Inhibition of galectin-3 ameliorates the consequences of cardiac lipotoxicity in a rat model of diet-induced obesity.

Josué Gutiérrez-Tenorio,María Luisa Nieto,Raquel Jurado-López,Beatriz Gutiérrez,Ernesto Martínez-Martínez,Victoria Cachofeiro,Isabel Gallardo,Natalia López-Andrés,Gema Marín-Royo,Mv Bartolome,Eduardo Rial

doi:10.1242/dmm.032086

Abstract

ABSTRACTObesity is accompanied by metabolic alterations characterized by insulin resistance and cardiac lipotoxicity. Galectin-3 (Gal-3) induces cardiac inflammation and fibrosis in the context of obesity; however, its role in the metabolic consequences of obesity is not totally established. We have investigated the potential role of Gal-3 in the cardiac metabolic disturbances associated with obesity. In addition, we have explored whether this participation is, at least partially, acting on mitochondrial damage. Gal-3 inhibition in rats that were fed a high-fat diet (HFD) for 6 weeks with modified citrus pectin (MCP; 100 mg/kg/day) attenuated the increase in cardiac levels of total triglyceride (TG). MCP treatment also prevented the increase in cardiac protein levels of carnitine palmitoyl transferase IA, mitofusin 1, and mitochondrial complexes I and II, reactive oxygen species accumulation and decrease in those of complex V but did not affect the reduction in 18F-fluorodeoxyglucose uptake observed in HFD rats. The exposure of cardiac myoblasts (H9c2) to palmitic acid increased the rate of respiration, mainly due to an increase in the proton leak, glycolysis, oxidative stress, β-oxidation and reduced mitochondrial membrane potential. Inhibition of Gal-3 activity was unable to affect these changes. Our findings indicate that Gal-3 inhibition attenuates some of the consequences of cardiac lipotoxicity induced by a HFD since it reduced TG and lysophosphatidyl choline (LPC) levels. These reductions were accompanied by amelioration of the mitochondrial damage observed in HFD rats, although no improvement was observed regarding insulin resistance. These findings increase the interest for Gal-3 as a potential new target for therapeutic intervention to prevent obesity-associated cardiac lipotoxicity and subsequent mitochondrial dysfunction.

Highlights

Obesity is a chronic disease characterized by excessive accumulation of adipose tissue and lipids forming ectopic fat deposits in different tissues, including the heart (Abdurrachim et al, 2014; French et al, 2016; Ghosh et al, 2011)
Effect of Gal-3 activity inhibition on cardiac glucose use and insulin resistance in high-fat diet (HFD)-fed rats we addressed whether upregulation of Gal-3 is involved in the changes of glucose use observed in obese rats
Given that phosphatidyl choline (PC) and lysophosphatidyl choline (LPC) are involved in various diseases and because altered levels of LPC in the serum is considered to be a specific metabolic trait associated with obesity (Li et al, 2014; Tulipani et al, 2016), we focused on the types of PC and LPC found in the hearts of HFD rats

Summary

Introduction

Obesity is a chronic disease characterized by excessive accumulation of adipose tissue and lipids forming ectopic fat deposits in different tissues, including the heart (Abdurrachim et al, 2014; French et al, 2016; Ghosh et al, 2011). A common additional feature of the obese heart is impaired insulin signaling, which represents an adaptation of the heart to an excess of calories, which promotes the development of diabetic cardiomyopathy (Guo and Guo, 2017; Jia et al, 2016; Riehle and Abel, 2016) This condition alters cardiac metabolism and increases myocardial oxygen consumption, reduces cardiac efficiency by affecting mitochondrial function and increases oxidative stress with the mitochondria being the main source of reactive oxygen species (ROS) (Boudina et al, 2007; Elezaby et al, 2015; McMurray et al, 2016).

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