within hepatocytes from acetyl-CoA, uptake of circulat- ing plasma free fatty acids released by adipose tissue with lipolysis and hydrolysis of intestinal chylomicrons ( McGarry and Foster, 1980
). Hepatic free fatty acids can either enter mitochondria to un- dergo b-oxidation or be esterified into triglycerides. Hepatic tri- glycerides in turn either accumulate within hepatocytes as cytoplasmic lipid droplets, or are secreted as very low density lipo- protein (VLDL) particles into blood circulation ( Lavoie and Gauthi- er, 2006; McGarry and Foster, 1980; Nguyen et al., 2008; Pessayre et al., 2001 ). The entry of long-chain free fatty acids into hepatic mitochondria is regulated by carnitine palmitoyl-transferase type I (CPT-I), which is located in the outer mitochondrial membrane and sensitive to inhibition by malonyl-CoA, the first substrate of hepatic de novo lipogenesis ( Pessayre et al., 2001 ). Successive cy- cles of b-oxidation split hepatic free fatty acids into subunits of acetyl-CoA, which are either completely degraded to carbon diox- ide in the TCA (or Krebs) cycle, or condensed to ketone bodies (ketogenesis), which are then secreted by hepatic cells into circula- tion (
Lavoie and Gauthier, 2006 ). Fatty acid oxidation in hepatic mitochondria is associated with the reduction of oxidized coen- zymes, which are in turn re-oxidized by the mitochondrial respira- tory chain ( Pessayre et al., 2002, 2001 ). During their re-oxidation, they transfer their electrons to the polypeptide complexes of the mitochondrial respiratory chain. The electron transfer along the respiratory chain is coupled with an export of protons from Fig. 1. Liver 31 P MRS spectrum of a representative healthy person obtained with the 3-Tesla whole-body magnetic resonance spectrometer (Philips Achieva, Best, The Netherlands) at the German Diabetes Center, Düsseldorf, Germany. The eleven peaks correspond to the phosphorous metabolites of liver cells. Upper right panel: transversal image with a voxel of interest (VOI) placement, using a 14 cm linear polarized surface coil, positioned over the lateral aspect of liver. ppm: parts per million; NTP: triphosphate nucleoside; NADPH: nicotinamide adenine dinucleotide phosphate; UDPG: uridine diphosphoglucose; PEP: phosphoenol-pyruvate; GPC: glycerol phospho- choline; GPE: glycerol phosphoethanolamine; Pi: inorganic phosphate; PC: phosphocholine; PE: phosphoethanolamine Phosphomonoesters (PME) include PE and PC, phosphodiesters (PDE) include GPE and GPC. C. Koliaki, M. Roden / Molecular and Cellular Endocrinology 379 (2013) 35–42 37
mitochondrial matrix to intermembrane space, creating a large electrochemical gradient across the inner mitochondrial mem- brane, which acts as an energy reservoir. When energy is needed, protons can re-enter matrix through ATP synthase (complex V), causing the conversion of adenosine diphosphate (ADP) into ATP. The adenine dinucleotide translocator proteins can then export mitochondrial ATP in exchange for cytosolic ADP, and the cytoplas- mic ATP can be used to power all hepatocellular energy-requiring metabolic processes ( Pessayre et al., 2002, 2001 ). 5. Liver mitochondrial function in healthy humans Despite the limited data on the normal range of mitochondrial function in human liver, some information can be derived from clinical studies, which have compared direct or indirect measures of hepatic mitochondrial function between insulin resistant and insulin sensitive humans. Table 1
summarizes the key data of these studies, while Fig. 2 depicts in a graphical way the percentage dif- ferences of liver mitochondrial function between healthy humans and several insulin resistant phenotypes. Employing 31 P MRS to assess liver ATP turnover revealed that young healthy humans display hepatic concentrations of c -ATP Table 1 Studies in humans on hepatic energy metabolism under conditions of type 2 diabetes mellitus (T2DM), insulin resistance and non-alcoholic fatty liver disease (NAFLD). Reference Cohort
Methods Results
Szendroedi et al. (2009) 9 T2DM
in vivo 31 P-MRS ; c ATP and Pi contents 9 matched a controls in T2DM 9 young lean controls Schmid et al. (2011) 9 T2DM
in vivo 31 P MRS ;flux through ATP synthase 8 matched a controls
in T2DM Abdelmalek et al. (2012) 25 obese T2DM in vivo
31 P MRS
;ATP recovery with high or low fructose consumption fructose challenge in high fructose consumers Nair et al. (2003) 7 overweight in vivo
31 P MRS
;ATP content 7 obese
fructose challenge in overweight and obese 5 lean controls unchanged ATP recovery Viljanen et al. (2009) 34 healthy obese 18-fluoro-6-thia- ;hepatic fatty acid uptake heptadecanoic acid PET imaging
