Adipocyte and cell biology

Effects of imidazoline-like drugs on liver and adipose tissues, and their role in preventing obesity and associated cardio-metabolic disorders



We previously observed that selective agonists of the sympatho-inhibitory I1 imidazoline receptors (LNP ligands) have favorable effects on several cardiovascular and metabolic disorders defining the metabolic syndrome, including body weight. The objectives of this study were to explore the effects of LNPs on adiposity and the mechanisms involved, and to evaluate their impact on metabolic homeostasis.


Young Zucker fa/fa rats were treated with LNP599 (10 mg/kg/day) for 12 weeks. Effects on body weight, adiposity (regional re-distribution, morphology, and function of adipose tissues), cardiovascular and metabolic homeostasis, and liver function were evaluated. Direct effects on insulin and AMP-activated protein kinase (AMPK) signaling were studied in human hepatoma HepG2 cells.


LNP599 treatment limited the age-dependent remodeling and inflammation of subcutaneous, epididymal, and visceral adipose tissues, and prevented total fat deposits and the development of obesity. Body-weight stabilization was not related to reduced food intake but rather to enhanced energy expenditure and thermogenesis. Cardiovascular and metabolic parameters were also improved and were significantly correlated with body weight but not with plasma norepinephrine. Insulin and AMPK signaling were enhanced in hepatic tissues of treated animals, whereas blood markers of hepatic disease and pro-inflammatory cytokine levels were reduced. In cultured HepG2 cells, LNP ligands phosphorylated AMPK and the downstream acetyl-CoA carboxylase and prevented oleic acid-induced intracellular lipid accumulation. They also significantly potentiated insulin-mediated AKT activation and this was independent from AMPK.


Selective I1 imidazoline receptor agonists protect against the development of adiposity and obesity, and the associated cardio-metabolic disorders. Activation of I1 receptors in the liver, leading to stimulation of the cellular energy sensor AMPK and insulin sensitization, and in adipose tissues, leading to improvement of morphology and function, are identified as peripheral mechanisms involved in the beneficial actions of these ligands.

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  1. 1.

    Alberti KG, Zimmet P, Shaw J. Metabolic syndrome–a new world-wide definition. A consensus statement from the International Diabetes Federation. Diabet Med. 2006;23:469–80.

    Article  CAS  Google Scholar 

  2. 2.

    Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112:2735–52.

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Harris MF. The metabolic syndrome. Aust Fam Physician. 2013;42:524–7.

    PubMed  Google Scholar 

  4. 4.

    Grassi G, Dell’Oro R, Quarti-Trevano F, Scopelliti F, Seravalle G, Paleari F, et al. Neuroadrenergic and reflex abnormalities in patients with metabolic syndrome. Diabetologia. 2005;48:1359–65.

    Article  CAS  PubMed  Google Scholar 

  5. 5.

    Mancia G, Bousquet P, Elghozi JL, Esler M, Grassi G, Julius S, et al. The sympathetic nervous system and the metabolic syndrome. J Hypertens. 2007;25:909–20.

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    Feldstein C, Julius S. The complex interaction between overweight, hypertension, and sympathetic overactivity. J Am Soc Hypertens. 2009;3:353–65.

    Article  PubMed  Google Scholar 

  7. 7.

    Mahfoud F, Schlaich M, Kindermann I, Ukena C, Cremers B, Brandt MC, et al. Effect of renal sympathetic denervation on glucose metabolism in patients with resistant hypertension: a pilot study. Circulation. 2011;123:1940–6.

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    Schlaich MP, Hering D, Sobotka P, Krum H, Lambert GW, Lambert E, et al. Effects of renal denervation on sympathetic activation, blood pressure, and glucose metabolism in patients with resistant hypertension. Front Physiol. 2012;3:10.

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Witkowski A, Prejbisz A, Florczak E, Kądziela J, Śliwiński P, Bieleń P, et al. Effects of renal sympathetic denervation on blood pressure, sleep apnea course, and glycemic control in patients with resistant hypertension and sleep apnea. Hypertension. 2011;58:559–65.

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    Bousquet P, Feldman J, Schwartz J. Central cardiovascular effects of alpha adrenergic drugs: differences between catecholamines and imidazolines. J Pharmacol Exp Ther. 1984;230:232–6.

    CAS  PubMed  Google Scholar 

  11. 11.

    Schann S, Bruban V, Pompermayer K, Feldman J, Pfeiffer B, Renard P, et al. Synthesis and biological evaluation of pyrrolinic isosteres of rilmenidine. Discovery of cis-/trans-dicyclopropylmethyl-(4,5-dimethyl-4,5-dihydro-3H-pyrrol-2-yl)-amine (LNP 509), an I1 imidazoline receptor selective ligand with hypotensive activity. J Med Chem. 2001;44:1588–93.

