nach oben

20.02.2024 | Original Article

Liraglutide induced browning of visceral white adipose through regulation of miRNAs in high-fat-diet-induced obese mice

verfasst von: Li Zhao, Wenxin Li, Panpan Zhang, Dong Wang, Ling Yang, Guoyue Yuan

Erschienen in: Endocrine

Einloggen, um Zugang zu erhalten

Abstract

Objective

Obesity is characterized by excessive accumulation of white adipose tissue (WAT). Conversely, brown adipose tissue is protective against obesity. We recently reported liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), could inhibit high-fat-diet-induced obesity by browning of WAT. However, the molecular mechanism involved is not well defined. Hence, we aimed to explore whether GLP-1RA could promote brown remodeling in WAT by regulating miRNAs.

Methods

After the obesity model was successfully constructed, C57BL/6J mice were treated with liraglutide (200 μg/kg/d) or equivoluminal saline subcutaneously for 12 weeks. Then, the deposition of abdominal fat was measured by CT scanning. At the end of the treatments, glucose and insulin tolerance in mice were assessed. Serum lipid levels were monitored and epididymal WAT (eWAT) were collected for analysis. Quantitative real-time PCR and western blot analyses were conducted to evaluate the expression of genes and miRNAs associated with white fat browning.

Results

Liraglutide significantly reduced body weight and visceral fat mass. Levels of lipid profile were also improved. Liraglutide upregulated the expression of browning-related genes in eWAT. Meanwhile, the expression level of miRNAs (miR-196a and miR-378a) positively associated with the browning of WAT were increased, while the expression of miR-155, miR-199a, and miR-382 negatively related with browning of WAT were decreased.

Conclusion

Our findings suggest that liraglutide could promote brown remodeling of visceral WAT by bi-regulating miRNAs; this might be one of the mechanisms underlying its effect on weight loss.

X. Jin, T. Qiu, L. Li, R. Yu, X. Chen, C. Li, C.G. Proud, T. Jiang, Pathophysiology of obesity and its associated diseases. Acta. Pharm. Sin. B 13, 2403–2424 (2023). https://doi.org/10.1016/j.apsb.2023.01.012CrossRefPubMedPubMedCentral

F. Shamsi, C.H. Wang, Y.H. Tseng, The evolving view of thermogenic adipocytes - ontogeny, niche and function. Nat. Rev. Endocrinol. 17, 726–744 (2021). https://doi.org/10.1038/s41574-021-00562-6CrossRefPubMedPubMedCentralADS

S. Heinonen, R. Jokinen, A. Rissanen, K.H. Pietiläinen, White adipose tissue mitochondrial metabolism in health and in obesity. Obes. Rev. 21, e12958 (2020). https://doi.org/10.1111/obr.12958CrossRefPubMed

D. Da Eira, S. Jani, R.B. Ceddia, An obesogenic diet impairs uncoupled substrate oxidation and promotes whitening of the brown adipose tissue in rats. J. Physiol. 601, 69–82 (2023). https://doi.org/10.1113/jp283721CrossRefPubMed

N. Vujović, M.J. Piron, J. Qian, S.L. Chellappa, A. Nedeltcheva, D. Barr, S.W. Heng, K. Kerlin, S. Srivastav, W. Wang, B. Shoji, M. Garaulet, M.J. Brady, F. Scheer, Late isocaloric eating increases hunger, decreases energy expenditure, and modifies metabolic pathways in adults with overweight and obesity. Cell Metab. 34, 1486–1498.e7 (2022). https://doi.org/10.1016/j.cmet.2022.09.007CrossRefPubMedPubMedCentral

Y. Li, P.C. Schwalie, A. Bast-Habersbrunner, S. Mocek, J. Russeil, T. Fromme, B. Deplancke, M. Klingenspor, Systems-genetics-based inference of a core regulatory network underlying white fat browning. Cell Rep. 29, 4099–4113.e5 (2019). https://doi.org/10.1016/j.celrep.2019.11.053CrossRefPubMed