after VLCD for 6 weeks Iozzo et al. (2010) 8 obese 11
"hepatic fatty acid oxidation 7 lean controls in obese Kotronen et al. (2009) 29 NAFLD plasma levels of no differences in hepatic lipid oxidation 29 controls 3-OHB Sharma et al. (2009) 20 obese + NAFLD in vivo
31 P MRS
"PME/Pi and PME/ c ATP ratios 20 non-obese + NAFLD in obese + NAFLD 20 non-obese -NAFLD Sunny et al. (2011) 8 high HCL in vivo
stable isotope tracers "TCA cycle, anaplerosis, lipolysis and gluconeogenesis 8 low HCL in high HCL Cortez-Pinto et al. (1999) 8 NASH
in vivo 31 P MRS ;ATP recovery 7 controls fructose challenge in NASH
Sanyal et al. (2001) 6-10 NASH in vitro hepatic
"ß-oxidation and ox. stress 6 steatosis lipid peroxidation in NASH and steatosis 6 controls serum b-OHB mitochondrial defects in NASH Miele et al. (2003) 10 NASH 13
"hepatic mitochondrial 20 controls ß-oxidation in NASH Pérez-Carreras et al. (2003) 43 NASH
in vitro ETC
;activity of ETC CI-V correlation with insulin resistance and inflammation 16 controls enzyme activity Serviddio et al. (2008b) 10 NASH
in vitro proton leak, "UCP-2, proton leak and oxidative stress 8 controls UCP-2 expression, ROS production, ATP content ATP: adenosine triphosphate; ß-OHB: ß-hydroxybutyrate; 3-OHB: 3-hydroxybutyrate; CI-V: complexes I–V; ETC: electron transport chain; HCL: hepatocellular lipids; 31 P
inorganic phosphate; PME: phosphomonoesters; ROS: reactive oxygen species; TCA: tricarboxylic acid cycle; T2DM: type 2 diabetes mellitus; UCP-2: uncoupling protein 2; VLCD: very low calorie diet. A Matched for age and body mass index. Fig. 2. Hypothetical changes in hepatic energy metabolism in states of obesity, steatosis, non-alcoholic steatohepatitis (NASH) and type 2 diabetes mellitus (T2DM). Different features of hepatic energy metabolism such as ATP, b-oxidation and respiratory complex activities were obtained from studies including healthy control groups. The respective percent changes are compared to the data of the respective healthy control group, which were set as 100%. Data are derived from the following references: Cortez-Pinto et al. (1999); Iozzo et al. (2010); Miele et al. (2003); Pérez-Carreras et al. (2003); Schmid et al. (2011); Sunny et al. (2011); Szendroedi et al. (2009) . 38
ranging from 2.0 to 2.6 mmol/l and hepatic Pi levels ranging from 1.2 to 1.7 mmol/l ( Szendroedi et al., 2009 ). Elderly non-diabetic, but slightly insulin resistant humans, display absolute c -ATP levels in the range of 1.9–3.1 mmol/l, Pi concentrations in the range of 1– 1.9 mmol/l and flux through ATP synthase in the range of 15– 41 mmol/l/min ( Schmid et al., 2011; Szendroedi et al., 2009 ). Com- bining
31 P MRS with an ATP-depleting fructose challenge identified that in healthy subjects, hepatic b-ATP levels fall by 50% to their nadir at 12 min, and recover fully at 60 min after fructose adminis- tration ( Cortez-Pinto et al., 1999 ). Furthermore, enzyme activities of mitochondrial respiratory chain proteins have been measured in biopsy-derived liver speci- mens obtained from healthy humans. Relative to citrate synthase activity, complex I activity was found to range between 30 and 43 nmol/min/mg protein, complex II activity between 28 and 46 nmol/min/mg protein, complex III activity between 38 and 60 nmol/min/mg protein, complex IV activity between 24 and 46 nmol/min/mg protein, and complex V activity between 99 and 167 nmol/min/mg protein ( Pérez-Carreras et al., 2003 ). In the same study, citrate synthase specific activity, reflecting mitochondrial protein mass, was found to range between 112 and 168 nmol/ min/mg protein in healthy controls. Measuring biochemical surrogates of hepatic lipid oxidation re- vealed that fasting b-hydroxybutyrate levels range between 81 and 99 l mol/l and are suppressed by 50% under conditions of hyperin- sulinemia in healthy humans ( Sanyal et al., 2001 ). Furthermore, it has been shown that hepatic fatty acid oxidation accounts for 40% of liver fat uptake and fatty acid esterification for 60%, as assessed with 11
( Iozzo et al., 2010 ). Of note, the rates of ATP synthesis in human liver are approxi- mately 50% lower than those in isolated perfused rat liver, indicat- ing species-specific differences in hepatic energy metabolism under normal conditions ( Schmid et al., 2008 ). 6. Liver mitochondrial function in T2DM Only recently, two studies reported that patients with T2DM have lower hepatic ATP turnover measured by 31 P MRS, when com- pared with age- and BMI-matched non-diabetic subjects ( Schmid
