The novel non-steroidal MR antagonist finerenone improves metabolic parameters in high-fat diet-fed mice and activates brown adipose tissue via AMPK-ATGL pathway.
AMP-Activated Protein Kinases
/ physiology
Adipose Tissue, Brown
/ drug effects
Animals
Cells, Cultured
Diet, High-Fat
Lipase
/ physiology
Lipid Metabolism
/ drug effects
Male
Mice
Mice, Inbred C57BL
Mineralocorticoid Receptor Antagonists
/ pharmacology
Naphthyridines
/ pharmacology
Signal Transduction
/ physiology
Thermogenesis
/ drug effects
Uncoupling Protein 1
/ analysis
adipocyte
aldosterone
metabolic syndrome
obesity
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
21
01
2020
revised:
30
06
2020
accepted:
06
07
2020
pubmed:
31
7
2020
medline:
17
3
2021
entrez:
31
7
2020
Statut:
ppublish
Résumé
Mineralocorticoid receptor antagonists (MRAs) are recommended for the treatment of heart failure and hypertension, mainly due to their natriuretic and anti-fibrotic mode of action. Rodent studies have shown that MRAs can prevent adverse metabolic consequences of obesity but an elucidation of underlying molecular mechanisms is missing. Here, we investigated metabolic effects of the novel non-steroidal MRA finerenone (FIN) in a mouse model of high-fat diet (HFD)-induced obesity and the signaling pathways activated by MR antagonism at level of interscapular brown adipose tissue (iBAT). C57BL/6J male mice were fed a normal diet or a HFD (with60% kcal from fat) containing or not FIN for 3 months. Metabolic parameters, adipose tissue morphology, gene and protein expression analysis were assessed. We also used brown adipocyte cultures (T37i cells) to investigate the effects of FIN-mediated MR antagonism upon lipid and mitochondrial metabolism. HFD + FIN-treated mice showed improved glucose tolerance together with increased multilocularity and higher expression of thermogenic markers at the level of iBAT, without differences in white adipose depots, suggesting an iBAT-specific effect of FIN. Mechanistically, FIN increased activation of AMP-activated protein kinase which, in turn, stimulated adipose triglyceride lipase activation, with subsequent increased expression of uncoupling protein-1 in brown adipocytes.
Identifiants
pubmed: 32729974
doi: 10.1096/fj.202000164R
doi:
Substances chimiques
Mineralocorticoid Receptor Antagonists
0
Naphthyridines
0
Ucp1 protein, mouse
0
Uncoupling Protein 1
0
finerenone
0
AMP-Activated Protein Kinases
EC 2.7.11.31
Lipase
EC 3.1.1.3
PNPLA2 protein, mouse
EC 3.1.1.3
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
12450-12465Informations de copyright
© 2020 Federation of American Societies for Experimental Biology.
Références
Ahima RS, Flier JS. Adipose tissue as an endocrine organ. Trends Endocrinol Metab. 2000;11:327-332.
Nicholls DG, Locke RM. Thermogenic mechanisms in brown fat. Physiol Rev. 1984;64:1-64.
Zechner R, Zimmermann R, Eichmann TO, et al. FAT SIGNALS-lipases and lipolysis in lipid metabolism and signaling. Cell Metab. 2012;15:279-291.
Duncan RE, Ahmadian M, Jaworski K, Sarkadi-Nagy E, Sul HS. Regulation of lipolysis in adipocytes. Annu Rev Nutr. 2007;27:79-101.
Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev. 2004;84:277-359.
Ahmadian M, Abbott MJ, Tang T, et al. Desnutrin/ATGL is regulated by AMPK and is required for a brown adipose phenotype. Cell Metab. 2011;13:739-748.
Arner P, Andersson DP, Backdahl J, Dahlman I, Ryden M. Weight gain and impaired glucose metabolism in women are predicted by inefficient subcutaneous fat cell lipolysis. Cell Metab. 2018;28:45-54.e43.