V.M. Lima, J. Liu, B.B. Brandão, C.A. Lino, C.S. Balbino Silva, M.A.C. Ribeiro, T.E. Oliveira, C.C. Real, D. de Paula Faria, C. Cederquist, Z.P. Huang, X. Hu, M.L. Barreto-Chaves, J.C.B. Ferreira, W.T. Festuccia, M.A. Mori, C.R. Kahn, D.Z. Wang, G.P. Diniz, miRNA-22 deletion limits white adipose expansion and activates brown fat to attenuate high-fat diet-induced fat mass accumulation. Metabolism 117, 154723 (2021). https://doi.org/10.1016/j.metabol.2021.154723CrossRefPubMedPubMedCentral

Y.F. Lv, J. Yu, Y.L. Sheng, M. Huang, X.C. Kong, W.J. Di, J. Liu, H. Zhou, H. Liang, G.X. Ding, Glucocorticoids suppress the browning of adipose tissue via miR-19b in male mice. Endocrinology 159, 310–322 (2018). https://doi.org/10.1210/en.2017-00566CrossRefPubMed

H. Zhang, M. Guan, K.L. Townsend, T.L. Huang, D. An, X. Yan, R. Xue, T.J. Schulz, J. Winnay, M. Mori, M.F. Hirshman, K. Kristiansen, J.S. Tsang, A.P. White, A.M. Cypess, L.J. Goodyear, Y.H. Tseng, MicroRNA-455 regulates brown adipogenesis via a novel HIF1an-AMPK-PGC1α signaling network. EMBO Rep. 16, 1378–1393 (2015). https://doi.org/10.15252/embr.201540837CrossRefPubMedPubMedCentral

10.

L. He, M. Tang, T. Xiao, H. Liu, W. Liu, G. Li, F. Zhang, Y. Xiao, Z. Zhou, F. Liu, F. Hu, Obesity-associated miR-199a/214 cluster inhibits adipose browning via PRDM16-PGC-1α transcriptional network. Diabetes 67, 2585–2600 (2018). https://doi.org/10.2337/db18-0626CrossRefPubMed

11.

N. Arias, L. Aguirre, A. Fernández-Quintela, M. González, A. Lasa, J. Miranda, M.T. Macarulla, M.P. Portillo, MicroRNAs involved in the browning process of adipocytes. J. Physiol. Biochem. 72, 509–521 (2016). https://doi.org/10.1007/s13105-015-0459-zCrossRefPubMed

12.

M. Mori, H. Nakagami, G. Rodriguez-Araujo, K. Nimura, Y. Kaneda, Essential role for miR-196a in brown adipogenesis of white fat progenitor cells. PLoS Biol. 10, e1001314 (2012). https://doi.org/10.1371/journal.pbio.1001314CrossRefPubMedPubMedCentral

13.

Y. Chen, F. Siegel, S. Kipschull, B. Haas, H. Fröhlich, G. Meister, A. Pfeifer, miR-155 regulates differentiation of brown and beige adipocytes via a bistable circuit. Nat. Commun. 4, 1769 (2013). https://doi.org/10.1038/ncomms2742CrossRefPubMedADS

14.

A. Astrup, S. Rossner, L. Van Gaal, A. Rissanen, L. Niskanen, M. Al Hakim, J. Madsen, M.F. Rasmussen, M.E. Lean; N.N.S. Group, Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet 374, 1606–1616 (2009). https://doi.org/10.1016/S0140-6736(09)61375-1CrossRefPubMed

15.

M.C. Thomas, M.T. Coughlan, M.E. Cooper, The postprandial actions of GLP-1 receptor agonists: the missing link for cardiovascular and kidney protection in type 2 diabetes. Cell Metab. 35, 253–273 (2023). https://doi.org/10.1016/j.cmet.2023.01.004CrossRefPubMed

16.

J. Chen, A. Mei, Y. Wei, C. Li, H. Qian, X. Min, H. Yang, L. Dong, X. Rao, J. Zhong, GLP-1 receptor agonist as a modulator of innate immunity. Front. Immunol. 13, 997578 (2022). https://doi.org/10.3389/fimmu.2022.997578CrossRefPubMedPubMedCentral

17.