et al., 2011; Szendroedi et al., 2009 ) and young lean controls ( Szendroedi et al., 2009 ) ( Table 1
). In detail, the absolute hepatic concentrations of c -ATP and Pi were 23–26% and 28–31% lower in T2DM ( Szendroedi et al., 2009 ) ( Fig. 2
). Furthermore, c -ATP and Pi absolute concentrations were negatively correlated with insulin-mediated endogenous glucose production (r = À0.67, p = 0.01), even after adjusting for hepatocellular fat content, but they were not significantly associated with peripheral insulin sen- sitivity (M-value) ( Szendroedi et al., 2009 ). Endogenous glucose production was the only significant independent predictor of c - ATP levels, explaining 57% of variance of hepatic ATP concentra- tions (
Szendroedi et al., 2009 ). A similar group of T2DM patients featured a 42% reduction in the hepatic flux through ATP synthase, which was mainly driven by decreased hepatic Pi levels ( Schmid et al., 2011 ). In this study, flux through ATP synthase was positively correlated with both peripheral and hepatic insulin sensitivity (r = 0.66–0.72, p < 0.05), independently of hepatic lipid content, and was negatively correlated with waist circumference and BMI (r = À0.52 to À0.81, p 0:001). Although the cohort of T2DM pa- tients displayed adequate glycemic control under oral glucose low- ering treatment, hepatic flux through ATP synthase correlated negatively with measures of short- and long-term glycemic control such as fasting glucose and glycosylated hemoglobin. This indi- cates that even minor degree of hyperglycemia for long time peri- ods might impair hepatic mitochondrial function ( Schmid et al., 2011 ).
severely deplete hepatic ATP stores and impair ATP re-synthesis after intravenous fructose challenge in obese patients with T2DM ( Abdelmalek et al., 2012 ) ( Table 1
). This was particularly true for patients with serum uric acid concentrations of 5.5 mg/dl or more. This study suggests that high dietary fructose intake could contrib- ute to the worsening of abnormal hepatic energy homeostasis in T2DM patients, and may further predispose them to the develop- ment and/or progression of NAFLD ( Abdelmalek et al., 2010; Ouy- ang et al., 2008 ). Studies in animal models of T2DM such as the diabetes-prone Psammomys obesus model, are in the same direction with the clin- ical studies, showing an impaired hepatic energy metabolism in rat liver tissue after a hypercaloric diabetogenic diet ( Bouderba et al., 2012 ). In this rat model, liver mitochondrial function was assessed with respirometry in isolated mitochondria and respiratory com- plex enzyme activities, and was found to be significantly declined in diabetic animals. In conclusion, patients with T2DM display lower hepatic energy metabolism compared to both young and elderly non-diabetic hu- mans, which is expressed as reduced hepatic flux through ATP syn- thase and reduced hepatic ATP and Pi concentrations. Of note, parameters of hepatic mitochondrial metabolism other than hepa- tic ATP homeostasis have not yet been evaluated in T2DM patients. 7. Liver mitochondrial function in obesity and steatosis Similar to T2DM, some studies found that overweight and obese humans have lower hepatic ATP levels compared to normal-weight humans ( Table 1
). Hepatic ATP content related inversely to BMI not only in the obese, but also in normal-weight subjects ( Cortez-Pinto et al., 1999; Nair et al., 2003 ). However, obese persons can feature impaired ( Cortez-Pinto et al., 1999 ) or normal ( Nair et al., 2003 ) repletion of hepatic ATP upon fructose challenging. Of note, liver mitochondria of rats with high fat diet-induced obesity and insulin resistance exhibit an elevated rate of b-oxidation and TCA cycle activity, which is however combined with an impaired respiratory capacity and greater oxidative stress ( Raffaella et al., 2008; Satapati et al., 2012 ). Hepatic fatty acid oxidation measured by 11 C-palmitate com- bined with PET imaging is 50% higher ( Fig. 2
), while fatty acid up- take and esterification are not different in obese compared to lean persons ( Iozzo et al., 2010 ). Another PET study found that a very low calorie diet decreases by 26% hepatic fatty acid uptake and ameliorates hepatic insulin resistance in healthy obese persons ( Viljanen et al., 2009 ), without however providing any data about other aspects of hepatic mitochondrial metabolism such as mito- chondrial respiration or fat oxidation. A very frequent comorbidity of obesity is liver steatosis, since 60–90% of persons with steatosis (based on liver biopsies) are over- weight or obese ( Choudhury and Sanyal, 2004 ). Considering that there are only limited data for obese humans, the few studies con- ducted in steatotic humans complement those in obese, and shed more light into the association of obesity with liver mitochondrial function. From plasma 3-hydroxybutyrate concentrations, hepatic lipid oxidation was rated similar in overweight patients with stea- tosis and healthy humans, under both basal and insulin-stimulated conditions ( Kotronen et al., 2009 ) ( Table 1
