BACKGROUND: Dysfunctional adipose tissue (AT) is known to contribute to the pathophysiology of metabolic disease, including type 2 diabetes mellitus (T2DM). This dysfunction may occur, in part, as a consequence of gut-derived endotoxaemia inducing changes in adipocyte mitochondrial function and reducing the proportion of BRITE (brown-in-white) adipocytes. Therefore, the present study investigated whether endotoxin (lipopolysaccharide; LPS) directly contributes to impaired human adipocyte mitochondrial function and browning in human adipocytes, and the relevant impact of obesity status pre and post bariatric surgery. METHODS: Human differentiated abdominal subcutaneous (AbdSc) adipocytes from participants with obesity and normal-weight participants were treated with endotoxin to assess in vitro changes in mitochondrial function and BRITE phenotype. Ex vivo human AbdSc AT from different groups of participants (normal-weight, obesity, pre- and 6 months post-bariatric surgery) were assessed for similar analyses including circulating endotoxin levels. RESULTS: Ex vivo AT analysis (lean & obese, weight loss post-bariatric surgery) identified that systemic endotoxin negatively correlated with BAT gene expression (p < 0.05). In vitro endotoxin treatment of AbdSc adipocytes (lean & obese) reduced mitochondrial dynamics (74.6% reduction; p < 0.0001), biogenesis (81.2% reduction; p < 0.0001) and the BRITE phenotype (93.8% reduction; p < 0.0001). Lean AbdSc adipocytes were more responsive to adrenergic signalling than obese AbdSc adipocytes; although endotoxin mitigated this response (92.6% reduction; p < 0.0001). CONCLUSIONS: Taken together, these data suggest that systemic gut-derived endotoxaemia contributes to both individual adipocyte dysfunction and reduced browning capacity of the adipocyte cell population, exacerbating metabolic consequences. As bariatric surgery reduces endotoxin levels and is associated with improving adipocyte functionality, this may provide further evidence regarding the metabolic benefits of such surgical interventions.

Aston Medical School College of Health and Life Sciences Aston University Birmingham B4 7ET UK

Centre for Sport Exercise and Life Sciences Research Institute for Health and Wellbeing Coventry University Coventry CV1 5FB UK

Department of Biosciences School of Science and Technology Nottingham Trent University Nottingham NG11 8NS UK

Division of Biomedical Sciences Warwick Medical School University of Warwick Coventry CV2 2DX UK

Human Sciences Research Centre College of Life and Natural Sciences University of Derby Derby DE22 1GB UK

Institute of Endocrinology Prague Czech Republic

Medical Technology Research Centre Anglia Ruskin University Cambridge UK

OB Clinic Prague Czech Republic

Warwick Medical School University of Warwick Coventry CV4 7AL UK

Warwickshire Institute for the Study of Diabetes Endocrinology and Metabolism University Hospitals Coventry and Warwickshire NHS Trust Coventry CV2 2DX UK

Zobrazit více v PubMed

Burhans MS, Hagman DK, Kuzma JN, Schmidt KA, Kratz M. Contribution of adipose tissue inflammation to the development of type 2 diabetes mellitus. Compr Physiol. 2019;9:1–58. PubMed PMC

Zatterale F, Longo M, Naderi J, Raciti GA, Desiderio A, Miele C, et al. Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes. Front Physiol. 2020;10:1607. doi: 10.3389/fphys.2019.01607. PubMed DOI PMC

Furman D, Campisi J, Verdin E, Carrera-Bastos P, Targ S, Franceschi C, et al. Chronic inflammation in the etiology of disease across the life span. Nat Med. 2019;25:1822–1832. doi: 10.1038/s41591-019-0675-0. PubMed DOI PMC

Fasano A. Gut permeability, obesity, and metabolic disorders: Who is the chicken and who is the egg? Am J Clin Nutr. 2017;105:3–4. doi: 10.3945/ajcn.116.148338. PubMed DOI

