Erkenntnisse aus der Fettgewebsforschung

Zusammenfassung

Das Fettgewebe spielt eine wichtige Rolle bei der Entstehung kardiometabolischer Erkrankungen. Eine Zunahme der Fettgewebsmasse im Rahmen der Adipositas, aber auch Fettverteilungsstörungen (z. B. bei Lipodystrophie) stehen im Zusammenhang mit Stoffwechselkrankheiten wie Typ 2 Diabetes, Fettlebererkrankung oder Lipidstoffwechselstörungen und kardiovaskulären Erkrankungen. Allerdings wird das individuelle Risiko für diese Erkrankungen nicht allein durch die Fettmasse bestimmt, sondern auch durch die Funktion des Gewebes und seine zelluläre Zusammensetzung. Auf der einen Seite gibt es Menschen, die trotz ausgeprägter Adipositas lange kardiometabolisch gesund bleiben, während andererseits auch schlanke Menschen Krankheiten entwickeln können, die als typische Folgen von Adipositas angesehen werden.

Durch die Untersuchung des Fettgewebes von extremen Subphänotypen der Adipositas und Fettverteilung (insulinsensitive Adipositas, Lipodystrophie), Adipositas-chirurgischen Interventionen sowie durch die Charakterisierung der Fettgewebsveränderungen im Rahmen der humanen Fettgewebebank (Leipzig Obesity BioBank, LOBB) mit aktuell mehr als 8.000 Gewebespendern zeigte sich, dass die Fehlfunktion des Fettgewebes im Wesentlichen durch eine Hypertrophie der Adipozyten, eine viszerale, ektope Fettverteilung und veränderte zelluläre Zusammensetzung gekennzeichnet ist. Im Rahmen dieser Übersicht werden aktuelle Erkenntnisse aus der Fettgewebsforschung zusammengefasst und die Rolle des Fettgewebes bei der Entstehung von Endorganschäden diskutiert.

Abstract

Adipose tissue plays an important role in the development of cardio-metabolic diseases.

Increased adipose tissue mass in people with obesity, but also impaired fat distribution (e. g., lipodystrophy) are associated with metabolic diseases including type 2 diabetes, fatty liver disease or lipid metabolism disorders as well as cardiovascular diseases. However, the individual risk to develop cardio-metabolic diseases is not entirely determined by fat mass, but also by the function and cellular composition of adipose tissue. There are people who remain metabolically healthy despite obesity, whereas on the other hand lean people may develop typical obesity diseases.

Analyses of human adipose tissue from people with extreme subphenotypes of obesity and fat distribution (e. g., insulin sensitive obesity, lipodystrophy), upon obesity surgery interventions and in the context of the large human adipose tissue biobank (Leipzig Obesity BioBank, LOBB) with currently more than 8,000 donors demonstrated that adipose tissue dysfunction is characterized by adipocyte hypertrophy, visceral, ectopic fat deposition and alterations in the cellular composition. This overview summarises recent advances in adipose tissue research and how adipose tissue dysfunction may contribute to end-organ damage.