    Article  CAS  PubMed  Google Scholar 

  12. 12.

    Bousquet P, Ehrhardt JD, Fellmann L, Gasparik V, Greney H, Hadjeri M, et al. Novel amino-pyrroline derivatives, and use thereof in the prevention and/or treatment of metabolic syndrome. WO 2012/143660 A1, 2011 [patent].

  13. 13.

    Gasparik V, Greney H, Schann S, Feldman J, Fellmann L, Ehrhardt JD, et al. Synthesis and biological evaluation of 2-aryliminopyrrolidines as selective ligands for I1 imidazoline receptors: discovery of new sympatho-inhibitory hypotensive agents with potential beneficial effects in metabolic syndrome. J Med Chem. 2015;58:878–87.

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    Fellmann L, Regnault V, Greney H, Gasparik V, Muscat A, Max JP, et al. A new pyrroline compound selective for i1-imidazoline receptors improves metabolic syndrome in rats. J Pharmacol Exp Ther. 2013;346:370–80.

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    Weiss M, Bouchoucha S, Aiad F, Ayme-Dietrich E, Dali-Youcef N, Bousquet P, et al. Imidazoline-like drugs improve insulin sensitivity through peripheral stimulation of adiponectin and AMPK pathways in a rat model of glucose intolerance. Am J Physiol Endocrinol Metab. 2015;309:E95–104.

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Shehzad A, Iqbal W, Shehzad O, Lee YS. Adiponectin: regulation of its production and its role in human diseases. Hormones (Athens). 2012;11:8–20.

    Article  Google Scholar 

  17. 17.

    Whitehead JP, Richards AA, Hickman IJ, Macdonald GA, Prins JB. Adiponectin–a key adipokine in the metabolic syndrome. Diabetes Obes Metab. 2006;8:264–80.

    Article  CAS  PubMed  Google Scholar 

  18. 18.

    Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors. Endocr Rev. 2005;26:439–51.

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Ruderman NB, Carling D, Prentki M, Cacicedo JM. AMPK, insulin resistance, and the metabolic syndrome. J Clin Invest. 2013;123:2764–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Hasenour CM, Berglund ED, Wasserman DH. Emerging role of AMP-activated protein kinase in endocrine control of metabolism in the liver. Mol Cell Endocrinol. 2013;366:152–62.

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    Luo L, Liu M. Adipose tissue in control of metabolism. J Endocrinol. 2016;231:R77–R99.

    Article  CAS  PubMed  Google Scholar 

  22. 22.

    Gómez-Hernández A, Beneit N, Díaz-Castroverde S, Escribano Ó. Differential role of adipose tissues in obesity and related metabolic and vascular complications. Int J Endocrinol. 2016;2016:1216783.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Bae YJ, Kim SH, Chung JH, Song SW, Kim KS, Kim MK, et al. Evaluation of adiposity-related biomarkers as metabolic syndrome indicators. Clin Nutr Res. 2013;2:91–9.

    Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Aubertin G, Sayeh A, Dillenseger JP, Ayme-Dietrich E, Choquet P, Niederhoffer N. Comparison of bioimpedance spectroscopy and X-Ray micro-computed tomography for total fat volume measurement in mice. PLoS ONE. 2017;12:e0183523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Erdös B, Snipes JA, Miller AW, Busija DW. Cerebrovascular dysfunction in Zucker obese rats is mediated by oxidative stress and protein kinase C. Diabetes. 2004;53:1352–9.

    Article  PubMed  Google Scholar 

  26. 26.

    Oltman CL, Richou LL, Davidson EP, Coppey LJ, Lund DD, Yorek MA. Progression of coronary and mesenteric vascular dysfunction in Zucker obese and Zucker diabetic fatty rats. Am J Physiol Heart Circ Physiol. 2006;291:H1780–7.

    Article  CAS  PubMed  Google Scholar 

  27. 27.

    Després JP, Lemieux I, Bergeron J, Pibarot P, Mathieu P, Larose E, et al. Abdominal obesity and the metabolic syndrome: contribution to global cardiometabolic risk. Arterioscler Thromb Vasc Biol. 2008;28:1039–49.

    Article  CAS  Google Scholar 

  28. 28.

    Lambert E, Straznicky NE, Dawood T, Ika-Sari C, Grima M, Esler MD, et al. Change in sympathetic nerve firing pattern associated with dietary weight loss in the metabolic syndrome. Front Physiol. 2011;2:52.

    Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Straznicky NE, Lambert GW, McGrane MT, Masuo K, Dawood T, Nestel PJ, et al. Weight loss may reverse blunted sympathetic neural responsiveness to glucose ingestion in obese subjects with metabolic syndrome. Diabetes. 2009;58:1126–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Skrapari I, Tentolouris N, Katsilambros N. Baroreflex function: determinants in healthy subjects and disturbances in diabetes, obesity and metabolic syndrome. Curr Diabetes Rev. 2006;2:329–38.