Piya MK, Harte AL, McTernan PG. Metabolic endotoxaemia: Is it more than just a gut feeling? Curr Opin Lipidol. 2013;24:78–85. doi: 10.1097/MOL.0b013e32835b4431. PubMed DOI

Varma MC, Kusminski CM, Azharian S, Gilardini L, Kumar S, Invitti C, et al. Metabolic endotoxaemia in childhood obesity. BMC Obes. 2016;3:1-8. PubMed PMC

Creely SJ, McTernan PG, Kusminski CM, Fisher FM, da Silva NF, Khanolkar M, et al. Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. Am J Physiol Endocrinol Metab. 2007;292:E740–7. PubMed

Harte AL, da Silva NF, Creely SJ, McGee KC, Billyard T, Youssef-Elabd EM, et al. Elevated endotoxin levels in non-alcoholic fatty liver disease. J Inflamm. 2010;7:1-10. PubMed PMC

Harte AL, Varma MC, Tripathi G, McGee KC, Al-Daghri NM, Al-Attas OS, et al. High fat intake leads to acute postprandial exposure to circulating endotoxin in type 2 diabetic subjects. Diabetes Care. 2012;35:375–382. doi: 10.2337/dc11-1593. PubMed DOI PMC

Martinez de la Escalera L, Kyrou I, Vrbikova J, Hainer V, Sramkova P, Fried M, et al. Impact of gut hormone FGF-19 on type-2 diabetes and mitochondrial recovery in a prospective study of obese diabetic women undergoing bariatric surgery. BMC Med. 2017;15:1-9. PubMed PMC

Bowser SM, Mcmillan RP, Boutagy NE, Tarpey MD, Smithson AT, Osterberg KL, et al. Serum endotoxin, gut permeability and skeletal muscle metabolic adaptations following a short term high fat diet in humans. Metabolism. 2020;103:154041. doi: 10.1016/j.metabol.2019.154041. PubMed DOI

Nascimento EBM, Sparks LM, Divoux A, van Gisbergen MW, Broeders EPM, Jörgensen JA, et al. Genetic Markers of Brown Adipose Tissue Identity and In Vitro Brown Adipose Tissue Activity in Humans. Obesity. 2018;26:135–140. doi: 10.1002/oby.22062. PubMed DOI

Al-Amrani A, AbdelKarim M, AlZabin M, Alzoghaibi M. Low expression of brown and beige fat genes in subcutaneous tissues in obese patients. Arch Med Sci. 2019;15:1113–1122. doi: 10.5114/aoms.2018.76684. PubMed DOI PMC

Pellegrinelli V, Carobbio S, Vidal-Puig A. Adipose tissue plasticity: how fat depots respond differently to pathophysiological cues. Diabetologia. 2016;59:1075–1088. doi: 10.1007/s00125-016-3933-4. PubMed DOI PMC

Orava J, Nuutila P, Noponen T, Parkkola R, Viljanen T, Enerbäck S, et al. Blunted metabolic responses to cold and insulin stimulation in brown adipose tissue of obese humans. Obesity. 2013;21:2279–2287. doi: 10.1002/oby.20456. PubMed DOI

Chait A, den Hartigh LJ. Adipose Tissue Distribution, Inflammation and Its Metabolic Consequences, Including Diabetes and Cardiovascular Disease. Front Cardiovasc Med. 2020;7:22. doi: 10.3389/fcvm.2020.00022. PubMed DOI PMC

Bond LM, Ntambi JM. UCP1 deficiency increases adipose tissue monounsaturated fatty acid synthesis and trafficking to the liver. J Lipid Res. 2018;59:224–236. doi: 10.1194/jlr.M078469. PubMed DOI PMC

Matsushita M, Yoneshiro T, Aita S, Kameya T, Sugie H, Saito M. Impact of brown adipose tissue on body fatness and glucose metabolism in healthy humans. Int J Obes (Lond) 2014;38:812–817. doi: 10.1038/ijo.2013.206. PubMed DOI