). However, significant differences not only in fat oxidation, but also in other aspects of he- patic mitochondrial function were observed in another study employing non-invasive in vivo tracer techniques. Sunny et al. re- ported that persons with steatosis, as defined by liver fat content of more than 6%, have two-fold greater hepatic mitochondrial oxi- C. Koliaki, M. Roden / Molecular and Cellular Endocrinology 379 (2013) 35–42 39
dative metabolism than those with liver fat content less than 6% ( Sunny et al., 2011 ). Both groups had similar age and comparable degree of obesity, elevation of liver enzymes and whole-body insu- lin resistance, whereas hepatic insulin resistance was more pro- nounced in those with steatosis. In detail, subjects with steatosis exhibited 100% higher TCA cycle flux, 50% higher rates of lipolysis and anaplerosis, and 25% higher rates of gluconeogenesis com- pared to those without steatosis ( Table 1
and Fig. 2
). Of note, hepa- tic fat content correlated positively with measures of both oxidative and non-oxidative mitochondrial metabolism. These findings support the concept that mitochondrial pathways could be upregulated in steatosis as an adaptive mechanism in response to chronic fat overload. Recent animal studies are in absolute accordance with this contention, by showing elevated TCA cycle function and mitochondrial b-oxidation in states of diet-induced hepatic insulin resistance and liver steatosis ( Satapati et al., 2012 ). Taken together, all the above data in humans with obesity and steatosis illustrate the importance of the homeostasis of hepatic fatty acid handling. Any increase in hepatic fatty acid uptake would be balanced by an up-regulation of b-oxidation, which – in the set- ting of chronic lipid overloading – would stimulate ATP production and generation of ROS. This would in turn lead to increased triglyc- eride synthesis and export as VLDL, as well as to hepatic oxidative stress with promotion of NAFLD and ultimately impairment of mitochondrial functionality. 8. Liver mitochondrial function in advanced NAFLD Advanced NAFLD typically associates with insulin resistance and unfavorable hepatic adaptations of hepatocellular energy homeostasis, which render the liver more vulnerable to oxidative injury and cell death, and are reflected by ultrastructural mito- chondrial defects ( Sanyal et al., 2001 ). It has been suggested that impaired mitochondrial respiratory capacity plays a key role in the pathogenesis of advanced NAFLD, particularly in the progres- sion to NASH and cirrhosis ( Begriche et al., 2006; Serviddio et al., 2011, 2008a ). Studies in humans have failed to support a concept of generalized defects in mitochondrial b-oxidation in biopsy-pro- ven NAFLD ( Sanyal et al., 2001 ). In contrast, patients with NAFLD and insulin resistance show greater liver mitochondrial b-oxida- tion, while those with drug-induced NAFLD have diminished mito- chondrial oxidation ( Fromenty et al., 2004; Miele et al., 2003 ). An augmented hepatic b-oxidation and oxidative stress seem thus to accompany peripheral insulin resistance as the most prominent characteristics of advanced NAFLD ( Sanyal et al., 2001 ). NASH is recognized as the most common subtype of advanced NAFLD ( Clark, 2006 ). In a pilotic study in eight patients with biopsy-proven NASH, it was found that the ability of these patients to regenerate their hepatic ATP reserve after a transient ATP deple- tion induced by fructose ingestion was reduced by 30% compared to age- and sex-matched controls ( Cortez-Pinto et al., 1999 ) (
). Of note, in human NASH, functional mitochondrial abnor- malities are furthermore combined with a number of structural de- fects such as loss of mitochondrial cristae and paracrystalline inclusions, and presence of linear crystalline inclusions in swollen mitochondria ( Sanyal et al., 2001 ). Furthermore, it has been shown that patients with NASH have a severely defective hepatic mito- chondrial respiratory chain, and this dysfunction correlates posi- tively with inflammation and peripheral insulin resistance ( Pérez-Carreras et al., 2003 ). More specifically, patients with NASH were found to exhibit significantly decreased activity of all respira- tory chain complexes compared to control subjects (42.4–70.6% reduction for complexes I–V), and increased availability of hepatic free fatty acids, expressed as an increased ratio of long-chain acylcarnitine esters relative to free carnitine ( Pérez-Carreras et al., 2003 ) ( Table 1
