Cellular Respiration Discussion

Cellular Respiration Discussion

Received: 19 May 2019 Revised: 27 August 2019 Accepted: 3 September 2019 DOI: 10.1111/obr.12958 ETIOLOGY AND PATHOPHYSIOLOGY White adipose tissue mitochondrial metabolism in health and in obesity Sini Heinonen1 | Riikka Jokinen1 | Aila Rissanen1,2 | Kirsi H. Pietiläinen1,3 1 Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland 2 Department of Psychiatry, Helsinki University Hospital, Helsinki, Finland 3 Summary White adipose tissue is one of the largest organs of the body. It plays a key role in whole‐body energy status and metabolism; it not only stores excess energy but also secretes various hormones and metabolites to regulate body energy balance. Healthy Endocrinology, Abdominal Center, Helsinki University Hospital, Helsinki, Finland adipose tissue capable of expanding is needed for metabolic well‐being and to pre- Correspondence Kirsi H. Pietiläinen, MD, PhD, Obesity Research Unit, Biomedicum Helsinki, Helsinki University Central Hospital, C424b, PO Box 700, Haartmaninkatu 8, Helsinki 00029, Finland. Email: kirsi.pietilainen@helsinki.fi important functions in the adipose tissue. We review the derangements of mitochon- Funding information Academy of Finland, Grant/Award Numbers: 272376, 266286 and 314383; Emil Aaltonen Foundation; Finnish Diabetes Research Foundation; Finnish Government Research Funds; Helsinki University Central Hospital; University of Helsinki; Helsinki University Hospital Research Funds; Jalmari and Rauha Ahokas Foundation; Novo Nordisk Foundation; Gyllenberg Foundation; Finnish Cultural Foundation; Finnish Medical Foundation; Finnish Foundation for Cardiovascular Research 1 | vent accumulation of triglycerides to other organs. Mitochondria govern several drial function in white adipose tissue in the obese state. Downregulation of mitochondrial function or biogenesis in the white adipose tissue is a central driver for obesity‐associated metabolic diseases. Mitochondrial functions compromised in obesity include oxidative functions and renewal and enlargement of the adipose tissue through recruitment and differentiation of adipocyte progenitor cells. These changes adversely affect whole‐body metabolic health. Dysfunction of the white adipose tissue mitochondria in obesity has long‐term consequences for the metabolism of adipose tissue and the whole body. Understanding the pathways behind mitochondrial dysfunction may help reveal targets for pharmacological or nutritional interventions that enhance mitochondrial biogenesis or function in adipose tissue. K E Y W OR D S adipose tissue, mitochondria, obesity I N T RO D U CT I O N Mitochondria are the energy centres of adipocytes and are involved in many of their key metabolic functions including ATP pro- Obesity is a global and rapidly increasing problem, tripled since 1975 duction, fatty acid synthesis and oxidation, and the triglyceride bal- by WHO 2018 standards in developed countries. Obesity is also ance of the cell. Although adipose tissue was long considered as an extremely difficult to treat. A key defining feature of obesity is an adi- inert reservoir of fat with low abundance of mitochondria, adipose tis- pose tissue dysfunction, which is considered to be a major contribu- sue and its active mitochondria have recently emerged as one of the tor to the development of obesity‐related metabolic problems,1,2 central regulators influencing whole‐body metabolism.1,3,4 Impair- such as metabolic syndrome, insulin resistance, hypertension, ments in adipocyte mitochondrial function are associated with meta- dyslipidaemia, and fatty liver. The underlying pathological mechanisms bolic diseases and the development of obesity‐related disorders.3-6 that impair adipose tissue function in obesity are incompletely under- Better understanding on the dysfunction of adipose tissue mitochon- stood, but in the light of recent scientific advances, it may be con- dria may yield insights on how the metabolic complications of obesity nected to insufficient storage capacity or impaired function of could be reversed. In this review, we concentrate on the metabolic mitochondria, or both. processes in white adipose tissue that are regulated by mitochondria Obesity Reviews. 2020;21:e12958. https://doi.org/10.1111/obr.12958 wileyonlinelibrary.com/journal/obr © 2019 World Obesity Federation 1 of 23 2 of 23 HEINONEN ET AL. and aim to highlight the functions of this organelle in current research white adipose tissue or BAT function to treat obesity and its metabolic on obesity and adipose tissue. outcomes.27-29 This review concentrates on the mitochondria of white adipose tissue. 