Funder, JW. Mineralocorticoid receptors: distribution and activation. Heart Fail Rev. 2005;10:15-22.
Caprio M, Feve B, Claes A, Viengchareun S, Lombes M, Zennaro MC. Pivotal role of the mineralocorticoid receptor in corticosteroid-induced adipogenesis. FASEB J. 2007;21:2185-2194.
Armani A, Marzolla V, Rosano G, Caprio M. Mineralocorticoid vs glucocorticoid receptors: solo players or team mates in the control of adipogenesis? Int J Obes. 2014;38:1580-1581.
Armani A, Marzolla V, Fabbri A, Caprio M. Cellular mechanisms of MR regulation of adipose tissue physiology and pathophysiology. J Mol Endocrinol. 2015;55:R1-10.
Kuhn E, Lamribet K, Viengchareun S, Le Menuet D, Feve B, Lombes M. UCP1 transrepression in brown fat in vivo and mineralocorticoid receptor anti-thermogenic effects. Ann Endocrinol. 2019;80:1-9.
Viengchareun S, Penfornis P, Zennaro MC, Lombes M. Mineralocorticoid and glucocorticoid receptors inhibit UCP expression and function in brown adipocytes. Am J Physiol Endocrinol Metab. 2001;280:E640-E649.
Kraus D, Jager J, Meier B, Fasshauer M, Klein J. Aldosterone inhibits uncoupling protein-1, induces insulin resistance, and stimulates proinflammatory adipokines in adipocytes. Horm Metab Res. 2005;37:455-459.
Rossi GP, Belfiore A, Bernini G, et al. Body mass index predicts plasma aldosterone concentrations in overweight-obese primary hypertensive patients. J Clin Endocrinol Metab. 2008;93:2566-2571.
Bochud M, Nussberger J, Bovet P, et al. Plasma aldosterone is independently associated with the metabolic syndrome. Hypertension. 2006;48:239-245.
Hirata A, Maeda N, Hiuge A, et al. Blockade of mineralocorticoid receptor reverses adipocyte dysfunction and insulin resistance in obese mice. Cardiovasc Res. 2009;84:164-172.
Armani A, Cinti F, Marzolla V, et al. Mineralocorticoid receptor antagonism induces browning of white adipose tissue through impairment of autophagy and prevents adipocyte dysfunction in high-fat-diet-fed mice. FASEB J. 2014;28:3745-3757.
Feraco A, Marzolla V, Scuteri A, Armani A, Caprio M. Mineralocorticoid receptors in metabolic syndrome: from physiology to disease. Trends Endocrinol Metab. 2020;31:205-217.
Urbanet R, Nguyen Dinh Cat A, Feraco A, et al. Adipocyte mineralocorticoid receptor activation leads to metabolic syndrome and induction of prostaglandin D2 synthase. Hypertension. 2015;66:149-157.
Hirata A, Maeda N, Nakatsuji H, et al. Contribution of glucocorticoid-mineralocorticoid receptor pathway on the obesity-related adipocyte dysfunction. Biochem Biophys Res Commun. 2012;419:182-187.
Wada T, Ishikawa A, Watanabe E, et al. Eplerenone prevented obesity-induced inflammasome activation and glucose intolerance. J Endocrinol. 2017;235:179-191.
van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, et al. Cold-activated brown adipose tissue in healthy men. N Engl J Med. 2009;360:1500-1508.
Celi FS. Human brown adipose tissue plasticity: hormonal and environmental manipulation. In: Spiegelman B, ed. Hormones, Metabolism and the Benefits of Exercise. Cham, Switzerland: Springer; 2017:1-11.
Thuzar M, Law WP, Dimeski G, Stowasser M, Ho KKY. Mineralocorticoid antagonism enhances brown adipose tissue function in humans: A randomized placebo-controlled cross-over study. Diabetes Obes Metab. 2019;21:509-516.
Armani A, Infante M, Fabbri A, Caprio M. Comment on “mineralocorticoid antagonism enhances brown adipose tissue function in humans: A randomized placebo-controlled cross-over study”. Diabetes Obes Metab. 2019;21:2024-2026.
Kolkhof P, Barfacker L. 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: mineralocorticoid receptor antagonists: 60 years of research and development. J Endocrinol. 2017;234:T125-T140.
Kolkhof P, Jaisser F, Kim SY, Filippatos G, Nowack C, Pitt B. Steroidal and novel non-steroidal mineralocorticoid receptor antagonists in heart failure and cardiorenal diseases: comparison at bench and bedside. Handb Exp Pharmacol. 2017;243:271-305.
Kolkhof P, Nowack C, Eitner F. Nonsteroidal antagonists of the mineralocorticoid receptor. Curr Opin Nephrol Hypertens. 2015;24:417-424.
Lainscak M, Pelliccia F, Rosano G, et al. Safety profile of mineralocorticoid receptor antagonists: Spironolactone and eplerenone. Int J Cardiol. 2015;200:25-29.
Navaneethan SD, Nigwekar SU, Sehgal AR, Strippoli GF. Aldosterone antagonists for preventing the progression of chronic kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol. 2009;4:542-551.
Liu LC, Schutte E, Gansevoort RT, van der Meer P, Voors AA. Finerenone: third-generation mineralocorticoid receptor antagonist for the treatment of heart failure and diabetic kidney disease. Expert Opin Investig Drugs. 2015;24:1123-1135.
Filippatos G, Anker SD, Bohm M, et al. A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease. Eur Heart J. 2016;37:2105-2114.
Penfornis P, Viengchareun S, Le Menuet D, Cluzeaud F, Zennaro MC, Lombes M. The mineralocorticoid receptor mediates aldosterone-induced differentiation of T37i cells into brown adipocytes. Am J Physiol Endocrinol Metab. 2000;279:E386-E394.
Bjursell M, Admyre T, Goransson M, et al. Improved glucose control and reduced body fat mass in free fatty acid receptor 2-deficient mice fed a high-fat diet. Am J Physiol Endocrinol Metab. 2011;300:E211-E220.
Zennaro MC, Le Menuet D, Viengchareun S, Walker F, Ricquier D, Lombes M. Hibernoma development in transgenic mice identifies brown adipose tissue as a novel target of aldosterone action. J Clin Invest. 1998;101:1254-1260.
O'Neill HM, Holloway GP, Steinberg GR. AMPK regulation of fatty acid metabolism and mitochondrial biogenesis: implications for obesity. Mol Cell Endocrinol. 2013;366:135-151.
Wu L, Zhang L, Li B, et al. AMP-activated protein kinase (AMPK) regulates energy metabolism through modulating thermogenesis in adipose tissue. Front Physiol. 2018;9:122.
Mummidi S, Das NA, Carpenter AJ, et al. Metformin inhibits aldosterone-induced cardiac fibroblast activation, migration and proliferation in vitro, and reverses aldosterone+salt-induced cardiac fibrosis in vivo. J Mol Cell Cardiol. 2016;98:95-102.
Anthony NM, Gaidhu MP, Ceddia RB. Regulation of visceral and subcutaneous adipocyte lipolysis by acute AICAR-induced AMPK activation. Obesity. 2009;17:1312-1317.
Gaidhu MP, Fediuc S, Anthony NM, et al. Prolonged AICAR-induced AMP-kinase activation promotes energy dissipation in white adipocytes: novel mechanisms integrating HSL and ATGL. J Lipid Res. 2009;50:704-715.
Schweiger M, Romauch M, Schreiber R, et al. Pharmacological inhibition of adipose triglyceride lipase corrects high-fat diet-induced insulin resistance and hepatosteatosis in mice. Nat Commun. 2017;8:14859.
Hankir MK, Klingenspor M. Brown adipocyte glucose metabolism: a heated subject. EMBO Rep. 2018;19:e46404.