Schlüsselwörter

Fettgewebe - Adipositas - Inflammation - Insulinresistenz - Adipokine

Key words

Adipose tissue - obesity - inflammation - insulin resistance - adipokines

Publication History

Article published online:
04 September 2023

• Literatur

• 1 WHO Consultation on Obesity- und World Health Organization, Hrsg. Obesity: preventing and managing the global epidemic: report of a WHO consultation. Geneva: World Health Organization; 2000. 894. 1-253
• 2 Mann JP, Savage DB. What lipodystrophies teach us about the metabolic syndrome. J Clin Invest 2019; 129: 4009-4021
• 3 Zhang Y, Proenca R, Maffei M. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372: 425-432
• 4 Scherer PE, Williams S, Fogliano M. et al. A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 1995; 270: 26746-26749
• 5 Fasshauer M, Blüher M. Adipokines in health and disease. Trends Pharmacol Sci 2015; 36: 461-470
• 6 Blüher M. Adipose tissue dysfunction contributes to obesity related metabolic diseases. Best Pract Res Clin Endocrinol Metab 2013; 27: 163-177
• 7 Dewal RS, Wolfrum C. Master of disguise: deconvoluting adipose tissue heterogeneity and its impact on metabolic health. Curr Opin Genet Dev 2023; 81: 102085
• 8 Markussen LK, Mandrup S. Adipocyte gene expression in obesity – insights gained and challenges ahead. Curr Opin Genet Dev 2023; 81: 102060
• 9 Rosen ED, Spiegelman BM. What we talk about when we talk about fat. Cell 2014; 156: 20-44
• 10 Weisberg SP, McCann D, Desai M. et al. Obesity Is Associated with Macrophage Accumulation in Adipose Tissue. J Clin Invest 2003; 112: 1796-1808
• 11 Xu H, Barnes GT, Yang Q. et al. Chronic Inflammation in Fat Plays a Crucial Role in the Development of Obesity-Related Insulin Resistance. J Clin Invest 2003; 112: 1821-1830
• 12 Klöting N, Fasshauer M, Dietrich A. et al. Insulin-sensitive obesity. Am J Physiol Endocrinol Metab 2010; 299: E506-E515
• 13 Cinkajzlova A, Mraz M, Haluzik M. Adipose Tissue Immune Cells in Obesity, Type 2 Diabetes Mellitus and Cardiovascular Diseases. J Endocrinol 2021; 252: R1-R22
• 14 Emont MP, Jacobs C, Essene AL. et al. A single-cell atlas of human and mouse white adipose tissue. Nature 2022; 603: 926-933
• 15 Massier L, Jalkanen J, Elmastas M. et al. An integrated single cell and spatial transcriptomic map of human white adipose tissue. Nat Commun 2023; 14: 1438
• 16 Habib N, Li Y, Heidenreich M. et al. Div-Seq: Single-Nucleus Rna-Seq Reveals Dynamics of Rare Adult Newborn Neurons. Science 2016; 353: 925-928
• 17 Habib N, Avraham-Davidi I, Basu A. et al. Massively Parallel Single-Nucleus Rna-Seq with Dronc-Seq. Nat Methods 2017; 14: 955-958
• 18 Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006; 444: 860-867
• 19 Cotillard A, Poitou C, Torcivia A. et al. Adipocyte size threshold matters: link with risk of type 2 diabetes and improved insulin resistance after gastric bypass. J Clin Endocrinol Metab 2014; 99: E1466-E1470
• 20 Skurk T, Alberti-Huber C, Herder C. et al. Relationship between adipocyte size and adipokine expression and secretion. J Clin Endocrinol Metab 2007; 92: 1023-1033
• 21 Cinti S. The adipose organ at a glance. Dis Model Mech 2012; 5: 588-594
• 22 Massier L, Chakaroun R, Tabei S. et al. Adipose tissue derived bacteria are associated with inflammation in obesity and type 2 diabetes. Gut 2020; 69: 1796-1806
• 23 Rolle-Kampczyk U, Gebauer S, Haange SB. et al. Accumulation of distinct persistent organic pollutants is associated with adipose tissue inflammation. Sci Total Environ 2020; 748: 142458
• 24 Cancello R, Henegar C, Viguerie N. et al. Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. Diabetes 2005; 54: 2277-2286
• 25 Schmitz J, Evers N, Awazawa M. et al. Obesogenic memory can confer long-term increases in adipose tissue but not liver inflammation and insulin resistance after weight loss. Mol Metab 2016; 5: 328-339
• 26 Wernstedt Asterholm I, Tao C, Morley TS. et al. Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling. Cell Metab 2014; 20: 103-118
• 27 Blüher M. Adipokines – removing road blocks to obesity and diabetes therapy. Mol Metab 2014; 3: 230-240
• 28 Ahima RS, Flier JS. Leptin. Annual Review of Physiology 2000; 62: 413-437
• 29 Farooqi IS, Jebb SA, Langmack G. et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999; 341: 879-884
• 30 Roth JD, Roland BL, Cole RL. et al. Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies. Proc Natl Acad Sci USA 2008; 105: 7257-7262
• 31 Ravussin E, Smith SR, Mitchell JA. et al. Enhanced weight loss with pramlintide/metreleptin: an integrated neurohormonal approach to obesity pharmacotherapy. Obesity (Silver Spring) 2009; 17: 1736-1743
• 32 Rudich A, Kanety H, Bashan N. Adipose stress-sensing kinases: linking obesity to malfunction. Trends Endocrinol Metab 2007; 18: 291-299
• 33 Braune J, Lindhorst A, Fröba J. et al. Multinucleated Giant Cells in Adipose Tissue Are Specialized in Adipocyte Degradation. Diabetes 2021; 70: 538-548
• 34 Reilly SM, Saltiel AR. Adapting to obesity with adipose tissue inflammation. Nat Rev Endocrinol 2017; 13: 633-643