Drug-induced metabolic alterations in adipose tissue - with an emphasis in epicardial adipose tissue

PINHO, ARYANE C.O.; BURGEIRO, ANA; PEREIRA, MARIA JOÃO; CARVALHO, EUGENIA

doi:10.1590/0001-3765202220201819

Acessibilidade / Reportar erro

Brasil

Anais da Academia Brasileira de Ciências

Español English

Brasil

Español English

sumário « anterior atual seguinte »

Sumário

HEALTH SCIENCES • An. Acad. Bras. Ciênc. 94 (1) • 2022 • https://doi.org/10.1590/0001-3765202220201819 copy

Drug-induced metabolic alterations in adipose tissue - with an emphasis in epicardial adipose tissue

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Currently, research on understanding adipose tissue (AT) metabolism has increased significantly. AT is an endocrine organ, that releases proteins, specific metabolites, hormones, micro-RNAs and signaling lipids, all involved in a network of inter-organ communication. Among other effects, AT dysfunction contributes to a proinflammatory and diabetogenic state, from an early stage in the disease development. Overweight and obesity have reached epidemic proportions worldwide, which has been linked to the development and progression of high-comorbidity and diseases, such as insulin resistance, type 2 diabetes mellitus, hypertension, and cardiovascular diseases (CVD). Therefore, therapeutic strategies have been devised to modulate the composition of fat stores, including changes in lifestyle and/or pharmacological treatment for weight management or attenuation of cardiometabolic risk factors. As a result, life expectancy has been increasing. However, the population is being overmedicated and secondary adverse effects due to drug usage can be serious. Commonly prescribed drugs for immunosuppression and psychiatric disorders, such as severe depression and anxiety, are known to alter metabolism, particularly, in AT depots. In this review, we discuss important molecular mechanisms in AT, especially in epicardial AT (EAT), that are highly modulated by these drugs, and put forth EAT as a potential therapeutic target for CVD.

Key words
epicardial adipose tissue; pharmacological drugs; metabolic modulation; cardiometabolic risk factors