Food and Drug Administration, Saxenda (Liraglutide 3.0 Mg) Prescribing Information, (Food and Drug Administration, Springer Field, Maryland, 2014)

18.

D. Beiroa, M. Imbernon, R. Gallego, A. Senra, D. Herranz, F. Villarroya, M. Serrano, J. Fernø, J. Salvador, J. Escalada, C. Dieguez, M. Lopez, G. Frühbeck, R. Nogueiras, GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK. Diabetes 63, 3346–3358 (2014). https://doi.org/10.2337/db14-0302CrossRefPubMed

19.

L. Lynch, A.E. Hogan, D. Duquette, C. Lester, A. Banks, K. LeClair, D.E. Cohen, A. Ghosh, B. Lu, M. Corrigan, D. Stevanovic, E. Maratos-Flier, D.J. Drucker, D. O’Shea, M. Brenner, iNKT cells induce FGF21 for thermogenesis and are required for maximal weight loss in GLP1 therapy. Cell Metab. 24, 510–519 (2016). https://doi.org/10.1016/j.cmet.2016.08.003CrossRefPubMedPubMedCentral

20.

P.L. Valenzuela, P. Carrera-Bastos, A. Castillo-García, D.E. Lieberman, A. Santos-Lozano, A. Lucia, Obesity and the risk of cardiometabolic diseases. Nat. Rev. Cardiol. 20, 475–494 (2023). https://doi.org/10.1038/s41569-023-00847-5CrossRefPubMed

21.

D.M. Rubino, F.L. Greenway, U. Khalid, P.M. O’Neil, J. Rosenstock, R. Sørrig, T.A. Wadden, A. Wizert, W.T. Garvey, Effect of weekly subcutaneous semaglutide vs daily liraglutide on body weight in adults with overweight or obesity without diabetes: The STEP 8 Randomized Clinical Trial. JAMA 327, 138–150 (2022). https://doi.org/10.1001/jama.2021.23619CrossRefPubMedPubMedCentral

22.

A.S. Kelly, P. Auerbach, M. Barrientos-Perez, I. Gies, P.M. Hale, C. Marcus, L.D. Mastrandrea, N. Prabhu, S. Arslanian, A randomized, controlled trial of liraglutide for adolescents with obesity. N. Eng. J. Med. 382, 2117–2128 (2020). https://doi.org/10.1056/NEJMoa1916038CrossRef

23.

D. Papamargaritis, C.W. le Roux, J.J. Holst, M.J. Davies, New therapies for obesity. Cardiovasc. Res. (2022). https://doi.org/10.1093/cvr/cvac176

24.

K. Raun, P. von Voss, C.F. Gotfredsen, V. Golozoubova, B. Rolin, L.B. Knudsen, Liraglutide, a long-acting glucagon-like peptide-1 analog, reduces body weight and food intake in obese candy-fed rats, whereas a dipeptidyl peptidase-IV inhibitor, vildagliptin, does not. Diabetes 56, 8–15 (2007). https://doi.org/10.2337/db06-0565CrossRefPubMed

25.

X. Pi-Sunyer, A. Astrup, K. Fujioka, F. Greenway, A. Halpern, M. Krempf, D.C. Lau, C.W. le Roux, R. Violante Ortiz, C.B. Jensen, J.P. Wilding, A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N. Eng. J. Med. 373, 11–22 (2015). https://doi.org/10.1056/NEJMoa1411892CrossRef

26.

R.Z. Ye, G. Richard, N. Gévry, A. Tchernof, A.C. Carpentier, Fat cell size: measurement methods, pathophysiological origins, and relationships with metabolic dysregulations. Endocr. Rev. 43, 35–60 (2022). https://doi.org/10.1210/endrev/bnab018CrossRefPubMed

27.

T. Skurk, C. Alberti-Huber, C. Herder, H. Hauner, Relationship between adipocyte size and adipokine expression and secretion. J. Clin. Endocrinol. Metab. 92, 1023–1033 (2007). https://doi.org/10.1210/jc.2006-1055CrossRefPubMed

28.