Koksharova E, Ustyuzhanin D, Philippov Y, Mayorov A, Shestakova M, Shariya M, et al. The Relationship Between Brown Adipose Tissue Content in Supraclavicular Fat Depots and Insulin Sensitivity in Patients with Type 2 Diabetes Mellitus and Prediabetes. Diabetes Technol Ther. 2017;19:96–102. doi: 10.1089/dia.2016.0360. PubMed DOI PMC

Chondronikola M, Volpi E, Børsheim E, Porter C, Annamalai P, Enerbäck S, et al. Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans. Diabetes. 2014;63:4089–4099. doi: 10.2337/db14-0746. PubMed DOI PMC

Leitner BP, Huang S, Brychta RJ, Duckworth CJ, Baskin AS, McGehee S, et al. Mapping of human brown adipose tissue in lean and obese young men. Proc Natl Acad Sci U S A. 2017;114:8649–8654. doi: 10.1073/pnas.1705287114. PubMed DOI PMC

Vijgen GHEJ, Bouvy ND, Teule GJJ, Brans B, Schrauwen P, van Marken Lichtenbelt WD. Brown adipose tissue in morbidly obese subjects. PLoS One. 2011;6:e17247. PubMed PMC

Dadson P, Hannukainen JC, Din MU, Lahesmaa M, Kalliokoski KK, Iozzo P, et al. Brown adipose tissue lipid metabolism in morbid obesity: Effect of bariatric surgery-induced weight loss. Diabetes Obes Metab. 2018;20:1280–1288. doi: 10.1111/dom.13233. PubMed DOI

Vijgen GHEJ, Bouvy ND, Teule GJJ, Brans B, Hoeks J, Schrauwen P, et al. Increase in Brown Adipose Tissue Activity after Weight Loss in Morbidly Obese Subjects. J Clin Endocrinol Metab. 2012;97:E1229–E1233. doi: 10.1210/jc.2012-1289. PubMed DOI

Hankir MK, Seyfried F. Do Bariatric Surgeries Enhance Brown/Beige Adipose Tissue Thermogenesis? Front Endocrinol. 2020;11:275. doi: 10.3389/fendo.2020.00275. PubMed DOI PMC

Adami GF, Carbone F, Montecucco F, Camerini G, Cordera R. Adipose Tissue Composition in Obesity and After Bariatric Surgery. Obes Surg. 2019;29:3030–3038. doi: 10.1007/s11695-019-04030-z. PubMed DOI

Chen Y, Yang J, Nie X, Song Z, Gu Y. Effects of Bariatric Surgery on Change of Brown Adipocyte Tissue and Energy Metabolism in Obese Mice. Obes Surg. 2018;28:820–830. doi: 10.1007/s11695-017-2899-8. PubMed DOI

Okla M, Wang W, Kang I, Pashaj A, Carr T, Chung S. Activation of Toll-like receptor 4 (TLR4) attenuates adaptive thermogenesis via endoplasmic reticulum stress. J Biol Chem. 2015;290:26476–26490. doi: 10.1074/jbc.M115.677724. PubMed DOI PMC

Gavaldà-Navarro A, Moreno-Navarrete JM, Quesada-López T, Cairó M, Giralt M, Fernández-Real JM, et al. Lipopolysaccharide-binding protein is a negative regulator of adipose tissue browning in mice and humans. Diabetologia. 2016;59:2208–2218. doi: 10.1007/s00125-016-4028-y. PubMed DOI

Mahdaviani K, Benador IY, Su S, Gharakhanian RA, Stiles L, Trudeau KM, et al. Mfn2 deletion in brown adipose tissue protects from insulin resistance and impairs thermogenesis. EMBO Rep. 2017;18:1123–1138. doi: 10.15252/embr.201643827. PubMed DOI PMC

Tilokani L, Nagashima S, Paupe V, Prudent J. Mitochondrial dynamics: Overview of molecular mechanisms. Essays Biochem. 2018;62:341–360. doi: 10.1042/EBC20170104. PubMed DOI PMC

Jornayvaz FR, Shulman GI. Regulation of mitochondrial biogenesis. Essays Biochem. 2010;47:69–84. doi: 10.1042/bse0470069. PubMed DOI PMC

Ferree A, Shirihai O. Mitochondrial dynamics: The intersection of form and function. Adv Exp Med Biol. 2012;748:13–40. doi: 10.1007/978-1-4614-3573-0_2. PubMed DOI PMC

Pearce SF, Rebelo-Guiomar P, D’Souza AR, Powell CA, Van Haute L, Minczuk M. Regulation of Mammalian Mitochondrial Gene Expression: Recent Advances. Trends Biochem Sci. 2017;42:625–639. doi: 10.1016/j.tibs.2017.02.003. PubMed DOI PMC

Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–419. doi: 10.1007/BF00280883. PubMed DOI

Friedewald WT, Levy RI, Fredrickson DS. Estimation of the Concentration of Low-Density Lipoprotein Cholesterol in Plasma, Without Use of the Preparative Ultracentrifuge. Clin Chem. 1972;18:499–502. doi: 10.1093/clinchem/18.6.499. PubMed DOI

McTernan PG, Anwar A, Eggo MC, Barnett AH, Stewart PM, Kumar S. Gender differences in the regulation of P450 aromatase expression and activity in human adipose tissue. Int J Obes. 2000;24:875–881. doi: 10.1038/sj.ijo.0801254. PubMed DOI

Kusminski CM, Da Silva NF, Creely SJ, Fisher FM, Harte AL, Baker AR, et al. The in vitro effects of resistin on the innate immune signaling pathway in isolated human subcutaneous adipocytes. J Clin Endocrinol Metab. 2007;92:270–276. doi: 10.1210/jc.2006-1151. PubMed DOI

Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012;9:676–682. doi: 10.1038/nmeth.2019. PubMed DOI PMC

Jackisch L, Murphy AM, Kumar S, Randeva H, Tripathi G, McTernan PG. Tunicamycin-Induced Endoplasmic Reticulum Stress Mediates Mitochondrial Dysfunction in Human Adipocytes. J Clin Endocrinol Metab. 2020;105:2905–2918. doi: 10.1210/clinem/dgaa258. PubMed DOI

Tong DL, Boocock DJ, Dhondalay GKR, Lemetre C, Ball GR. Artificial Neural Network Inference (ANNI): A Study on Gene-Gene Interaction for Biomarkers in Childhood Sarcomas. PLoS ONE. 2014;9:e102483. doi: 10.1371/journal.pone.0102483. PubMed DOI PMC

Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13:2498–2504. doi: 10.1101/gr.1239303. PubMed DOI PMC

IBM Corp . Released 2012. IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp; 2012.

Yeo CR, Agrawal M, Hoon S, Shabbir A, Shrivastava MK, Huang S, et al. SGBS cells as a model of human adipocyte browning: A comprehensive comparative study with primary human white subcutaneous adipocytes. Sci Rep. 2017;7:4031. doi: 10.1038/s41598-017-04369-2. PubMed DOI PMC

Pisani DF, Barquissau V, Chambard JC, Beuzelin D, Ghandour RA, Giroud M, et al. Mitochondrial fission is associated with UCP1 activity in human brite/beige adipocytes. Mol Metab. 2018;7:35–44. doi: 10.1016/j.molmet.2017.11.007. PubMed DOI PMC

Villarroya F, Cereijo R, Gavaldà-Navarro A, Villarroya J, Giralt M. Inflammation of brown/beige adipose tissues in obesity and metabolic disease. J Intern Med. 2018;284:492–504. doi: 10.1111/joim.12803. PubMed DOI

Cui X-B, Chen S-Y. White adipose tissue browning and obesity. 2017. 10.7555/JBR.31.20160101. PubMed PMC