MAIN ROLES OF THE ADIPOSE TISSUE	REFERENCES
Energy metabolism: energy homeostasis	Luna-Luna et al. (2015)LUNA-LUNA M, MEDINA-URRUTIA A, VARGAS-ALARCÓN G, COSS-ROVIROSA F, VARGAS-BARRÓN J & PÉREZ-MENDEZA Ó. 2015. Adipose Tissue in Metabolic Syndrome: Onset and Progression of Atherosclerosis. Arch Med Res 46(5): 392-407., Boumelhem et al. (2017)BOUMELHEM BB, ASSINDER SJ, BELL-ANDERSON KS & FRASER ST. 2017. Flow cytometric single cell analysis reveals heterogeneity between adipose depots. Adipocyte 6(2): 112-123., Scherer (2019)SCHERER PE. 2019. The Many Secret Lives of Adipocytes: Implications for Diabetes. Diabetologia 62(2): 223-232.
Lipid metabolism	Ahima (2006)AHIMA RS. 2006. Adipose tissue as an endocrine organ. Obesity 14(Suppl 5): 242S–249S., Boumelhem et al. (2017)BOUMELHEM BB, ASSINDER SJ, BELL-ANDERSON KS & FRASER ST. 2017. Flow cytometric single cell analysis reveals heterogeneity between adipose depots. Adipocyte 6(2): 112-123.
Glucose metabolism	Ahima (2006)AHIMA RS. 2006. Adipose tissue as an endocrine organ. Obesity 14(Suppl 5): 242S–249S., Boumelhem et al. (2017)BOUMELHEM BB, ASSINDER SJ, BELL-ANDERSON KS & FRASER ST. 2017. Flow cytometric single cell analysis reveals heterogeneity between adipose depots. Adipocyte 6(2): 112-123.
Thermoregulation: body temperature control	Luna-Luna et al. (2015)LUNA-LUNA M, MEDINA-URRUTIA A, VARGAS-ALARCÓN G, COSS-ROVIROSA F, VARGAS-BARRÓN J & PÉREZ-MENDEZA Ó. 2015. Adipose Tissue in Metabolic Syndrome: Onset and Progression of Atherosclerosis. Arch Med Res 46(5): 392-407., Boumelhem et al. (2017)BOUMELHEM BB, ASSINDER SJ, BELL-ANDERSON KS & FRASER ST. 2017. Flow cytometric single cell analysis reveals heterogeneity between adipose depots. Adipocyte 6(2): 112-123.
Signaling: interaction with neural/sympathetic (e.g., adrenergic) or hormonal (e.g., insulin) stimuli	Ahima (2006)AHIMA RS. 2006. Adipose tissue as an endocrine organ. Obesity 14(Suppl 5): 242S–249S., Luna-Luna et al. (2015)LUNA-LUNA M, MEDINA-URRUTIA A, VARGAS-ALARCÓN G, COSS-ROVIROSA F, VARGAS-BARRÓN J & PÉREZ-MENDEZA Ó. 2015. Adipose Tissue in Metabolic Syndrome: Onset and Progression of Atherosclerosis. Arch Med Res 46(5): 392-407., Poloni et al. 2015POLONI A, MAURIZI G, CIARLANTINI M, MEDICI M, MATTIUCCI D, MANCINI S, MAURIZI A, FALCONI M, OLIVIERI A & LEONI P. 2015. Interaction between human mature adipocytes and lymphocytes induces T-cell proliferation. Cytotherapy 17(9): 1292-1301.)
Inflammation: secretes anti- (e.g., adiponectin) and proinflammatory (e.g., tumor necrosis factor (TNF), interleukin-6 (IL-6), leptin, resistin) adipokines	Ahima (2006)AHIMA RS. 2006. Adipose tissue as an endocrine organ. Obesity 14(Suppl 5): 242S–249S., Poloni et al. 2015POLONI A, MAURIZI G, CIARLANTINI M, MEDICI M, MATTIUCCI D, MANCINI S, MAURIZI A, FALCONI M, OLIVIERI A & LEONI P. 2015. Interaction between human mature adipocytes and lymphocytes induces T-cell proliferation. Cytotherapy 17(9): 1292-1301.), Scherer (2019)SCHERER PE. 2019. The Many Secret Lives of Adipocytes: Implications for Diabetes. Diabetologia 62(2): 223-232.
Regulation of immunometabolism	Vielma et al. (2013), Kumari et al. (2018), Zhao et al. (2018)ZHAO H, SHANG Q, PAN Z, BAI Y, LI Z, ZHANG H, ZHANG Q, GUO C, ZHANG L & WANG Q. 2018. Exosomes from adipose-derived stem cells attenuate adipose inflammation and obesity through polarizing M2 macrophages and beiging in white adipose tissue. Diabetes 67: 235-247.

