Obesity is characterized by accumulation of adipose tissue and is one the most important risk factors in the development of insulin resistance. Carbon monoxide-releasing (CO-releasing) molecules (CO-RMs) have been reported to improve the metabolic profile of obese mice, but the underlying mechanism remains poorly defined. Here, we show that oral administration of CORM-401 to obese mice fed a high-fat diet (HFD) resulted in a significant reduction in body weight gain, accompanied by a marked improvement in glucose homeostasis. We further unmasked an action we believe to be novel, by which CO accumulates in visceral adipose tissue and uncouples mitochondrial respiration in adipocytes, ultimately leading to a concomitant switch toward glycolysis. This was accompanied by enhanced systemic and adipose tissue insulin sensitivity, as indicated by a lower blood glucose and increased Akt phosphorylation. Our findings indicate that the transient uncoupling activity of CO elicited by repetitive administration of CORM-401 is associated with lower weight gain and increased insulin sensitivity during HFD. Thus, prototypic compounds that release CO could be investigated for developing promising insulin-sensitizing agents.

Department of Molecular Chemistry and Biochemistry Faculty of Science and Engineering Doshisha University Kyotanabe Kyoto Japan

Faculty of Medicine University Paris Est Créteil France

Inserm U955 Team 12 Créteil France

Inserm U955 Team 8 Créteil France

Institute of Medical Biochemistry and Laboratory Diagnostics 1st Faculty of Medicine Charles University Prague Czech Republic

Zobrazit více v PubMed

Stumvoll M, Goldstein BJ, van Haeften TW. Type 2 diabetes: principles of pathogenesis and therapy. Lancet. 2005;365(9467):1333–1346. doi: 10.1016/S0140-6736(05)61032-X. PubMed DOI

Guilherme A, Virbasius JV, Puri V, Czech MP. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol. 2008;9(5):367–377. doi: 10.1038/nrm2391. PubMed DOI PMC

Barazzoni R, Gortan Cappellari G, Ragni M, Nisoli E. Insulin resistance in obesity: an overview of fundamental alterations. Eat Weight Disord. 2018;23(2):149–157. doi: 10.1007/s40519-018-0481-6. PubMed DOI

Montgomery MK, Turner N. Mitochondrial dysfunction and insulin resistance: an update. Endocr Connect. 2015;4(1):R1–R15. doi: 10.1530/EC-14-0092. PubMed DOI PMC

Fazakerley DJ, et al. Mitochondrial oxidative stress causes insulin resistance without disrupting oxidative phosphorylation. J Biol Chem. 2018;293(19):7315–7328. doi: 10.1074/jbc.RA117.001254. PubMed DOI PMC

Pospisilik JA, et al. Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes. Cell. 2007;131(3):476–491. doi: 10.1016/j.cell.2007.08.047. PubMed DOI

Nair KS, et al. Asian Indians have enhanced skeletal muscle mitochondrial capacity to produce ATP in association with severe insulin resistance. Diabetes. 2008;57(5):1166–1175. doi: 10.2337/db07-1556. PubMed DOI PMC

Green K, Brand MD, Murphy MP. Prevention of mitochondrial oxidative damage as a therapeutic strategy in diabetes. Diabetes. 2004;53 Suppl 1:S110–S118. PubMed

Harper JA, Dickinson K, Brand MD. Mitochondrial uncoupling as a target for drug development for the treatment of obesity. Obes Rev. 2001;2(4):255–265. doi: 10.1046/j.1467-789X.2001.00043.x. PubMed DOI

Tao H, Zhang Y, Zeng X, Shulman GI, Jin S. Niclosamide ethanolamine-induced mild mitochondrial uncoupling improves diabetic symptoms in mice. Nat Med. 2014;20(11):1263–1269. doi: 10.1038/nm.3699. PubMed DOI PMC

Crunkhorn S. Metabolic disease: Mitochondrial uncoupler reverses diabetes. Nat Rev Drug Discov. 2014;13(12):885. doi: 10.1038/nrd4491. PubMed DOI

Wilson JL, et al. Carbon monoxide reverses the metabolic adaptation of microglia cells to an inflammatory stimulus. Free Radic Biol Med. 2017;104:311–323. doi: 10.1016/j.freeradbiomed.2017.01.022. PubMed DOI

Lavitrano M, et al. Carbon monoxide improves cardiac energetics and safeguards the heart during reperfusion after cardiopulmonary bypass in pigs. FASEB J. 2004;18(10):1093–1095. doi: 10.1096/fj.03-0996fje. PubMed DOI