    Article  PubMed  Google Scholar 

  31. 31.

    Huber DA, Schreihofer AM. Attenuated baroreflex control of sympathetic nerve activity in obese Zucker rats by central mechanisms. J Physiol. 2010;588(Pt 9):1515–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Straznicky NE, Lambert GW, Masuo K, Dawood T, Eikelis N, Nestel PJ, et al. Blunted sympathetic neural response to oral glucose in obese subjects with the insulin-resistant metabolic syndrome. Am J Clin Nutr. 2009;89:27–36.

    Article  CAS  PubMed  Google Scholar 

  33. 33.

    Lidell ME, Betz MJ, Enerbäck S. Brown adipose tissue and its therapeutic potential. J Intern Med. 2014;276:364–77.

    Article  CAS  PubMed  Google Scholar 

  34. 34.

    Thoonen R, Hindle AG, Scherrer-Crosbie M. Brown adipose tissue: the heat is on the heart. Am J Physiol Heart Circ Physiol. 2016;310:H1592–605.

    Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Peterson CM, Orooji M, Johnson DN, Naraghi-Pour M, Ravussin E. Brown adipose tissue does not seem to mediate metabolic adaptation to overfeeding in men. Obesity (Silver Spring). 2017;25:502–5.

    Article  Google Scholar 

  36. 36.

    Pita J, Panadero A, Soriano-Guillén L, Rodríguez E, Rovira A. The insulin sensitizing effects of PPAR-γ agonist are associated to changes in adiponectin index and adiponectin receptors in Zucker fatty rats. Regul Pept. 2012;174:18–25.

    Article  CAS  PubMed  Google Scholar 

  37. 37.

    Masaki T, Chiba S, Yasuda T, Tsubone T, Kakuma T, Shimomura I, et al. Peripheral, but not central, administration of adiponectin reduces visceral adiposity and upregulates the expression of uncoupling protein in agouti yellow (Ay/a) obese mice. Diabetes. 2003;52:2266–73.

    Article  CAS  PubMed  Google Scholar 

  38. 38.

    Ohno H, Shinoda K, Spiegelman BM, Kajimura S. PPARγ agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein. Cell Metab. 2012;15:395–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Seale P, Bjork B, Yang W, Kajimura S, Chin S, Kuang S, et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature. 2008;454:961–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Edwards L, Fishman D, Horowitz P, Bourbon N, Kester M, Ernsberger P. The I1-imidazoline receptor in PC12 pheochromocytoma cells activates protein kinases C, extracellular signal-regulated kinase (ERK) and c-jun N-terminal kinase (JNK). J Neurochem. 2001;79:931–40.

    Article  CAS  PubMed  Google Scholar 

  41. 41.

    Greney H, Ronde P, Magnier C, Maranca F, Rascente C, Quaglia W, et al. Coupling of I(1) imidazoline receptors to the cAMP pathway: studies with a highly selective ligand, benazoline. Mol Pharmacol. 2000;57:1142–51.

    CAS  PubMed  Google Scholar 

  42. 42.

    Regunathan S, Evinger MJ, Meeley MP, Reis DJ. Effects of clonidine and other imidazole-receptor binding agents on second messenger systems and calcium influx in bovine adrenal chromaffin cells. Biochem Pharmacol. 1991;42:2011–8.

    Article  CAS  PubMed  Google Scholar 

  43. 43.

    Ernsberger P, Ishizuka T, Liu S, Farrell CJ, Bedol D, Koletsky RJ, et al. Mechanisms of antihyperglycemic effects of moxonidine in the obese spontaneously hypertensive Koletsky rat (SHROB). J Pharmacol Exp Ther. 1999;288:139–47.

    CAS  PubMed  Google Scholar 

  44. 44.

    O’Neill HM, Holloway GP, Steinberg GR. AMPK regulation of fatty acid metabolism and mitochondrial biogenesis: implications for obesity. Mol Cell Endocrinol. 2013;366:135–51.

    Article  CAS  PubMed  Google Scholar 

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This work was financially supported by the SATT Conectus Alsace, the University of Strasbourg, and the Région Alsace (fellowship to MW). We acknowledge Stéphanie Dal and Elodie Seyfritz from the Centre Européen d’Etude du Diabète for their advice and help at imunofluorescence analysis, and Lucie Tischmacher for her technical assistance.

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Correspondence to Nathalie Niederhoffer.

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Aubertin, G., Weiss, M., Traversi, F. et al. Effects of imidazoline-like drugs on liver and adipose tissues, and their role in preventing obesity and associated cardio-metabolic disorders. Int J Obes 43, 2163–2175 (2019).

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