DRUG-TYPES			Main effects in isolated adipocytes or adipose tissue depots	REFERENCES
Immunosuppressive agents (IAs)	Calcineurin inhibitors	Cyclosporin A (CsA)	- Impairs glucose tolerance and increases lipolysis of both human and rodent adipocytes - Increases adipocyte weight and diameter - Removes GLUT4 from the cell surface of differentiated human adipocytes via an increased rate of endocytosis	Lopes et al. 2013LOPES P, FUHRMANN A, SERENO J, PEREIRA MJ, NUNES P, PEDRO J, MELÃO A, REIS F & CARVALHO E. 2013. Effects of Cyclosporine and Sirolimus on Insulin-Stimulated Glucose Transport and Glucose Tolerance in a Rat Model. Transplant Proc 45(3): 1142-1148., Lopes et al. 2014aLOPES PC, FUHRMANNA A, SERENOB J, ESPINOZA DO, PEREIRA MJ, ERIKSSON JW, REIS F & CARVALHO E. 2014a. Short and long term in vivo effects of Cyclosporine A and Sirolimus on genes and proteins involved in lipid metabolism in Wistar rats. Metab Clin Exp 63(5): 702-715., Pereira et al. 2013PEREIRA MJ, PALMING J, RIZELL M, AURELIANO M, CARVALHO E, SVENSSON MK & ERIKSSON JW. 2013. The immunosuppressive agents rapamycin, cyclosporin A and tacrolimus increase lipolysis, inhibit lipid storage and alter expression of genes involved in lipid metabolism in human adipose tissue. Mol Cell Endocrinol 365(2): 260-269., Pereira et al. 2014PEREIRA MJ, PALMING J, RIZELL M, AURELIANO M, CARVALHO E, SVENSSON MK & ERIKSSON JW. 2014. Cyclosporine A and tacrolimus reduce the amount of GLUT4 at the cell surface in human adipocytes: Increased endocytosis as a potential mechanism for the diabetogenic effects of immunosuppressive agents. J Clin Endocrinol Metab 99(10): E1885-94.
	Calcineurin inhibitors	Tacrolimus (Tac)	- Increases lipolysis and inhibits lipid storage in isolated human adipocytes and/or adipose tissue - Removes GLUT4 from the cell surface of differentiated human adipocytes via an increased rate of endocytosis	Pereira et al. 2013PEREIRA MJ, PALMING J, RIZELL M, AURELIANO M, CARVALHO E, SVENSSON MK & ERIKSSON JW. 2013. The immunosuppressive agents rapamycin, cyclosporin A and tacrolimus increase lipolysis, inhibit lipid storage and alter expression of genes involved in lipid metabolism in human adipose tissue. Mol Cell Endocrinol 365(2): 260-269., Pereira et al. 2014PEREIRA MJ, PALMING J, RIZELL M, AURELIANO M, CARVALHO E, SVENSSON MK & ERIKSSON JW. 2014. Cyclosporine A and tacrolimus reduce the amount of GLUT4 at the cell surface in human adipocytes: Increased endocytosis as a potential mechanism for the diabetogenic effects of immunosuppressive agents. J Clin Endocrinol Metab 99(10): E1885-94.
	Rapamycin (RAPA) = Sirolimus (SRL)		- Impairs glucose tolerance and increases lipolysis in human adipocytes or in isolated rodent adipocytes in WAT - Reduces the phosphorylation and/or protein levels of the insulin signaling proteins of both human and rodent adipocytes - Inhibits lipolysis, alters mitochondrial bioenergetics and reduces thermogenesis in BAT of the rats	Lopes el at. 2013, Lopes et al. 2014aLOPES PC, FUHRMANNA A, SERENOB J, ESPINOZA DO, PEREIRA MJ, ERIKSSON JW, REIS F & CARVALHO E. 2014a. Short and long term in vivo effects of Cyclosporine A and Sirolimus on genes and proteins involved in lipid metabolism in Wistar rats. Metab Clin Exp 63(5): 702-715., Lopes et al. 2014bLOPES PC, FUHRMANN A, CARVALHO F, SERENO J, SANTOS MR, PEREIRA MJ, ERIKSSON JW, REIS F & CARVALHO E. 2014b. Cyclosporine A enhances gluconeogenesis while sirolimus impairs insulin signaling in peripheral tissues after 3 weeks of treatment. Biochem Pharmacol 91(1): 61-73., Pereira et al. 2012PEREIRA MJ, PALMING J, RIZELL M, AURELIANO M, CARVALHO E, SVENSSON MK & ERIKSSON JW. 2012. MTOR inhibition with rapamycin causes impaired insulin signalling and glucose uptake in human subcutaneous and omental adipocytes. Mol Cell Endocrinol 355(1): 96-105., Pereira et al. 2013PEREIRA MJ, PALMING J, RIZELL M, AURELIANO M, CARVALHO E, SVENSSON MK & ERIKSSON JW. 2013. The immunosuppressive agents rapamycin, cyclosporin A and tacrolimus increase lipolysis, inhibit lipid storage and alter expression of genes involved in lipid metabolism in human adipose tissue. Mol Cell Endocrinol 365(2): 260-269., García-Casarrubios E et al. 2016