and Fig. 2
). It has been also reported that pa- tients with NASH display an increased proton leak across the elec- tron transport chain due to a 2-fold increased hepatic expression of uncoupling protein 2 (UCP-2) ( Serviddio et al., 2008b ) (
Table 1 ). The upregulation of UCP-2 in human NASH induces an uncoupling between oxidative phosphorylation and ATP production, reduces the redox pressure on mitochondrial respiratory chain, and acts as a potential protective mechanism against further liver damage. UCP-2-dependent mitochondrial uncoupling can be perceived as a protective mechanism to halt damage progression but compro- mises on the other hand the liver capacity to respond to acute high-energy demands, such as ischaemia–reperfusion injury. Addi- tional abnormalities of hepatic energy metabolism that have been reported in human and animal NASH (rat models of high fat, methionine and choline-deficient diet) include increased ROS pro- duction, abnormal cellular and mitochondrial redox homeostasis, oxidative stress-mediated depletions of mitochondrial DNA encod- ing some of the polypeptide components of mitochondrial respira- tory chain and increased rate of b-oxidation ( Miele et al., 2003; Morris et al., 2011; Serviddio et al., 2008a; Romestaing et al., 2008 ) (
Table 1 ). The underlying pathophysiology of perturbed hepatic energy metabolism in NASH can be described by a vicious circle, involving free fatty acids, lipid peroxidation products and inflammatory markers ( Fromenty et al., 2004; Pessayre, 2007; Pessayre et al., 2002, 2001 ). This ominous cascade begins with a mild respiratory dysfunction induced by lipid oversupply in hepatocytes. In addi- tion, the increased availability of hepatic free fatty acids results in an increased import of free fatty acids into hepatic mitochondria and an elevated rate of mitochondrial fatty acid b-oxidation ( Miele et al., 2003 ). Due to the increased rate of b-oxidation, an imbalance occurs between a high electron input and a restricted electron out- flow, leading to accumulation of electrons within respiratory com- plexes I and III and a subsequent reaction of these electrons with oxygen to form ROS. ROS can promote lipid peroxidation and lipid peroxidation products can in turn alter mitochondrial DNA and cause severe oxidative damage to critical mitochondrial proteins such as cytochrome c oxidase and adenine nucleotide translocator proteins, resulting in impaired electron flow along the respiratory chain and establishing a vicious circle between impaired respira- tory chain capacity, ROS formation, lipid peroxidation and mito- chondrial damage ( Fromenty et al., 2004; Pessayre, 2007; Pessayre et al., 2002, 2001 ). ROS and lipid peroxidation products can also promote hepatic inflammation, fibrosis and cell death, leading to the characteristic necroinflammatory and fibrotic alter- ations of hepatic tissue observed in advanced stages of NAFLD. Due to excessive ROS production, the anti-oxidant defense systems of mitochondria (enzymes and vitamins) are rapidly consumed, and this depletion of anti-oxidant capacity hampers the inactivation of ROS and may further augment ROS-mediated damage. 9. Conclusions The liver is a central player in the physiological regulation of whole-body energy homeostasis as well as the pathogenesis of the epidemiologically relevant endocrine disorders obesity and diabetes. Patients with long-standing T2DM can have lower hepa- tic ATP synthesis during fasting and after fructose administration. In advanced NAFLD, abnormal hepatic mitochondrial function and morphology may occur, possibly due to local lipotoxic, inflam- matory and oxidative stress pathways. On the other hand, non-dia- betic obese humans can show normal or even greater hepatic mitochondrial function than lean humans. Such increases in b-oxi- dation, ketogenesis and anaplerotic fluxes can be interpreted as a response to lipid oversupply and may correlate with steatosis. 40 C. Koliaki, M. Roden / Molecular and Cellular Endocrinology 379 (2013) 35–42 Thus, we propose that hepatic energy metabolism transitionally adapts to chronic lipid overload in states of obesity and steatosis by upregulated oxidative capacity, which can be followed by pro- gressive decline in liver mitochondrial function during prolonged chronic insulin resistance, associated with T2DM and NASH ( Fig. 2 ). Of note, these conclusions are based on a limited number of small-scale human studies. More clinical studies combining in vivo
