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Pharmacological correction of obesity-induced autophagy arrest using calcium channel blockers.

Park HW, Park H, Semple IA, Jang I, Ro SH, Kim M, Cazares VA, Stuenkel EL, Kim JJ, Kim JS, Lee JH - Nat Commun (2014)

Bottom Line: Here we show that a chronic increase of the cytosolic calcium concentration in hepatocytes during obesity and lipotoxicity attenuates autophagic flux by preventing the fusion between autophagosomes and lysosomes.Such treatment successfully increases autophagosome-lysosome fusion in liver, preventing accumulation of protein inclusions and lipid droplets and suppressing inflammation and insulin resistance.As calcium channel blockers have been safely used in clinics for the treatment of hypertension for more than 30 years, our results suggest they may be a safe therapeutic option for restoring autophagic flux and treating metabolic pathologies in obese patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.

ABSTRACT
Autophagy deregulation during obesity contributes to the pathogenesis of diverse metabolic disorders. However, without understanding the molecular mechanism of obesity interference in autophagy, development of therapeutic strategies for correcting such defects in obese individuals is challenging. Here we show that a chronic increase of the cytosolic calcium concentration in hepatocytes during obesity and lipotoxicity attenuates autophagic flux by preventing the fusion between autophagosomes and lysosomes. As a pharmacological approach to restore cytosolic calcium homeostasis in vivo, we administered the clinically approved calcium channel blocker verapamil to obese mice. Such treatment successfully increases autophagosome-lysosome fusion in liver, preventing accumulation of protein inclusions and lipid droplets and suppressing inflammation and insulin resistance. As calcium channel blockers have been safely used in clinics for the treatment of hypertension for more than 30 years, our results suggest they may be a safe therapeutic option for restoring autophagic flux and treating metabolic pathologies in obese patients.

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Related in: MedlinePlus

Effects of verapamil on blood pressure and cardiac functionality of obese mice(a–g) 4 month-old C57BL/6 male mice kept on HFD for two months were subjected to daily administration of PBS (Con, n = 4) or verapamil (Ver, 25 mg/Kg body weight, i.p. n = 4) for 10 days. Systolic blood pressure (a), left ventricular (LV) wall mass (b), diastolic LV volume (c), systolic LV volume (d), ejection fraction (e, % EF), stroke volume (f, SV), and cardiac output (g, CO) were analyzed by tail-cuff method (a) or echocardiography (b–g). All data are shown as mean ± s.e.m. *P < 0.05 (Student’s t test).
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Figure 7: Effects of verapamil on blood pressure and cardiac functionality of obese mice(a–g) 4 month-old C57BL/6 male mice kept on HFD for two months were subjected to daily administration of PBS (Con, n = 4) or verapamil (Ver, 25 mg/Kg body weight, i.p. n = 4) for 10 days. Systolic blood pressure (a), left ventricular (LV) wall mass (b), diastolic LV volume (c), systolic LV volume (d), ejection fraction (e, % EF), stroke volume (f, SV), and cardiac output (g, CO) were analyzed by tail-cuff method (a) or echocardiography (b–g). All data are shown as mean ± s.e.m. *P < 0.05 (Student’s t test).

Mentions: Finally, we tested the effect of verapamil on blood pressure and cardiac functionality, which are partially controlled by voltage-dependent calcium channels. Verapamil administration induced only a slight decrease in blood pressure of HFD-kept obese mice, which was not enough to reach the level of statistical significance (Fig. 7a). We also did not observe substantial changes in heart size; left ventricular (LV) wall mass (Fig. 7b) and diastolic LV volume (Fig. 7c) remained similar between verapamil-treated and untreated groups. Intriguingly, there was a significant reduction in systolic LV volume (Fig. 7d) and an increase in LV ejection fraction (% EF) (Fig. 7e), suggesting that heart contractility may have been improved by verapamil treatment. However, verapamil-induced elevation of LV stroke volume (SV) and cardiac output (CO) was not statistically significant (Fig. 7f, g).