Antipsychotic drugs (ASDs)	Olanzapine		- Upregulates several genes involved in lipid biosynthesis in adipose tissues and decreases lipolytic activity on rat adipocyte - Induces low grade inflammatory state in adipose tissue of the rodent models - Reduces BAT thermogenesis in female rats	Skrede et al. 2012SKREDE S ET AL. 2012. Olanzapine, but not aripiprazole, weight-independently elevates serum triglycerides and activates lipogenic gene expression in female rats. Int J Neuropsychopharmacol 15(2): 163-179., Albaugh et al. 2011ALBAUGH VL, JUDSON JG, SHE P, LANG CH, MARESCA KP, JOYAL JL & LYNCH CJ. 2011. Olanzapine promotes fat accumulation in male rats by decreasing physical activity, repartitioning energy and increasing adipose tissue lipogenesis while impairing lipolysis. Mol Psychiatr 16(5): 569-581., Victoriano et al. 2010VICTORIANO M, BEAUREPAIRE RD, NAOUR N, GUERRE-MILLO M, QUIGNARD-BOULANGÉ A, HUNEAU JF, MATHÉ V, TOMÉ D & HERMIR D. 2010. Olanzapine-induced accumulation of adipose tissue is associated with an inflammatory state. Brain Res 1350: 167-175., Li et al. 2019LI H, PENG S, LI S, LIU S, LV Y, YANG N & YU L. 2019. Chronic olanzapine administration causes metabolic syndrome through inflammatory cytokines in rodent models of insulin resistance. Nature 9: 1582., Zhang et al. 2014ZHANG Q, LIAN J, HE M, DENG C & WANG H. 2014. Olanzapine reduced brown adipose tissue thermogenesis and locomotor activity in female rats. Prog Neuro-Psychopharmacol Biological Psychiatry 51:172-180.
Antipsychotic drugs (ASDs)	Aripiprazole		- Decreases triglyceride content of adipose tissue, increases multivacuolar cell presence, increase the pre-adipocytes proliferation in rats	Skrede et al. 2012SKREDE S ET AL. 2012. Olanzapine, but not aripiprazole, weight-independently elevates serum triglycerides and activates lipogenic gene expression in female rats. Int J Neuropsychopharmacol 15(2): 163-179., Gall et al. 2013GALL Z, VANCEA S, MEZEI T & KOLCSAR M. 2013. Adipocyte Triglyceride Content and Adipogenesis in Aripiprazole Treated Rats. Int J Pharmacol 9(4): 251-257.
Drugs used to treat cardiovascular risk factors	Statins		- Modulates thickness and inflammatory profile of human EAT (simvastatin and atorvastatin)	Grosso et al. 2014GROSSO AF, OLIVEIRA SFD, HIGUCHI MDL, FAVARATO D, DALLAN LADO & LUZ PLD. 2014. Synergistic anti-inflammatory effect: Simvastatin and pioglitazone reduce inflammatory markers of plasma and epicardial adipose tissue of coronary patients with metabolic syndrome. Diabetol Metab Syndr 6(1): 1-8., Parisi et al. 2019PARISI V ET AL. 2019. Statin therapy modulates thickness and inflammatory profile of human epicardial adipose tissue. Int J Cardiol 274: 326-330.
	Antidiabetics	Biguanides	- No effect/Possible synergistic effect with DPP-4 inhibitors and/or GLP-1RAs on human EAT - Positive effects on VAT, inducing its reduction on diabetic subjects through a possible mechanism of fatty acid oxidation (metformin)	Xourgia et al. 2018XOURGIA E, PAPAZAFIROPOULOU A & MELIDONIS A. 2018. Effects of antidiabetic drugs on epicardial fat. World J Diabetes 9(9): 141-148., Lima-Martínez et al. 2016LIMA-MARTÍNEZ MM, PAOLI M, RODNEY M, BALLADARES N, CONTRERAS M, D’MARCO L & IACOBELLIS G. 2016. Effect of sitagliptin on epicardial fat thickness in subjects with type 2 diabetes and obesity: a pilot study. Endocrine 51(3): 448-455., Iacobellis et al. 2017bIACOBELLIS G, MOHSENI M, BIANCO SD & BANGA PK. 2017b. Liraglutide causes large and rapid epicardial fat reduction. Obesity 25(2): 311-316., Tokubuchi et al. 2017TOKUBUCHI I, TAJIRI Y, IWATA S, HARA K, WADA N, HASHINAGA T, NAKAYAMA H, MIFUNE H & YAMADA K. 2017. Beneficial effects of metformin on energy metabolism and visceral fat volume through a possible mechanism of fatty acid oxidation in human subjects and rats. PLoS One 12(2): e0171293.