Almeida AS, Sonnewald U, Alves PM, Vieira HL. Carbon monoxide improves neuronal differentiation and yield by increasing the functioning and number of mitochondria. J Neurochem. 2016;138(3):423–435. doi: 10.1111/jnc.13653. PubMed DOI

Motterlini R, Foresti R. Biological signaling by carbon monoxide and carbon monoxide-releasing molecules. Am J Physiol, Cell Physiol. 2017;312(3):C302–C313. doi: 10.1152/ajpcell.00360.2016. PubMed DOI

Motterlini R, Foresti R. Heme oxygenase-1 as a target for drug discovery. Antioxid Redox Signal. 2014;20(11):1810–1826. doi: 10.1089/ars.2013.5658. PubMed DOI

Motterlini R, Otterbein LE. The therapeutic potential of carbon monoxide. Nat Rev Drug Discov. 2010;9(9):728–743. doi: 10.1038/nrd3228. PubMed DOI

Foresti R, Braud L, Motterlini R. Signaling and Cellular Functions of Carbon Monoxide (CO). In: Wang R, ed. Metallobiology Series - Gasotransmitters. Cambridge, UK: RSC Publishing; 2018:161–191.

Clark JE, et al. Cardioprotective actions by a water-soluble carbon monoxide-releasing molecule. Circ Res. 2003;93(2):e2–e8. PubMed

Fayad-Kobeissi S, et al. Vascular and angiogenic activities of CORM-401, an oxidant-sensitive CO-releasing molecule. Biochem Pharmacol. 2016;102:64–77. doi: 10.1016/j.bcp.2015.12.014. PubMed DOI

Hosick PA, et al. Chronic carbon monoxide treatment attenuates development of obesity and remodels adipocytes in mice fed a high-fat diet. Int J Obes (Lond) 2014;38(1):132–139. doi: 10.1038/ijo.2013.61. PubMed DOI PMC

Hosick PA, AlAmodi AA, Hankins MW, Stec DE. Chronic treatment with a carbon monoxide releasing molecule reverses dietary induced obesity in mice. Adipocyte. 2016;5(1):1–10. doi: 10.1080/21623945.2015.1038443. PubMed DOI PMC

Wegiel B, et al. Carbon monoxide expedites metabolic exhaustion to inhibit tumor growth. Cancer Res. 2013;73(23):7009–7021. doi: 10.1158/0008-5472.CAN-13-1075. PubMed DOI PMC

Cai D, et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med. 2005;11(2):183–190. doi: 10.1038/nm1166. PubMed DOI PMC

Kim HJ, et al. Differential effects of interleukin-6 and -10 on skeletal muscle and liver insulin action in vivo. Diabetes. 2004;53(4):1060–1067. doi: 10.2337/diabetes.53.4.1060. PubMed DOI

Jais A, et al. Heme oxygenase-1 drives metaflammation and insulin resistance in mouse and man. Cell. 2014;158(1):25–40. doi: 10.1016/j.cell.2014.04.043. PubMed DOI PMC

Li M, et al. Treatment of obese diabetic mice with a heme oxygenase inducer reduces visceral and subcutaneous adiposity, increases adiponectin levels, and improves insulin sensitivity and glucose tolerance. Diabetes. 2008;57(6):1526–1535. doi: 10.2337/db07-1764. PubMed DOI

Ndisang JF, Lane N, Jadhav A. Upregulation of the heme oxygenase system ameliorates postprandial and fasting hyperglycemia in type 2 diabetes. Am J Physiol Endocrinol Metab. 2009;296(5):E1029–E1041. doi: 10.1152/ajpendo.90241.2008. PubMed DOI

Nicolai A, et al. Heme oxygenase-1 induction remodels adipose tissue and improves insulin sensitivity in obesity-induced diabetic rats. Hypertension. 2009;53(3):508–515. doi: 10.1161/HYPERTENSIONAHA.108.124701. PubMed DOI PMC

Burgess A, et al. Adipocyte heme oxygenase-1 induction attenuates metabolic syndrome in both male and female obese mice. Hypertension. 2010;56(6):1124–1130. doi: 10.1161/HYPERTENSIONAHA.110.151423. PubMed DOI PMC

Huang JY, Chiang MT, Yet SF, Chau LY. Myeloid heme oxygenase-1 haploinsufficiency reduces high fat diet-induced insulin resistance by affecting adipose macrophage infiltration in mice. PLoS ONE. 2012;7(6):e38626. doi: 10.1371/journal.pone.0038626. PubMed DOI PMC

