TNF-alpha downregulates eNOS expression and mitochondrial biogenesis in fat and muscle of obese rodents (original) (raw)
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TNF downregulates eNOS expression and mitochondrial biogenesis in fat and muscle of obese rodents
Journal of Clinical Investigation, 2006
Obesity is associated with chronic low-grade inflammation. Thus, at metabolically relevant sites, including adipose tissue and muscle, there is abnormal production of proinflammatory cytokines such as TNF-α. Here we demonstrate that eNOS expression was reduced, with a concomitant reduction of mitochondrial biogenesis and function, in white and brown adipose tissue and in the soleus muscle of 3 different animal models of obesity. The genetic deletion of TNF receptor 1 in obese mice restored eNOS expression and mitochondrial biogenesis in fat and muscle; this was associated with less body weight gain than in obese wild-type controls. Furthermore,
Impaired mitochondrial biogenesis in adipose tissue in acquired obesity
Diabetes, 2015
Low mitochondrial number and activity have been suggested as underlying factors in obesity, type 2 diabetes, and metabolic syndrome. However, the stage at which mitochondrial dysfunction manifests in adipose tissue after the onset of obesity remains unknown. Here we examined subcutaneous adipose tissue (SAT) samples from healthy monozygotic twin pairs, aged 22.8 -36.2 years, who were discordant (∆BMI >3 kg/m 2 , mean length of discordance 6.3 ± 0.3 years, n = 26) and concordant (∆BMI <3 kg/m 2 , n = 14) for body weight and assessed their detailed mitochondrial metabolic characteristics: mitochondrial-related transcriptomes with dysregulated pathways, mitochondrial DNA (mtDNA) amount, mtDNA-encoded transcripts, and mitochondrial oxidative phosphorylation (OXPHOS) protein levels. We report global expressional downregulation of mitochondrial oxidative pathways, with concomitant downregulation of mtDNA amount, mtDNAdependent translation system, and protein levels of the OXPHOS machinery in the obese compared with the lean co-twins. Pathway analysis indicated downshifting of fatty acid oxidation, ketone body production and breakdown, and the tricarboxylic acid cycle, which inversely correlated with adiposity, insulin resistance, and inflammatory cytokines. Our results suggest that mitochondrial biogenesis, oxidative metabolic pathways and OXPHOS proteins in SAT are downregulated in acquired obesity, and associated with metabolic disturbances already at the pre-clinical stage.
Antioxidants & Redox Signaling, 2014
Aims: Studies in skeletal muscle demonstrate a strong association of mitochondrial dysfunction with insulin resistance (IR). However, there is still a paucity of knowledge regarding the alteration of mitochondria in adipose tissue (AT) in the pathogenesis of IR in obesity. We investigated the mitochondrial biogenesis in visceral fat (VF) and subcutaneous fat (SF) in C57BL/6J mice fed a high-fat high-sucrose diet for 12 months. Results: Impairment of glucose tolerance and insulin sensitivity developed after 1 month of the diet and was associated with a prompt increase of VF. The VF adipocytes were larger than those in the SF and had increased expressions of HIF-1a and p-NFjB p65. However, the alteration of mitochondrial biogenesis did not occur in the early stage when increased intracellular reactive oxygen species (ROS), mitochondrial oxygen consumption rate, and mitochondrial ROS emerged at the 1st, 2nd and 2nd month, respectively. Until the 6th month, the VF had markedly increased mitochondrial DNA content and expression of PGC-1a, Tfam, ATP5A, and MnSOD. This increase of mitochondrial biogenesis was followed by a generalized decrease at the 12th month and the mitochondrial morphology altered markedly. In the late stage, although mitochondrial ROS decreased, the increased expression of 8-OHdG in VF continued. Innovation and Conclusion: These data suggest that IR and ROS production occur before the biphasic changes of mitochondrial biogenesis in AT, and the VF plays a more crucial role.