2 | A D I P O SE TI S S U E White adipose tissue is one of the largest organs of the body. Approx- 3 MITOCHONDRIA | imately 10% to 20% of total body weight in lean adults is white adipose tissue, but in individuals with obesity, the amount can increase7 up to 40% to 70%. By harvesting excess lipids and glucose from the circulation, it protects other tissues from the pathological accumulation of triglycerides.2,8 When this storage capacity is disrupted, lipids may spill over into ectopic sites like internal organs and vasculature resulting in low‐grade inflammation, insulin resistance, and metabolic problems.2,8,9 Intriguingly, both a total lack of adipose tissue in lipodystrophies and an unhealthy excess of adipose tissue in obesity lead to the same complications, including liver fat accumulation and Mitochondria are essential for key adipose tissue functions (Figure 1). Mitochondria produce energy in the form of ATP through oxidative phosphorylation (OXPHOS), generate substrates for cell metabolism (eg, de novo fatty acid synthesis), regulate lipid turnover, and control the generation of new adipocytes and adipokine secretion.3,30 Mitochondria are double‐membrane organelles with an outer and an inner membrane and an intermembrane space. The inner membrane is folded into cristae and surrounds a mitochondrial matrix, where many chemical reactions of energy metabolism take place. Moreover, adipose tissue is an active endocrine Mitochondria possess their own genome, a circular mitochondrial organ that regulates many metabolic responses at the whole‐body DNA (mtDNA), which encodes 13 proteins critical for OXPHOS and level through adipocytokines.10 Changes in the main adipokines have two ribosomal and 22 transfer RNAs required for mitochondrial ribo- 2,8 insulin resistance. been implicated in many obesity‐related metabolic problems, such as somes and translation, respectively.31,32 In addition, over one thou- type 2 diabetes, metabolic syndrome, and cardiovascular diseases. sand Adipose tissue consists of adipocytes and a matrix, which includes collagen, blood and lymphatic vessels, and the stromal vascular frac- mitochondrial proteins, including essential proteins of OXPHOS, mitochondrial translation, and other mitochondrial processes are encoded by nuclear DNA.31,33,34 tion of adipose tissue with endothelial cells, smooth muscle cells, immune cells, adipocyte precursor cells (preadipocytes), and mesen- 3.1 | Mitochondrial oxidative energy metabolism chymal stem cells.11,12 Approximately 75% of adipose tissue weight and 95% of an adipocyte consist of triglycerides. The main depots of The main energy derivation pathways of the cell, including pyruvate white adipose tissue are subcutaneous (80% to 90% of body fat), vis- oxidation, fatty acid β‐oxidation, the tricarboxylic acid (TCA) cycle, ceral (10% of body fat), and ectopic (intrahepatic, intramuscular, and and OXPHOS, occur in mitochondria (Figure 1).35 intrapancreatic) fat.13,14 Different adipose depots have differences in 15,16 capacity for adipocytokine secretion and cell type composition. In aerobic energy production through OXPHOS, high‐energy electrons (derived from substrate oxidation) are transferred through the In addition to white adipose tissue, also brown adipose tissue electron transport chain in the inner mitochondrial membrane (com- (BAT) and beige/brite adipose tissue (having mixed characteristics of plexes I‐IV of the OXPHOS system). The electron transport is coupled both white and brown adipose cells) in humans exist.17-19 BAT has a with proton pumping at complexes I, III, and IV, generating an electro- distinctive brown colour, which originates from the high iron and cyto- chemical potential difference across the inner membrane. The energy chrome content of the dense network of mitochondria and vascula- of the gradient is utilized by complex V (ATP synthase) to phosphory- ture within the tissue.20 In contrast to the large unilocular late ADP to ATP.36 triglyceride droplets in white adipocytes, brown adipocytes are com- The TCA cycle is the final common oxidative pathway for all sub- posed of small, multilocular lipid droplets. BAT is the site of strates (carbohydrates, fatty acids, and amino acids) and generates nonshivering thermogenesis, where the brown adipocyte‐specific pro- the high‐energy electron carriers (NADH and FADH2) that supply tein, uncoupling protein‐1 (UCP1), physiologically uncouples the respi- OXPHOS, energy compounds ATP and GTP, and metabolites needed ratory chain to generate heat, and its mitochondria could thus “burn” as carbon skeletons for many biosynthetic processes of the cell, such 17 away fat. An extensive previous research shows that BAT function as de novo fatty acid synthesis. is impaired and its activity reduced in obesity.21,22 Cold‐induced BAT Pyruvate derived from glucose is transported to the mitochondria glucose uptake and stimulation of blood flow are reduced in individ- and oxidized in the matrix yielding acetyl‐CoA. The pyruvate dehydro- uals with obesity23 as well as glucose uptake rates into BAT lower in genase