Pharmacological correction of obesity-induced autophagy arrest using calcium channel blockers.

Park HW, Park H, Semple IA, Jang I, Ro SH, Kim M, Cazares VA, Stuenkel EL, Kim JJ, Kim JS, Lee JH - Nat Commun (2014)

Effects of verapamil on blood pressure and cardiac functionality of obese mice(a–g) 4 month-old C57BL/6 male mice kept on HFD for two months were subjected to daily administration of PBS (Con, n = 4) or verapamil (Ver, 25 mg/Kg body weight, i.p. n = 4) for 10 days. Systolic blood pressure (a), left ventricular (LV) wall mass (b), diastolic LV volume (c), systolic LV volume (d), ejection fraction (e, % EF), stroke volume (f, SV), and cardiac output (g, CO) were analyzed by tail-cuff method (a) or echocardiography (b–g). All data are shown as mean ± s.e.m. *P < 0.05 (Student’s t test).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4157315&req=5

Figure 7: Effects of verapamil on blood pressure and cardiac functionality of obese mice(a–g) 4 month-old C57BL/6 male mice kept on HFD for two months were subjected to daily administration of PBS (Con, n = 4) or verapamil (Ver, 25 mg/Kg body weight, i.p. n = 4) for 10 days. Systolic blood pressure (a), left ventricular (LV) wall mass (b), diastolic LV volume (c), systolic LV volume (d), ejection fraction (e, % EF), stroke volume (f, SV), and cardiac output (g, CO) were analyzed by tail-cuff method (a) or echocardiography (b–g). All data are shown as mean ± s.e.m. *P < 0.05 (Student’s t test).
Mentions: Finally, we tested the effect of verapamil on blood pressure and cardiac functionality, which are partially controlled by voltage-dependent calcium channels. Verapamil administration induced only a slight decrease in blood pressure of HFD-kept obese mice, which was not enough to reach the level of statistical significance (Fig. 7a). We also did not observe substantial changes in heart size; left ventricular (LV) wall mass (Fig. 7b) and diastolic LV volume (Fig. 7c) remained similar between verapamil-treated and untreated groups. Intriguingly, there was a significant reduction in systolic LV volume (Fig. 7d) and an increase in LV ejection fraction (% EF) (Fig. 7e), suggesting that heart contractility may have been improved by verapamil treatment. However, verapamil-induced elevation of LV stroke volume (SV) and cardiac output (CO) was not statistically significant (Fig. 7f, g).

Bottom Line: Here we show that a chronic increase of the cytosolic calcium concentration in hepatocytes during obesity and lipotoxicity attenuates autophagic flux by preventing the fusion between autophagosomes and lysosomes.Such treatment successfully increases autophagosome-lysosome fusion in liver, preventing accumulation of protein inclusions and lipid droplets and suppressing inflammation and insulin resistance.As calcium channel blockers have been safely used in clinics for the treatment of hypertension for more than 30 years, our results suggest they may be a safe therapeutic option for restoring autophagic flux and treating metabolic pathologies in obese patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.

ABSTRACT
Autophagy deregulation during obesity contributes to the pathogenesis of diverse metabolic disorders. However, without understanding the molecular mechanism of obesity interference in autophagy, development of therapeutic strategies for correcting such defects in obese individuals is challenging. Here we show that a chronic increase of the cytosolic calcium concentration in hepatocytes during obesity and lipotoxicity attenuates autophagic flux by preventing the fusion between autophagosomes and lysosomes. As a pharmacological approach to restore cytosolic calcium homeostasis in vivo, we administered the clinically approved calcium channel blocker verapamil to obese mice. Such treatment successfully increases autophagosome-lysosome fusion in liver, preventing accumulation of protein inclusions and lipid droplets and suppressing inflammation and insulin resistance. As calcium channel blockers have been safely used in clinics for the treatment of hypertension for more than 30 years, our results suggest they may be a safe therapeutic option for restoring autophagic flux and treating metabolic pathologies in obese patients.

Show MeSH
Related in: MedlinePlus