Y. Wan, X. Bao, J. Huang, X. Zhang, W. Liu, Q. Cui, D. Jiang, Z. Wang, R. Liu, Q. Wang, Novel GLP-1 analog supaglutide reduces HFD-induced obesity associated with increased Ucp-1 in white adipose tissue in mice. Front. Physiol. 8, 294 (2017). https://doi.org/10.3389/fphys.2017.00294CrossRefPubMedPubMedCentral

29.

S. Kajimura, B.M. Spiegelman, P. Seale, Brown and beige fat: physiological roles beyond heat generation. Cell Metab. 22, 546–559 (2015). https://doi.org/10.1016/j.cmet.2015.09.007CrossRefPubMedPubMedCentral

30.

A. Bartelt, C. John, N. Schaltenberg, J.F.P. Berbée, A. Worthmann, M.L. Cherradi, C. Schlein, J. Piepenburg, M.R. Boon, F. Rinninger, M. Heine, K. Toedter, A. Niemeier, S.K. Nilsson, M. Fischer, S.L. Wijers, W. van Marken Lichtenbelt, L. Scheja, P.C.N. Rensen, J. Heeren, Thermogenic adipocytes promote HDL turnover and reverse cholesterol transport. Nat. Commun. 8, 15010 (2017). https://doi.org/10.1038/ncomms15010CrossRefPubMedPubMedCentralADS

31.

J. Wu, P. Cohen, B.M. Spiegelman, Adaptive thermogenesis in adipocytes: is beige the new brown? Genes Dev. 27, 234–250 (2013). https://doi.org/10.1101/gad.211649.112CrossRefPubMedPubMedCentral

32.

F. Xu, B. Lin, X. Zheng, Z. Chen, H. Cao, H. Xu, H. Liang, J. Weng, GLP-1 receptor agonist promotes brown remodelling in mouse white adipose tissue through SIRT1. Diabetologia 59, 1059–1069 (2016). https://doi.org/10.1007/s00125-016-3896-5CrossRefPubMed

33.

H.J. Jun, Y. Joshi, Y. Patil, R.C. Noland, J.S. Chang, NT-PGC-1α activation attenuates high-fat diet-induced obesity by enhancing brown fat thermogenesis and adipose tissue oxidative metabolism. Diabetes 63, 3615–3625 (2014). https://doi.org/10.2337/db13-1837CrossRefPubMedPubMedCentral

34.

K.J. Chung, A. Chatzigeorgiou, M. Economopoulou, R. Garcia-Martin, V.I. Alexaki, I. Mitroulis, M. Nati, J. Gebler, T. Ziemssen, S.E. Goelz, J. Phieler, J.H. Lim, K.P. Karalis, T. Papayannopoulou, M. Blüher, G. Hajishengallis, T. Chavakis, A self-sustained loop of inflammation-driven inhibition of beige adipogenesis in obesity. Nat. Immunol. 18, 654–664 (2017). https://doi.org/10.1038/ni.3728CrossRefPubMedPubMedCentral

35.

M. Uldry, W. Yang, J. St-Pierre, J. Lin, P. Seale, B.M. Spiegelman, Complementary action of the PGC-1 coactivators in mitochondrial biogenesis and brown fat differentiation. Cell Metab. 3, 333–341 (2006). https://doi.org/10.1016/j.cmet.2006.04.002CrossRefPubMed

36.

D. Cuevas-Ramos, R. Mehta, C.A. Aguilar-Salinas, Fibroblast growth factor 21 and browning of white adipose tissue. Front. Physiol. 10, 37 (2019). https://doi.org/10.3389/fphys.2019.00037CrossRefPubMedPubMedCentral

37.

S. Jash, S. Banerjee, M.J. Lee, S.R. Farmer, V. Puri, CIDEA transcriptionally regulates UCP1 for britening and thermogenesis in human fat cells. iScience 20, 73–89 (2019). https://doi.org/10.1016/j.isci.2019.09.011CrossRefPubMedPubMedCentralADS

38.