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a b s t r a c t In rodents, brown adipose tissue (BAT) is a metabolic organ that produces heat in response to cold and dietary intake through mitochondrial uncoupling. For long time, BAT was considered to be solely impor- tant in small mammals and infants, however recent studies have shown that BAT is also functional in adult humans. Interestingly, the presence and/or functionality of this thermogenic tissue is diminished in obese people, suggesting a link between human BAT and body weight regulation. In the last years, evi- dence has also emerged for the existence of adipocytes that may have an intermediate thermogenic phe- notype between white and brown adipocytes, so called brite or beige adipocytes. Together, these findings have resulted in a renewed interested in (human) brown adipose tissue and pathways to increase the activity and recruitment of these thermogenic cells. Stimulating BAT hypertrophy and hyperplasia in humans could be a potential strategy to target obesity. Here we will review suggested pathways leading to BAT activation in humans, and discuss novel putative BAT activators in rodents into human perspective. Ó 2013 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Brown adipose tissue (BAT) is a crucial organ in facultative thermogenesis (acute response) and has a great plasticity to re- spond to long-term changes (e.g. cold acclimation), known as adaptive thermogenesis. In addition to its important role in main- taining thermal homeostasis, BAT is likely to be involved in en- ergy homeostasis as well, since ablation of the essential protein for heat production in BAT, uncoupling protein-1 (UCP-1), leads to an obese phenotype in mice housed at a thermoneutral tem- perature ( Feldmann et al., 2009 ). Furthermore, it has been shown in mice that BAT is involved in plasma triglyceride clearance ( Bar-
telt et al., 2011 ) and glucose homeostasis ( Guerra et al., 2001; Gunawardana and Piston, 2012 ). This implies the important role of BAT in rodents to combat obesity and its related metabolic dis- eases, such as diabetes and cardiovascular disease. Interestingly, prospective studies have now demonstrated BAT to be present and functional in most (prevalence varying from 40% to 100%) young lean human adults by exposing them to cold ( Cypess et al., 2012; Orava et al., 2011; Ouellet et al., 2012; Vijgen et al., 2011; Vosselman et al., 2012; Yoneshiro et al., 2012, 2011
). Importantly, an inverse relationship has been shown be- tween adiposity and BAT activity, indicating a relationship be- tween BAT and obesity ( Cypess et al., 2009; Saito et al., 2009; van Marken Lichtenbelt et al., 2009; Vijgen et al., 2011 ). In addi- tion, there is evidence that BAT contributes to nonshivering ther- mogenesis ( Orava et al., 2011; Ouellet et al., 2012; Vijgen et al., 2011; Yoneshiro et al., 2011 ), although this relationship has not always been found ( van Marken Lichtenbelt et al., 2009; Vossel- man et al., 2012 ). It has been estimated that fully activated BAT in humans can contribute to 5% of the basal metabolic rate ( van Marken Lichtenbelt and Schrauwen, 2011 ). This means that stim- ulation of BAT can have an impact on long-term energy balance and thus body weight, however only when other factors (e.g. food intake) remain stable ( Christiansen and Garby, 2002 ). Maybe
more important, stimulation of BAT could be supportive in body weight maintenance. Therefore, finding strategies to increase BAT activity and recruitment in humans could be important to combat obesity and its related chronic metabolic diseases. Cur- rently, much effort is being put in finding ways to increase BAT thermogenesis and the recruitment of brown adipocytes in ro- dents. The recent discovery of the so-called brown-in-white (brite) or beige adipocytes has further increased the interest in BAT. Increased ‘‘browning’’ of WAT could be an attractive way to induce weight loss. It is therefore important to find strategies to increase the thermogenic machinery of BAT and brown-like tis- sues in humans. This review will provide an overview of the most promising pathways to increase BAT activity and recruitment in humans.