Kim HJ, et al. Carbon monoxide protects against hepatic ischemia/reperfusion injury via ROS-dependent Akt signaling and inhibition of glycogen synthase kinase 3β. Oxid Med Cell Longev. 2013;2013:306421. PubMed PMC

Yang PM, Huang YT, Zhang YQ, Hsieh CW, Wung BS. Carbon monoxide releasing molecule induces endothelial nitric oxide synthase activation through a calcium and phosphatidylinositol 3-kinase/Akt mechanism. Vascul Pharmacol. 2016;87:209–218. doi: 10.1016/j.vph.2016.09.010. PubMed DOI

Wegiel B, et al. Nitric oxide-dependent bone marrow progenitor mobilization by carbon monoxide enhances endothelial repair after vascular injury. Circulation. 2010;121(4):537–548. doi: 10.1161/CIRCULATIONAHA.109.887695. PubMed DOI PMC

Lo Iacono L, et al. A carbon monoxide-releasing molecule (CORM-3) uncouples mitochondrial respiration and modulates the production of reactive oxygen species. Free Radic Biol Med. 2011;50(11):1556–1564. doi: 10.1016/j.freeradbiomed.2011.02.033. PubMed DOI

Kaczara P, et al. Carbon monoxide released by CORM-401 uncouples mitochondrial respiration and inhibits glycolysis in endothelial cells: A role for mitoBKCa channels. Biochim Biophys Acta. 2015;1847(10):1297–1309. PubMed

Sandouka A, et al. Carbon monoxide-releasing molecules (CO-RMs) modulate respiration in isolated mitochondria. Cell Mol Biol (Noisy-le-grand) 2005;51(4):425–432. PubMed

González-Barroso MM, Anedda A, Gallardo-Vara E, Redondo-Horcajo M, Rodríguez-Sánchez L, Rial E. Fatty acids revert the inhibition of respiration caused by the antidiabetic drug metformin to facilitate their mitochondrial β-oxidation. Biochim Biophys Acta. 2012;1817(10):1768–1775. PubMed

Zhang Y, Ye J. Mitochondrial inhibitor as a new class of insulin sensitizer. Acta Pharm Sin B. 2012;2(4):341–349. doi: 10.1016/j.apsb.2012.06.010. PubMed DOI PMC

Speakman JR, et al. Uncoupled and surviving: individual mice with high metabolism have greater mitochondrial uncoupling and live longer. Aging Cell. 2004;3(3):87–95. doi: 10.1111/j.1474-9728.2004.00097.x. PubMed DOI

Crook SH, et al. [Mn(CO)4{S2CNMe(CH2CO2H)}], a new water-soluble CO-releasing molecule. Dalton Trans. 2011;40(16):4230–4235. doi: 10.1039/c1dt10125k. PubMed DOI

Lee S, et al. Comparison between surrogate indexes of insulin sensitivity and resistance and hyperinsulinemic euglycemic clamp estimates in mice. Am J Physiol Endocrinol Metab. 2008;294(2):E261–E270. doi: 10.1152/ajpendo.00676.2007. PubMed DOI

Sawaki D, et al. Visceral adipose tissue drives cardiac aging through modulation of fibroblast senescence by osteopontin production. Circulation. 2018;138(8):809–822. doi: 10.1161/CIRCULATIONAHA.117.031358. PubMed DOI

Ternacle J, et al. Short-term high-fat diet compromises myocardial function: a radial strain rate imaging study. Eur Heart J Cardiovasc Imaging. 2017;18(11):1283–1291. doi: 10.1093/ehjci/jew316. PubMed DOI

Nikam A, et al. Diverse Nrf2 activators coordinated to cobalt carbonyls induce heme oxygenase-1 and release carbon monoxide in vitro and in vivo. J Med Chem. 2016;59(2):756–762. doi: 10.1021/acs.jmedchem.5b01509. PubMed DOI

Rodkey FL, Hill TA, Pitts LL, Robertson RF. Spectrophotometric measurement of carboxyhemoglobin and methemoglobin in blood. Clin Chem. 1979;25(8):1388–1393. PubMed

Vreman HJ, Wong RJ, Kadotani T, Stevenson DK. Determination of carbon monoxide (CO) in rodent tissue: effect of heme administration and environmental CO exposure. Anal Biochem. 2005;341(2):280–289. doi: 10.1016/j.ab.2005.03.019. PubMed DOI

Minegishi S, et al. Detection and removal of endogenous carbon monoxide by selective and cell-permeable hemoprotein model complexes. J Am Chem Soc. 2017;139(16):5984–5991. doi: 10.1021/jacs.7b02229. PubMed DOI