J. Wang, Y. Zhou, D. Long, Y. Wu, F. Liu, GLP-1 receptor agonist, liraglutide, protects podocytes from apoptosis in diabetic nephropathy by promoting white fat browning. Biochem. Biophys. Res. Commun. 664, 142–151 (2023). https://doi.org/10.1016/j.bbrc.2023.04.012CrossRefPubMed

39.

L. Zhao, C. Zhu, M. Lu, C. Chen, X. Nie, B. Abudukerimu, K. Zhang, Z. Ning, Y. Chen, J. Cheng, F. Xia, N. Wang, M.D. Jensen, Y. Lu, The key role of a glucagon-like peptide-1 receptor agonist in body fat redistribution. J. Endocrinol. 240, 271–286 (2019). https://doi.org/10.1530/joe-18-0374CrossRefPubMed

40.

X. Zhang, D.C. Yeung, M. Karpisek, D. Stejskal, Z.G. Zhou, F. Liu, R.L. Wong, W.S. Chow, A.W. Tso, K.S. Lam, A. Xu, Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes 57, 1246–1253 (2008). https://doi.org/10.2337/db07-1476CrossRefPubMed

41.

P.Y. Ma, X.Y. Li, Y.L. Wang, D.Q. Lang, L. Liu, Y.K. Yi, Q. Liu, C.Y. Shen, Natural bioactive constituents from herbs and nutraceuticals promote browning of white adipose tissue. Pharmacol. Res. 178, 106175 (2022). https://doi.org/10.1016/j.phrs.2022.106175CrossRefPubMed

42.

N. Huang, J. Wang, W. Xie, Q. Lyu, J. Wu, J. He, W. Qiu, N. Xu, Y. Zhang, MiR-378a-3p enhances adipogenesis by targeting mitogen-activated protein kinase 1. Biochem. Biophys. Res. Commun. 457, 37–42 (2015). https://doi.org/10.1016/j.bbrc.2014.12.055CrossRefPubMed

43.

W.H. Choi, J. Ahn, C.H. Jung, Y.J. Jang, T.Y. Ha, β-lapachone prevents diet-induced obesity by increasing energy expenditure and stimulating the browning of white adipose tissue via downregulation of miR-382 expression. Diabetes 65, 2490–2501 (2016). https://doi.org/10.2337/db15-1423CrossRefPubMed

Titel: Liraglutide induced browning of visceral white adipose through regulation of miRNAs in high-fat-diet-induced obese mice
verfasst von: Li Zhao
Wenxin Li
Panpan Zhang
Dong Wang
Ling Yang
Guoyue Yuan
Publikationsdatum: 20.02.2024
Verlag: Springer US
Erschienen in: Endocrine
Print ISSN: 1355-008X
Elektronische ISSN: 1559-0100
DOI: https://doi.org/10.1007/s12020-024-03734-2

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Notfall-TEP der Hüfte ist auch bei 90-Jährigen machbar

26.04.2024 Hüft-TEP Nachrichten

Ob bei einer Notfalloperation nach Schenkelhalsfraktur eine Hemiarthroplastik oder eine totale Endoprothese (TEP) eingebaut wird, sollte nicht allein vom Alter der Patientinnen und Patienten abhängen. Auch über 90-Jährige können von der TEP profitieren.

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

25.04.2024 Hypotonie Nachrichten

Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.

Bei schweren Reaktionen auf Insektenstiche empfiehlt sich eine spezifische Immuntherapie

25.04.2024 Allergien und Intoleranzreaktionen Nachrichten

Insektenstiche sind bei Erwachsenen die häufigsten Auslöser einer Anaphylaxie. Einen wirksamen Schutz vor schweren anaphylaktischen Reaktionen bietet die allergenspezifische Immuntherapie. Jedoch kommt sie noch viel zu selten zum Einsatz.

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

25.04.2024 Hypertonie Nachrichten

Beginnen ältere Männer im Pflegeheim eine Antihypertensiva-Therapie, dann ist die Frakturrate in den folgenden 30 Tagen mehr als verdoppelt. Besonders häufig stürzen Demenzkranke und Männer, die erstmals Blutdrucksenker nehmen. Dafür spricht eine Analyse unter US-Veteranen.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen