; Maddux, B.A. These mitochondria are apparently more numerous and bigger in size and contain more cristae than mitochondria in white adipocytes. Mitochondrial dysfunction, which is induced by obesity, Mitochondrial dysfunction, which is induced by obesity, are critical mediators in initiating inflammation in macrophages and adipocytes, and subsequent systemic insulin resistance. ; Wright, D.C. Time course of high-fat diet-induced reductions in adipose tissue mitochondrial proteins: potential mechanisms and the relationship to glucose intolerance. Selective targeting of an antioxidant to mitochondria. Rodgers, J.T. In addition, mitochondrial dysfunction has a significant association with obesity, which can eventually develop into metabolic diseases, including type 2 diabetes [, However, excessive mitochondrial ROS generation by chronic oxidative stress activates various stress pathways such as nuclear factor kappa light chain enhancer of activated B cells (NF-κB), c-Jun, Alteration of the mitochondrial genome can be more specifically divided into two types: reduction of the mitochondrial mass caused by the decrease of mtDNA related to mitochondrial biogenesis and mutation of mtDNA. Adipocytes do gradually die off and get replaced, according to that study. Mitochondria are impaired in the adipocytes of type 2 diabetic mice. FGF21 regulates PGC-1alpha and browning of white adipose tissues in adaptive thermogenesis. Thus, understanding the molecular mechanisms of mitochondrial dysfunction of adipocytes implicated in the pathogenesis of metabolic diseases could provide potential opportunities for prevention and therapeutic intervention. ; Szpyt, J.; Pierce, K.A. Endoplasmic reticulum (ER)–associated degradation (ERAD) is a quality control mechanism that allows for targeted degradation of proteins in the ER. Mitochondrial dysfunction and complications associated with diabetes. Wai, T.; Langer, T. Mitochondrial Dynamics and Metabolic Regulation. Altshuler-Keylin, S.; Kajimura, S. Mitochondrial homeostasis in adipose tissue remodeling. A biochemical approach to the problem of aging: “megaproject” on membrane-penetrating ions. ; Wells, N.; Giakoumaki, I.I. Mammals express five UCP homologues (UCP1 also named thermogenin), UCP2, UCP3, UCP4, and UCP5, also known as brain mitochondrial carrier protein 1 (BMCP1) [60]. Rosiglitazone-induced mitochondrial biogenesis in white adipose tissue is independent of peroxisome proliferator-activated receptor gamma coactivator-1alpha. Low mitochondrial number and activity have been suggested as underlying factors in obesity, type 2 diabetes, and metabolic syndrome. Brown adipose tissue activity controls triglyceride clearance. Liguori, R.; Mazzaccara, C.; Pasanisi, F.; Buono, P.; Oriani, G.; Finelli, C.; Contaldo, F.; Sacchetti, L. The mtDNA 15497 G/A polymorphism in cytochrome b in severe obese subjects from Southern Italy. Understanding adipocyte differentiation. Keijer, J.; van Schothorst, E.M. Adipose tissue failure and mitochondria as a possible target for improvement by bioactive food components. This review summarizes the main characteristics of each adipose tissue subtype and describes morphological and functional modifications focusing on mitochondria and their activity in healthy and unhealthy adipocytes. suggested that during cold-induced “browning” of subcutaneous fat, most “beige” adipose cells stem from de novo differentiated adipocytes [46]. demonstrated the mitochondrial feature of brown and activated beige adipocytes by proteomic analysis of mitochondria from mouse BAT and WAT [, Mitochondria are key organelles that control the physiological role of adipocytes such as adipocyte differentiation, lipid homeostasis, insulin sensitivity, oxidative capacity, adaptive thermogenesis, and browning of WATs (, Previous studies have shown that the induction of mitochondria is essential for ATP production, which is necessary for increasing the metabolic activity during the adipogenic program. The physiological function of UCP1 is to mediate a regulated proton leak and thus dissipate the proton electrochemical gradient built up by the respiratory chain in the form of heat. ; Chatterjee, G.; Ganguly, A.; Mukhopadhyay, S.; Chakrabarti, S. Enhanced ROS production and oxidative damage in subcutaneous white adipose tissue mitochondria in obese and type 2 diabetes subjects. Taken together, the improvement of the function of mitochondria by thermogenesis, PPARγ agonist TZD, mitochondria-targeted antioxidants, exercise, caloric restriction, and dietary natural compounds can be considered as a new potential therapeutic approach for the treatment of metabolic diseases (. Lee, M.S. ; Chen, X.H. D Based on previous studies and our current work, we speculate that some mitochondria in brown adipocytes are anchored on LDs, which we term as LDAM. Citrate is the only precursor of cytosolic acetyl-CoA, key intermediate used for fatty acid synthesis. CD40: CD40 molecule, TNF receptor superfamily member 5; CD137: tumour necrosis factor receptor superfamily, member 9; C/EBP, A. V. B. Castro, C. M. Kolka, S. P. Kim, and R. N. Bergman, “Obesity, insulin resistance and comorbidities—mechanisms of association,”, M. Luna-Luna, A. Medina-Urrutia, G. Vargas-Alarcón, F. Coss-Rovirosa, J. Vargas-Barrón, and Ó. Pérez-Méndez, “Adipose tissue in metabolic syndrome: onset and progression of atherosclerosis,”, J. F. Mission, N. E. Marshall, and A. The nucleus is flattened and pushed to the periphery. Kajimura, S.; Saito, M. A new era in brown adipose tissue biology: molecular control of brown fat development and energy homeostasis. ; Jin, S.M. ; Cannon, B.; Nedergaard, J. UCP1 in brite/beige adipose tissue mitochondria is functionally thermogenic. It contains a large number of