Guo C, Ricchiuti V, Lian BQ, et al. Mineralocorticoid receptor blockade reverses obesity-related changes in expression of adiponectin, peroxisome proliferator-activated receptor-gamma, and proinflammatory adipokines. Circulation. 2008;117:2253-2261.
Stanford KI, Middelbeek RJ, Townsend KL, et al. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J Clin Invest. 2013;123:215-223.
Wu C, Cheng W, Sun Y, et al. Activating brown adipose tissue for weight loss and lowering of blood glucose levels: a microPET study using obese and diabetic model mice. PLoS One. 2014;9:e113742.
Daval M, Foufelle F, Ferre P. Functions of AMP-activated protein kinase in adipose tissue. J Physiol. 2006;574:55-62.
Mottillo EP, Desjardins EM, Crane JD, et al. Lack of adipocyte AMPK exacerbates insulin resistance and hepatic steatosis through brown and beige adipose tissue function. Cell Metab. 2016;24:118-129.
Wu L, Xia M, Duan Y, et al. Berberine promotes the recruitment and activation of brown adipose tissue in mice and humans. Cell Death Dis. 2019;10:468.
Fedorenko A, Lishko PV, Kirichok Y. Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria. Cell. 2012;151:400-413.
Kim SJ, Tang T, Abbott M, Viscarra JA, Wang Y, Sul HS. AMPK phosphorylates desnutrin/ATGL and hormone-sensitive lipase to regulate lipolysis and fatty acid oxidation within adipose tissue. Mol Cell Biol. 2016;36:1961-1976.
Mottillo EP, Bloch AE, Leff T, Granneman JG. Lipolytic products activate peroxisome proliferator-activated receptor (PPAR) alpha and delta in brown adipocytes to match fatty acid oxidation with supply. J Biol Chem. 2012;287:25038-25048.
Barbera MJ, Schluter A, Pedraza N, Iglesias R, Villarroya F, Giralt M. Peroxisome proliferator-activated receptor alpha activates transcription of the brown fat uncoupling protein-1 gene. A link between regulation of the thermogenic and lipid oxidation pathways in the brown fat cell. J Biol Chem. 2001;276:1486-1493.
Modica S, Straub LG, Balaz M, et al. Bmp4 promotes a brown to white-like adipocyte shift. Cell Rep. 2016;16:2243-2258.
Townsend KL, Tseng YH. Brown fat fuel utilization and thermogenesis. Trends Endocrinol Metab. 2014;25:168-177.
Yu XX, Lewin DA, Forrest W, Adams SH. Cold elicits the simultaneous induction of fatty acid synthesis and beta-oxidation in murine brown adipose tissue: prediction from differential gene expression and confirmation in vivo. FASEB J. 2002;16:155-168.
Bartelt A, Bruns OT, Reimer R, et al. Brown adipose tissue activity controls triglyceride clearance. Nat Med. 2011;17:200-205.
Berbee JF, Boon MR, Khedoe PP, et al. Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development. Nat Commun. 2015;6:6356.
Loutradis C, Tolika P, Skodra A, Avdelidou A, Sarafidis PA. Prevalence of hyperkalemia in diabetic and non-diabetic patients with chronic kidney disease: a nested case-control study. Am J Nephrol. 2015;42:351-360.
Pitt B, Kober L, Ponikowski P, et al. Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial. Eur Heart J. 2013;34:2453-2463.
Kovesdy CP, Furth SL, Zoccali C, World Kidney Day Steering, C. Obesity and kidney disease: hidden consequences of the epidemic. Can J Kidney Health Dis. 2017;4:2054358117698669.
Anders HJ, Huber TB, Isermann B, Schiffer M. CKD in diabetes: diabetic kidney disease versus nondiabetic kidney disease. Nat Rev Nephrol. 2018;14:361-377.
Bakris GL, Agarwal R, Chan JC, et al. Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial. JAMA. 2015;314:884-894.