Beiroa D, Imbernon M, Gallego R, Senra A, Herranz D, Villarroya F, et al. GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK. Diabetes. 2014;63:3346–3358. doi: 10.2337/db14-0302. PubMed DOI

Cero C, Lea HJ, Zhu KY, Shamsi F, Tseng Y-H, Cypess AM. β3-Adrenergic receptors regulate human brown/beige adipocyte lipolysis and thermogenesis. JCI Insight. 2021;6:e139160. PubMed PMC

Melby CL, Paris HL, Foright RM, Peth J. Attenuating the Biologic Drive for Weight Regain Following Weight Loss: Must What Goes Down Always Go Back Up? Nutrients. 2017;9. PubMed PMC

Bae J, Ricciardi CJ, Esposito D, Komarnytsky S, Hu P, Curry BJ, et al. Activation of pattern recognition receptors in brown adipocytes induces inflammation and suppresses uncoupling protein 1 expression and mitochondrial respiration. Am J Physiol Cell Physiol. 2014;306:C918–C930. doi: 10.1152/ajpcell.00249.2013. PubMed DOI

Nøhr MK, Bobba N, Richelsen B, Lund S, Pedersen SB. Inflammation downregulates UCP1 expression in brown adipocytes potentially via SIRT1 and DBC1 interaction. Int J Mol Sci. 2017;18. PubMed PMC

Okla M, Zaher W, Alfayez M, Chung S. Inhibitory Effects of Toll-Like Receptor 4, NLRP3 Inflammasome, and Interleukin-1β on White Adipocyte Browning. Inflammation. 2018;41:626–642. doi: 10.1007/s10753-017-0718-y. PubMed DOI PMC

van Marken Lichtenbelt WD, Schrauwen P. Implications of nonshivering thermogenesis for energy balance regulation in humans. Am J Physiol Regul Integr Comp Physiol. 2011;301:R285–96. PubMed

Wikstrom JD, Mahdaviani K, Liesa M, Sereda SB, Si Y, Las G, et al. Hormone-induced mitochondrial fission is utilized by brown adipocytes as an amplification pathway for energy expenditure. EMBO J. 2014;33:418–436. PubMed PMC

Woo CY, Jang JE, Lee SE, Koh EH, Lee KU. Mitochondrial dysfunction in adipocytes as a primary cause of adipose tissue inflammation. Diabetes Metab J. 2019;43:247–256. doi: 10.4093/dmj.2018.0221. PubMed DOI PMC

Radilla-Vázquez RB, Parra-Rojas I, Martínez-Hernández NE, Márquez-Sandoval YF, Illades-Aguiar B, Castro-Alarcón N. Gut Microbiota and Metabolic Endotoxemia in Young Obese Mexican Subjects. Obes Facts. 2016;9:1–11. doi: 10.1159/000442479. PubMed DOI PMC

Creely SJ, McTernan PG, Kusminski CM, Fisher ff. M, Silva NF da, Khanolkar M, et al. Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. 2007;292:740–7. 10.1152/ajpendo.00302.2006. PubMed

Ziegler AK, Damgaard A, Mackey AL, Schjerling P, Magnusson P, Olesen AT, et al. An anti-inflammatory phenotype in visceral adipose tissue of old lean mice, augmented by exercise. Sci Rep. 2019;9. PubMed PMC

Alvehus M, Burén J, Sjöström M, Goedecke J, Olsson T. The human visceral fat depot has a unique inflammatory profile. Obesity. 2010;18:879–883. doi: 10.1038/oby.2010.22. PubMed DOI

Kristóf E, Klusóczki Á, Veress R, Shaw A, Combi ZS, Varga K, et al. Interleukin-6 released from differentiating human beige adipocytes improves browning. Exp Cell Res. 2019;377:47–55. doi: 10.1016/j.yexcr.2019.02.015. PubMed DOI

Postprandial Triglyceride, Glucose and Insulin Levels 10 Years After Bariatric Surgery in Women With Severe Obesity - A Pilot Study: Part 2 - Biliopancreatic Diversion