complex catalyses the reaction and controls the amount of 24 both individuals with obesity and with type 2 diabetes. Studies have acetyl‐CoA fed into the TCA cycle. also shown that animals with more BAT are more resistant to obesity Free fatty acids (FFAs) are metabolized, esterified, or β‐oxidized in and type 2 diabetes.25,26 However, as the amount of BAT in human adipocyte mitochondria. The long‐chain fatty acids are transported adults is very low, the clinical significance and contribution of BAT from the cell cytosol into the mitochondrial matrix by carnitine 27 to energy expenditure are still debated. There is active research, reviewed elsewhere, on the possibilities of inducing “browning” of palmitoyltransferases (CPTs; CPT1, CACT, and CPT2).37 β‐oxidation of the fatty acids produces acetyl‐CoA, which enters the TCA cycle. HEINONEN 3 of 23 ET AL. Catabolism of branched‐chain amino acids (BCAA, ie, leucine, iso- sense the signals of mitochondrial activity. AMP‐activated protein leucine, and valine) also occurs in mitochondria. Branched‐chain amino kinase (AMPK) is activated when AMP levels are high. This induces acid aminotransferase (BCAT) forms α‐ketoacids (BCKAs) from BCAAs oxidative phosphorylation and suppresses cell growth and prolifera- via both cytosolic (BCATc, BCAT1) and mitochondrial (BCATm, tion.45 NAD+‐dependent deacetylase sirtuin 1 (SIRT1) is activated 38 The BCKAs are transported into mitochondria, when NAD+ levels are high, and this upregulates mitochondrial mass, where they are decarboxylated by the mitochondrial branched‐chain ATP generation, and nutrient oxidation. Both AMPK and SIRT1 acti- α‐ketoacid dehydrogenase (BCKD) complex. Finally, the products are vate the peroxisome proliferator‐activated receptor gamma coactiva- BCAT2) isoenzymes. used in the TCA cycle. tor 1 alpha (PGC‐1α). PGC‐1α is one of the main inducers of mitochondrial oxidative metabolism, has a major role in mitochondrial biogenesis,46 and interacts with many mitochondria‐related transcrip- 3.2 | Energy‐status–dependent regulation of mitochondria tion factors.47 In energy excess, PGC‐1α is acetylated and silenced. Caloric restriction leads to PGC‐1α activation through SIRT1.48 An By changing the morphology, distribution, and mass of mitochondria, activated PGC‐1α induces oestrogen‐related receptor α (ERRα) and the cell adapts to different energetic and metabolic demands.39 Mito- GA‐binding protein α (GABPα), which increase the function of the chondria are remodelled by fusion and fission, and changes in their OXPHOS complexes including cytochrome c and ATP synthase.49,50 40,41 Studies PGC‐1α enhances nuclear respiratory factor 1 (NRF‐1), which is on mitochondrial remodelling in adipose tissue are, however, sparse. needed for the induction of mitochondrial biogenesis51 and TFAM, Mitochondrial network fragmentation and fission appears to improve which controls mtDNA stability and the transcription of mtDNA‐ mitochondrial bioenergetics and make adipose tissue more insulin sen- encoded genes.52 Transcription factor Forkhead box O 1, FOXO1, rate of biogenesis and distribution in the cell are frequent. 42 sitive. This is in contrast to skeletal muscle, where fission contrib- utes to insulin resistance. 43 The energy status of the cell is signalled through the NAD+: NADH ratio, the AMP:ATP ratio, and acetyl‐CoA levels,44,45 which enhances adipogenesis53 and controls adipocyte stress response.54 Also, mitochondrial DNA methylation may be a control factor of mitochondria, although recent studies have challenged its existence altogether.55,56 FIGURE 1 Normal mitochondrial function in adipose tissue. Mitochondria (in green) are regulated by various nuclear‐related transcription factors. Most of the regulators are under the influence of PGC‐1α (in nucleus, yellow background). In normal conditions, transcription factors enhance mitochondrial biogenesis and function. MtDNA (green circle) encodes proteins critical for mitochondrial ribosomes (12S and 16S subunits, in grey) and for the OXPHOS complexes (in the mitochondrial membrane, in grey). The translation of these proteins is processed in the mitochondrial ribosomes. Glucose, FFA, and BCAAs derived from nutrients (above the two lines, cell surface) are used for the energy production and other maintenance functions of the cell. Glucose is converted into pyruvate via glycolysis, and pyruvate‐derived acetyl‐CoA enters the TCA‐ cycle (dotted line, circle) for the production of ATP and GTP, NADH and FADH2, as well as TCA‐metabolites, like citrate. FFA‐derived acyl‐CoA enters beta‐oxidation and acetyl‐CoA further to TCA cycle. BCAAs are catabolized via BCAT1 in cytosol and BCAT2 in mitochondria. BCKD complex frees acetyl‐CoA into the TCA cycle. Citrate is used for biosynthetic processes of the cell, like production of other TCA metabolites and as precursor for lipogenesis as