Sick fat (adiposopathy) as the main contributor to metabolic syndrome

• Azamat Kh. Kade
• Elena A. Chabanets
• Sergey A. Zanin
• Pavel P. Polyakov

Abstract

Obesity, primarily the accumulation of visceral fat (prone to lipolysis and inflammation) is considered the most important pathogenetic link in insulin resistance, metabolic syndrome and type 2 diabetes mellitus.

The purpose of the review was to present and summarize current information on the negative impact of adipose tissue dysfunction and the role of this phenomenon in the pathogenesis of the metabolic syndrome and type 2 diabetes mellitus.

Material and methods. A systematic search of Web of Science, EMBASE, MEDLINE, and Google Scholar databases was performed.

Results. Adipose tissue secretes a huge variety of biologically active substances - free fatty acids, adipokines, inflammatory mediators. These substances have a negative effect on insulin-sensitive and all other tissues, inducing inextricably linked free-radical oxidation, mitochondrial dysfunction, histotoxic hypoxia, maladaptive autophagy, apoptosis, dysregulation of transcriptome and post-translational processes, overload of non-fat tissues with lipids (lipotoxicity) enhanced by hyperinsulinemia, and many other cytotoxic mechanisms. Target organ damage disrupts the finely tuned network of feedbacks between the brain, liver, gut, microbiome, muscles, adipose tissue, classic glands and the rest of the organs, provided by myokines, hepatokines, bathokines and other substances, among others. Based on some experimental and clinical data, we agree with the notions that the qualitative aspect - adipocyte dysfunction (adiposopathy) - is at least as important as cell mass. Sick fat has a number of differences from healthy tissue, among which there are indicated mitochondrial dysfunction, inflammation, disorders of browning, cell death, and removal of senescent cells (senolysis). The obesity paradox can be explained from the pathophysiological point of view by this distinction (although the main explanation, in our opinion, should be sought in the internal validity of the works revealing this phenomenon).

Conclusion. The treatment of obesity and its consequences should be based on «healing» rather than «extermination» of adipocytes. Implementation of this approach requires homeostatic influence on neuroimmunoendocrine regulation. Of the available tools, metformin, incretin drugs, sodium-glucose transporter inhibitors, and bariatric surgery probably meet this requirement the most.

Keywords:obesity; metabolic syndrome; insulin resistance; adipokines; browning

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Дисфункция жировой ткани

Adipose tissue dysfunction

Заключение

Патогенез ожирения и МС представляет собой многомерную сеть нарушений интра-, ауто-, паракринной, нервной, эндокринной, иммунной регуляции, изобилующую петлями положительной обратной связи. При этом дисфункция адипоцитов играет не менее важную роль, чем их масса. Важными звеньями патогенеза дисфункции жировой ткани являются воспаление, гипоксия, окислительный стресс, истощение регенеративного пула, мальадаптивные формы клеточной гибели, нарушения сенолиза и др. Жировая ткань, даже будучи поврежденной, частично сохраняет функции регуляторного органа. Из данного предположения следуют определенные тактические выводы. Лечение ожирения и МС должно быть направлено не на "истребление" или "истощение" адипоцита, а на его "исцеление". Таким образом, методы коррекции данных метаболических расстройств должны иметь гомеостатическую направленность. Этому требованию отвечают метформин, инкретиномиметики, ингибиторы натрий-глюкозного котранспортера и бариатрическая хирургия.

Литература

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23. Marton A., Kaneko T., Kovalik J.P., Yasui A., Nishiyama A., Kitada K. et al. Organ protection by SGLT2 inhibitors: role of metabolic energy and water conservation // Nat. Rev. Nephrol. 2021. Vol. 17, N 1. P. 65-77. DOI: https://doi.org/10.1038/s41581-020-00350-x

24. Mestres-Arenas A., Villarroya J., Giralt M., Villarroya F., Peyrou M. A differential pattern of batokine expression in perivascular adipose tissue depots from mice // Front. Physiol. 2021. Vol. 12. P. 1232. DOI: https://doi.org/10.3389/fphys.2021.714530

25. Lee M.W., Lee M., Oh K.J. Adipose tissue-derived signatures for obesity and type 2 diabetes: adipokines, batokines and microRNAs // J. Clin. Med. 2019. Vol. 8, N 6. P. 854. DOI: https://doi.org/10.3390/jcm8060854

26. Meloux A., Rochette L., Maza M., Bichat F., Tribouillard L., Cottin Y. et al. Growth differentiation factor-8 (GDF8)/myostatin is a predictor of troponin I peak and a marker of clinical severity after acute myocardial infarction // J. Clin. Med. 2020. Vol. 9, N 1. P. 116. DOI: https://doi.org/10.3390/jcm9010116

27. Berk K.A., Vongpromek R., Jiang M., Schneider W.J., Timman R., Verhoeven A.J. Levels of the soluble LDL receptor-relative LR11 decrease in overweight individuals with type 2 diabetes upon diet-induced weight loss // Atherosclerosis. 2016. Vol. 254. P. 67-72. DOI: https://doi.org/10.1016/j.atherosclerosis.2016.09.066

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31. Simon J., Nuñez-García M., Fernández-Tussy P., Barbier-Torres L., Fernández-Ramos D., Gómez-Santos B. et al. Targeting hepatic glutaminase 1 ameliorates non-alcoholic steatohepatitis by restoring very-low-density lipoprotein triglyceride assembly // Cell Metab. 2020. Vol. 31, N 3. P. 605-622. DOI: https://doi.org/10.1016/j.cmet.2020.01.013

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