mitochondria and contains multiple small lipid droplets. The current clinical approaches for the treatment of obesity include diet control, physical activity, drug therapy, and surgery [, Recently, WAT browning has been proposed as an alternative to BAT thermogenesis. have reported that higher intracellular ROS levels elicited by mitochondrial dysfunction resulted in the impairment of adipocyte function in the maintenance of glucose homeostasis through attenuation of insulin signalling, downregulation of the glucose transporter (GLUT4) expression, and decrease in adiponectin secretion [97]. Adipose mitochondrial biogenesis is suppressed in db/db and high-fat diet-fed mice and improved by rosiglitazone. Impaired Mitochondrial Biogenesis in Adipose Tissue in Acquired Obesity. ; Boss, O.; Hadro, E.; Minnemann, T.; Shulman, G.I. Although an important source of energy for other tissues, chronically elevated circulating FAs in obesity are associated with insulin resistance and progression to type 2 diabetes The role of mitochondria in white adipocytes has long been neglected because of their low abundance. In addition, tricarboxylic acid cycle generates citrate, which is then transported from the mitochondrion into the cytosol via the tricarboxylate carrier. Adipose Tissue I-Adipocytes define adipose tissue (fat), which is a type of loose connective tissue. Toledo, F.G.; Menshikova, E.V. Uncoupling proteins belong to a family of mitochondrial carrier proteins that are present in the mitochondrial inner membrane. Bartelt, A.; Heeren, J. Adipose tissue browning and metabolic health. Mitochondrial reactive oxygen species and adipose tissue thermogenesis: Bridging physiology and mechanisms. UCP2 and UCP3 mRNAs have been detected in a number of tissues and organs, for example, thymus, stomach, testis, white and brown adipocytes, pancreatic β-cells (UCP2) and skeletal muscle, heart, and brown adipocytes (UCP3) [63–67]. ; Grodsky, G.M. Compelling lines of evidence indicate that major factors contributing to mitochondrial defects in adipose tissues are (i) oxidative stress, (ii) insulin resistance, (iii) genetic factors, and also (iv) sedentary lifestyle without physical activity [93]. The present results clearly substantiate our previous finding of reduced adipocyte mitochondrial respiratory capacity and impaired mitochondrial functional integrity in adipocytes of obese mice . Mitochondrial dysfunction leads to impairment of insulin sensitivity and adiponectin secretion in adipocytes. Two potential models of mature WAT into bAT transformation are shown in Figure 2. Spare mitochondrial respiratory capacity permits human adipocytes to maintain ATP homeostasis under hypoglycemic conditions. Levels of mitochondrial DNA were also found to be considerably reduced in the adipocytes of db/db mice. Critical nodes in signalling pathways: insights into insulin action. Cypess, A.M.; Kahn, C.R. Cyclooxygenase-2 controls energy homeostasis in mice by de novo recruitment of brown adipocytes. Puigserver, P.; Wu, Z.; Park, C.W. ; Kahn, B.B. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. ; Waters, K.M. Chen, X.H. Mitochondria-targeted antioxidants as therapies. Stoicheiometries of proton translocation by mitochondria. ; Kim, H.J. ; Galluzzi, L.; Kroemer, G. Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Nicholls, D.G. Although it is not clear whether low PGC-1α expression is a prelude to the development of obesity or a consequence of it, upregulation of expression of thermogenic genes in white adipose tissue could offer new tool in the therapy of obesity [114]. have recently shown that acute treatment with mitochondria-targetedparaquat(mPQ)increasedmitoROSandcausedinsu-lin resistance, without impacting mitochondrial respiration (11). ; Tulinius, M.H. It is now widely accepted that adipose tissue acts not only as repository for excess nutrients but also as integrator and regulator of the balance between food intake and energy output. Brown adipocyte mitochondria are morphologically different from white adipocyte mitochondria. Thus, mitochondria-targeted antioxidants could be a potential therapy for metabolic and neurodegenerative diseases, which are associated with mitochondrial dysfunction. Oxidative stress is defined as a disturbance in the balance between the production of ROS and antioxidant defence [94]. Wilson-Fritch, L.; Nicoloro, S.; Chouinard, M.; Lazar, M.A. Altshuler-Keylin, S.; Shinoda, K.; Hasegawa, Y.; Ikeda, K.; Hong, H.; Kang, Q.; Yang, Y.; Perera, R.M. ; Debnath, J.; Kajimura, S. Beige Adipocyte Maintenance Is Regulated by Autophagy-Induced Mitochondrial Clearance. J. Physiol. Seale, P.; Conroe, H.M.; Estall, J.; Kajimura, S.; Frontini, A.; Ishibashi, J.; Cohen, P.; Cinti, S.; Spiegelman, B.M. Interestingly, Morroni and coworkers suggested a new mechanism of reversible physiological transdifferentiation of adipocytes in the mammary gland: mouse mammary adipocytes are able to transform into secretory epithelial cells during pregnancy and revert to adipocytes after lactation [45]. Fisher, F.M. ; Maratos-Flier, E.; et al. Orava, J.; Nuutila, P.; Lidell, M.E. Short answer: It depends. ; Shen, J.; Cookson, M.R. ; Gao, C.L. Classical brown fat is primarily distributed in the interscapular space, paravertebrally, axillary, and perirenally. Thermogenic mechanisms in brown fat. Elgass, K.; Pakay, J.; Ryan, M.T. The role of mitochondria in adipose tissues in the onset and progression of insulin resistance is still a matter of controversy. However, in the past few years, many studies have targeted mitochondria in adipocytes or adipose tissues providing convincing evidence that impairment of mitochondrial functions in adipocytes could have the whole body pathological consequences [12, 51].