malonyl‐CoA, which also inhibits beta‐oxidation through CPT1 transporters. Mark explanations: an arrow, induction; a T‐line, inhibition; green area, mitochondrion; yellow area, cell nucleus 4 of 23 HEINONEN 4 | MITOCHONDRIAL METABOLISM IN WHITE AT IN HEALTH AND IN OBESITY ET AL. imilar results have been obtained in studies of unrelated individuals. Downregulation of mitochondrial mtDNA in individuals with obesity has been shown by several studies,61,62,65-69 although not all.70-72 4.1 | Mitochondrial oxidative metabolism in white AT is altered in obesity The expression of PGC‐1α73 and the activities of the OXPHOS complexes I to IV, mitochondrial phosphate utilization, and mitochondrial membrane potential74 were downregulated in subcutaneous adipose In recent decades, altered mitochondrial oxidative metabolism has tissue of patients with obesity, compared with lean controls. The emerged as a molecular hallmark of obese adipose tissue (Figure 2). activities of the OXPHOS complexes were reduced in simple obesity Reduction of mitochondrial oxidative metabolism in adipose tissue and in obesity with diabetes.74 Obesity also links to decreased levels in obesity57,58 and in diabetes59 has been demonstrated in several ani- of OXPHOS complexes I and IV75 in adipocytes, decreased mitochon- mal studies: In diet‐induced or genetic mouse models of obesity, lim- drial oxygen consumption rates in isolated adipocyte mitochon- ited OXPHOS capacity, measured by maximal respiration capacity dria,71,75 and reduced oxygen consumption rates in preadipocytes and cell respiratory control ratios via cell respirometer, was observed after in white adipocytes, both in the absence and the presence of impaired preadipocytes has revealed changes in the methylation pattern of glucose tolerance.58 The authors concluded that impairments in mito- the preadipocytes obtained from individuals with obesity, with loss 58 beta‐adrenergic stimulation.71 A study with human Mitochondria‐ of DNA methylation in selected regions, where adipogenesis, inflam- related transcription was reduced, and mitochondrial staining, DNA mation, and immunosuppression were the most affected pathways.76 chondria relate to obesity, not to glucose intolerance. quantification, and measurements of citrate synthase activity revealed 60 Proteomic studies revealed that BMI was inversely associated with The four important omental adipose tissue mitochondrial proteins—citrate gene transcripts encoding mitochondrial proteins were decreased in synthase, HADHA, LETM1, and mitofilin.77 A lower abundance of reduced mitochondrial biogenesis in both obesity and diabetes. 57 After treatment with rosiglitazone, mitochondrial proteins in subcutaneous adipose tissue has been half of the genes were upregulated, and the change was accompanied recorded in insulin resistance without the presence of obesity78 and by an increase in mitochondrial mass.57 However, another study found in visceral fat of individuals with type 2 diabetes.79 These studies sug- reduced levels of OXPHOS mitochondrial protein subunits, cellular gest changes in the mitochondrial proteome with metabolic disorders mitochondrial DNA content by qPCR, oxygen consumption by cell res- in general, but exact studies on obesity have yet to be performed. obese mice without diabetes. pirometer, and number of mitochondria by MitoTracker staining and 59 Primary mitochondrial defects in adipose tissue affect metabolic electron microscopy in diabetic, but not obese mice. Also, several human studies have linked obesity to mitochondrial health also in transgenic mice. The results here, however, seem more dysfunction and to impaired glucose and lipid metabolism in adipose ATP depletion by knocking out the TCA enzyme fumarase hydroge- tissue.3,4,30 We have previously shown that mtDNA amount and gene nase in white and brown adipocytes resulted in low adipose mass, expression levels of mitochondria‐related pathways are downregu- small adipocytes, and protection against obesity, insulin resistance, lated in co‐twins with obesity compared with their co‐twins who are and fatty liver despite a high‐fat diet.80 Mice genetically overexpress- lean, a rare study setting that distinguishes the acquired features of ing prohibitin (needed in adipocyte differentiation) had enhanced obesity from potential genetic effects.61 Moreover, we have demon- mitochondrial biogenesis and consequently developed obesity.69 strated downregulation of mitochondrial biogenesis in these twins These studies suggest that mitochondrial downregulation in adipose with obesity compared with their lean identical co‐twins by reduced tissue could be beneficial, raising the question if the downregulation expression of genes encoding for mitochondrial proteins, expression of mitochondria in obesity is a compensatory mechanism. However, o…


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