British Journal of Pharmacology, 2017
BACKGROUND AND PURPOSE Obesity is associated with structural and functional changes in perivascular adipose tissue (PVAT), favouring release of reactive oxygen species (ROS), vasoconstrictor and proinflammatory factors. The cytokine TNF-α induces vascular dysfunction and is produced by PVAT. We tested the hypothesis that obesity-associated PVAT dysfunction was mediated by augmented mitochondrial ROS (mROS) generation due to increased TNF-α production in this tissue. EXPERIMENTAL APPROACH C57Bl/6J and TNF-α receptor-deficient mice received control or high fat diet (HFD) for 18 weeks. We used pharmacological tools to determine the participation of mROS in PVAT dysfunction. Superoxide anion (O 2 .-) and H 2 O 2 were assayed in PVAT and aortic rings were used to assess vascular function. KEY RESULTS Aortae from HFD-fed obese mice displayed increased contractions to phenylephrine and loss of PVAT anti-contractile effect. Inactivation of O 2 .-, dismutation of mitochondria-derived H 2 O 2 , uncoupling of oxidative phosphorylation and Rho kinase inhibition, decreased phenylephrine-induced contractions in aortae with PVAT from HFD-fed mice. O 2 .and H 2 O 2 were increased in PVAT from HFD-fed mice. Mitochondrial respiration analysis revealed decreased O 2 consumption rates in PVAT from HFD-fed mice. TNF-α inhibition reduced H 2 O 2 levels in PVAT from HFD-fed mice. PVAT dysfunction, i.e. increased contraction to phenylephrine in PVAT-intact aortae, was not observed in HFD-obese mice lacking TNF-α receptors. Generation of H 2 O 2 was prevented in PVAT from TNF-α receptor deficient obese mice. CONCLUSION AND IMPLICATIONS TNF-α-induced mitochondrial oxidative stress is a key and novel mechanism involved in obesity-associated PVAT dysfunction. These findings elucidate molecular mechanisms whereby oxidative stress in PVAT could affect vascular function.
Scientific reports, 2017
Obesity is associated with severe metabolic diseases such as type 2 diabetes, insulin resistance, cardiovascular disease and some forms of cancer. The pathophysiology of obesity-induced metabolic diseases has been strongly related to white adipose tissue (WAT) dysfunction through several mechanisms such as fibrosis, apoptosis, inflammation, ER and oxidative stress. However, little is known of whether these processes are also present in brown adipose tissue (BAT) during obesity, and the potential consequences on mitochondrial activity. Here we characterized the BAT of obese and hyperglycemic mice treated with a high-fat diet (HFD) for 20 weeks. The hypertrophic BAT from obese mice showed no signs of fibrosis nor apoptosis, but higher levels of inflammation, ER stress, ROS generation and antioxidant enzyme activity than the lean counterparts. The response was attenuated compared with obesity-induced WAT derangements, which suggests that BAT is more resistant to the obesity-induced ins...
Mitochondrial oxidative phosphorylation, obesity and diabetes
and their dysfunction may cause energy deficiency in cells resulting in metabolic disorders: obesity and diabetes. Obesity or excessive bodyweight with elevated free fatty acids in the blood stream affects 2.1 billion people worldwide, and one of its adverse consequences is type 2 diabetes mellitus (T2DM). T2DM is characterized by hyperglycemia resulting from insufficient production of insulin by pancreatic β-cells, and insulin resistance in target tissues (muscle, liver and fat). Lipotoxicity and glucotoxicity in obesity and T2DM induce the β-cell overexpression of uncoupling protein 2 which increases proton leakage across the mitochondrial inner membrane and decreases ATP synthesis leading to insufficient secretion of insulin. Insulin resistance in the target tissues has been related to decreased mitochondrial content, reduced fatty acid oxidation, defective OXPHOS, and poor ATP production. This review focuses on the cellular and molecular mechanisms underlying defective mitochondrial OXPHOS in obesity and T2DM. Joseph JW, Koshkin V, Zhang CY, et al. Uncoupling protein 2 knockout mice have enhanced insulin secretory capacity after a high-fat diet. Diabetes 2002; 51 (11):3211-9. Kang D, Hamasaki N. Alterations of mitochondrial DNA in common diseases and disease states: aging, neurodegeneration, heart failure, diabetes, and cancer. Curr Med Chem 2005; 12 (4):429-41. Kelley DE. Skeletal muscle fat oxidation: timing and flexibility are everything. J Clin Invest 2005; 115 (7):1699-702. Kennedy ED, Maechler P, Wollheim CB. Effects of depletion of mitochondrial DNA in metabolism secretion coupling in INS-1 cells. Diabetes 1998; 47 (3):374-80. Kim JK, Fillmore JJ, Sunshine MJ, et al. PKC-theta knockout mice are protected from fat-induced insulin Mitochondria, obesity & diabetes resistance. J Clin Invest 2004; 114 (6):823-7. Kim JY, Hickner RC, Cortright RL, Dohm GL, Houmard JA. Lipid oxidation is reduced in obese human skeletal muscle. Am J Physiol Endocrinol Metab 2000; 279 (5):E1039-E1044. King MP, Attardi G. Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science 1989; 246 (4929):500-3. Kobayashi T, Nakanishi K, Nakase H, et al. In situ characterization of islets in diabetes with a mitochondrial DNA mutation at nucleotide position 3243. Diabetes 1997; 46 (10):1567-71. Kopecky J, Rossmeisl M, Flachs P, Bardova K, Brauner P. Mitochondrial uncoupling and lipid metabolism in adipocytes. Biochem Soc Trans 2001; 29 (Pt 6):791-7. Krauss S, Zhang CY, Lowell BB. A significant portion of mitochondrial proton leak in intact thymocytes depends on expression of UCP2. Proc Natl Acad Sci U S A 2002; 99 (1):118-22. Krauss S, Zhang CY, Scorrano L, et al. Superoxide-mediated activation of uncoupling protein 2 causes pancreatic beta cell dysfunction. J Clin Invest 2003; 112 (12):1831-42. Krempler F, Esterbauer H, Weitgasser R, et al. A functional polymorphism in the promoter of UCP2 enhances obesity risk but reduces type 2 diabetes risk in obese middle-aged humans. Diabetes 2002; 51 (11):3331-5. Lang J. Molecular mechanisms and regulation of insulin exocytosis as a paradigm of endocrine secretion. Eur J Biochem 1999; 259 (1-2):3-17. Larson-Meyer DE, Newcomer BR, Hunter GR, et al. Effect of weight reduction, obesity predisposition, and aerobic fitness on skeletal muscle mitochondrial function. Am J Physiol Endocrinol Metab 2000; 278 (1):E153-E161. Larsson NG, Wang J, Wilhelmsson H, et al. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nat Genet 1998; 18 (3):231-6. Laybutt DR, Sharma A, Sgroi DC, et al. Genetic regulation of metabolic pathways in beta-cells disrupted by hyperglycemia. J Biol Chem 2002; 277 (13):10912-21. Li Z, Bowerman S, Heber D. Health ramifications of the obesity epidemic. Surg Clin North Am 2005; 85 (4):681-701, v. Lillioja S, Mott DM, Howard BV, et al. Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima Indians. N Engl J Med 1988; 318 (19):1217-25. Lillioja S, Mott DM, Spraul M, et al. Insulin resistance and insulin secretory dysfunction as precursors of noninsulin-dependent diabetes mellitus. Prospective studies of Pima Indians. N Engl J Med 1993; 329 (27):1988-92. Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 2006; 443 (7113):787-95. Ling C, Poulsen P, Simonsson S, et al. Genetic and epigenetic factors are associated with expression of respiratory chain component NDUFB6 in human skeletal muscle. J Clin Invest 2007; 117 (11):3427-35.
Redox Biology
Metabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to different environmental stressors. We used a whole-body and tissue-specific phenotypic, functional, proteomic, metabolomic and transcriptomic approach to systematically assess metabolic plasticity in diet-induced obese mice after a com- bined nutritional and exercise intervention. Although most obesity and overnutrition-related pathological features were successfully reverted, we observed a high degree of metabolic dysfunction in visceral white adipose tissue, characterized by abnormal mitochondrial morphology and functionality. Despite two sequential therapeutic interventions and an apparent global healthy phenotype, obesity triggered a cascade of events in visceral adipose tissue progressing from mitochondrial metabolic and proteostatic alterations to widespread cellular stress, which compromises its biosynthetic and recycling capacity. In humans, weight loss after bariatric surgery showed a transcriptional signature in visceral adipose tissue similar to our mouse model of obesity reversion. Overall, our data indicate that obesity prompts a lasting metabolic fingerprint that leads to a progressive breakdown of metabolic plasticity in visceral adipose tissue
2020
Metabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to different environmental stressors. We used a whole-body and tissue-specific phenotypic, functional, metabolomic and transcriptomic approach to systematically assess metabolic plasticity in diet-induced obese mice after a combined nutritional and exercise intervention. Although most pathological features were successfully reverted, we observed a high degree of metabolic dysfunction irreversibility in visceral white adipose tissue, characterised by abnormal mitochondrial morphology and functionality. Despite two sequential therapeutic interventions and apparent global phenotypic recovery, obesity specifically triggered in visceral adipose a cascade of events progressing from mitochondrial metabolic and proteostatic defects to widespread cellular stress, which compromises its biosynthetic and recycling capacity. Our data indicate that obesity prompts a lasting metabolic fingerprint that leads...
The Association between Obesity and Mitochondrial Dysfunction: A Mini Review
2020
In times where the prevalence of obesity increases steadily and has become one of the so called “top killers” of the world, it is necessary to understand more how obesity affects our body and more importantly why it affects our body in that manner. To do that this article will emphasize on the bidirectional relationship between obesity and mitochondrial dysfunction. Overall said it appears that in patients suffering from obesity the total number of mitochondria seems to decrease in the different tissues due to an increase in production of the Tumor necrosis factor alpha (TNFa), which stimulates the extrinsic apoptotic pathway. However, it is of high importance to notice that the effects of obesity differ from tissue to tissue (as discussed later). Likewise, the production of Reactive Oxygen Species (ROS) inside the mitochondria, seems to increase also. This increase in ROS is often also associated with damage of the mitochondrial DNA (mtDNA) leading to mutations that may affect imp...