0303-7207/$ - see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mce.2013.04.017 ⇑ Corresponding author. Address: Department of Human Biology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, P.O. Box 616, 6200 MD Maastricht, The Netherlands. Tel.: +31 (0) 43 3881502; fax: +31 (0) 43 3670976. E-mail addresses: mj.vosselman@maastrichtuniversity.nl (M.J. Vosselman), markenlichtenbelt@maastrichtuniversity.nl (W.D. van Marken Lichtenbelt), p.schrauwen@maastrichtuniversity.nl (P. Schrauwen). Molecular and Cellular Endocrinology 379 (2013) 43–50 Contents lists available at SciVerse ScienceDirect Molecular and Cellular Endocrinology j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / m c e
2. Brown, beige and white adipose tissue 2.1. Brown versus white adipose tissue In rodents, brown adipose tissue is clearly distinguishable from white adipose tissue, since it is richly innervated by the sympa- thetic nervous system (SNS), is highly vascularized, and contains brown adipocytes with several small lipid vacuoles and many large mitochondria ( Frontini and Cinti, 2010 ). Unique for the brown adi- pocyte is the protein UCP-1 located in the inner mitochondrial membrane, which allows protons in the intermembrane space to re-enter the mitochondrial matrix without generating ATP, ulti- mately resulting in heat production. White and brown adipose tissue in mice can be found in distinc- tive or classical (i.e. pure white or pure brown) depots ( Fig. 1
A). All these depots have been characterized by genetic markers, and have a distinct genetic profile that probably determines its function ( Waldén et al., 2012 ). Note that these adipose tissue depots some- times are also viewed as one organ, known as the adipose organ ( Cinti, 2001 ). The largest BAT depot found in mice, iBAT, is predominantly found in human neonates and infants, and then gradually disap- pears after childhood ( Heaton, 1972 ) and is rarely seen in human adults ( Fig. 1
B). In adult humans, BAT ([ 18 F]FDG-uptake) is often found in the neck, the mediastinum (para-aortic), and above the kidney (suprarenal), which is comparable to some BAT depots (cBAT, mBAT, prBAT) in mice. Furthermore, BAT in humans is lo- cated along the spinal cord, in the axillary and abdominal region (suprarenal and perihepatic), and sometimes in areas such as the abdominal wall and acromial–clavicular area. The most prominent and most reported BAT depot in humans is supraclavicular BAT, which has not been found as a distinct depot in mice. 2.2. Brown like cells in white adipose tissue In addition to classical BAT, a distinct type of adipocytes has been found within WAT depots, the so-called brite ( Petrovic
et al., 2010 ) or beige adipocytes ( Wu et al., 2012 ). However, this is still under dispute as white fat cells may differentiate into brown fat cells ( Cinti, 2002 ). At present, no consensus on the terminology of these brown-like white adipocytes has been reached, and is ur- gently awaited. However, for sake of clarity we will refer to these cells as beige adipocytes in the remainder of this review. These beige adipocytes can appear within WAT depots after long-term adrenergic stimulation and cold exposure, and especially appear in the inguinal depot. In the basal state, these beige cells resemble the unilocular white adipocytes, whereas upon stimulation these cells obtain a more brown like phenotype. Furthermore, these cells do not express the myogenic markers nor the brown adipocyte specific markers Zic1, Lhx8, Meox2, and PRDM16 ( Petrovic et al., 2010
), but express specific markers as well (e.g. Hoxc9) ( Waldén
et al., 2012 ). Interestingly, Wu et al. (2012) were able to isolate brown-like cells from the subcutaneous (inguinal) adipose depot and found a distinct pool of progenitors giving rise to these so- called beige cell lines. Linkage of the expressed genes after micro- array analysis in these cell lines revealed that beige adipocytes are Download 2.44 Mb. Do'stlaringiz bilan baham: 
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