		Thiazolidinediones	- Decreases inflammatory cytokine release and thickness of human EAT (pioglitazone) - Induces a browning of the EAT of obese fatty Zucker rat that probably contributes to the increase in lipid turnover (rosiglitazone)	Grosso et al. 2014GROSSO AF, OLIVEIRA SFD, HIGUCHI MDL, FAVARATO D, DALLAN LADO & LUZ PLD. 2014. Synergistic anti-inflammatory effect: Simvastatin and pioglitazone reduce inflammatory markers of plasma and epicardial adipose tissue of coronary patients with metabolic syndrome. Diabetol Metab Syndr 6(1): 1-8., Xourgia et al. 2018XOURGIA E, PAPAZAFIROPOULOU A & MELIDONIS A. 2018. Effects of antidiabetic drugs on epicardial fat. World J Diabetes 9(9): 141-148., Nagai et al. 2008NAGAI H ET AL. 2008. Pioglitazone Treatment Reduces Epicardial Fat in Patients with Type 2 Diabetes Mellitus and Improves Left Ventricular Diastolic Function. Circulation 118., Distel et al. 2012DISTEL E, PENOT G, CADOUDAL T, BALGUY I, DURANT S & BENELLI C. 2012. Early induction of a brown-like phenotype by rosiglitazone in the epicardial adipose tissue of fatty Zucker rats. Biochimie 94(8):1660-1667.
		GLP-1RAs	- Reduces human EAT thickness (liraglutide and exenatide)	Xourgia et al. 2018XOURGIA E, PAPAZAFIROPOULOU A & MELIDONIS A. 2018. Effects of antidiabetic drugs on epicardial fat. World J Diabetes 9(9): 141-148., Dutour et al 2016, Iacobellis et al. 2017bIACOBELLIS G, MOHSENI M, BIANCO SD & BANGA PK. 2017b. Liraglutide causes large and rapid epicardial fat reduction. Obesity 25(2): 311-316.
		DPP-4 inhibitors	- Reduces human EAT thickness (sitagliptin) - UCP-1 up-regulation in BAT of the obese mice (sitagliptin)	Xourgia et al. 2018XOURGIA E, PAPAZAFIROPOULOU A & MELIDONIS A. 2018. Effects of antidiabetic drugs on epicardial fat. World J Diabetes 9(9): 141-148., Lima-Martínez et al. 2016LIMA-MARTÍNEZ MM, PAOLI M, RODNEY M, BALLADARES N, CONTRERAS M, D’MARCO L & IACOBELLIS G. 2016. Effect of sitagliptin on epicardial fat thickness in subjects with type 2 diabetes and obesity: a pilot study. Endocrine 51(3): 448-455., Shimasaki et al. 2013SHIMASAKI T, MASAKI T, MITSUTOMI K, UENO D, GOTOH K, CHIBA S, KAKUMA T & YOSHIMATSU H. 2013. The Dipeptidyl Peptidase-4 Inhibitor Des-Fluoro-Sitagliptin Regulates Brown Adipose Tissue Uncoupling Protein Levels in Mice with Diet-Induced Obesity. PLoS One 8(5): 1-11.
		SGLT2 inhibitors	- Increases glucose uptake, reduced proinflammatory chemokines secretion and Improves differentiation of human EAT cells (dapagliflozin)	Xourgia et al. 2018XOURGIA E, PAPAZAFIROPOULOU A & MELIDONIS A. 2018. Effects of antidiabetic drugs on epicardial fat. World J Diabetes 9(9): 141-148., Díaz-Rodríguez et al. 2018DÍAZ-RODRÍGUEZ E, AGRA RM, FERNÁNDEZ ÁL, ADRIO B, GARCÍA-CABALLERO T, GONZÁLEZ-JUANATEY JR & EIRAS S. 2018. Effects of dapagliflozin on human epicardial adipose tissue: Modulation of insulin resistance, inflammatory chemokine production, and differentiation ability. Cardiovasc Res 114(2): 336-346., Sato et al. 2018SATO T ET AL. 2018. The effect of dapagliflozin treatment on epicardial adipose tissue volume. Cardiovasc Diabetol 17(6): 1-9.

Academia Brasileira de Ciências Rua Anfilófio de Carvalho, 29, 3º andar, 20030-060 Rio de Janeiro RJ Brasil, Tel: +55 21 3907-8100 - Rio de Janeiro - RJ - Brazil
E-mail: aabc@abc.org.br

Acompanhe os números deste periódico no seu leitor de RSS

[1] E-mail: aryanecruz.op@gmail.com