Adipose tissue-derived autotaxin causes cardiomyopathy in obese mice

Abstract

The prevalence of obesity is dramatic increased and strongly associated with cardiovascular disease. Adipokines, secreted from adipose tissues, are critical risk factors for the development of cardiomyopathy. Present study aimed to investigate the pathophysiological role of autotaxin in obesity-related cardiomyopathy. In high-fat diet-fed mice, autotaxin was mainly synthesized and secreted from adipocytes. The increased accumulation of cardiac autotaxin was positively associated with cardiac dysfunction in obese mice. Interestingly, specific blockage of adipose tissue autotaxin effectively protected against high-fat diet-induced cardiac structural disorders, left ventricular hypertrophy and dysfunction. Inhibition of autotaxin further improved high-fat diet-induced cardiac fibrosis and mitochondrial dysfunction, including improvement of mitochondrial structure, mass and activities. Our findings demonstrated intervention of adipose tissue biology could influence cardiac modification in obese mice, and adipocyte-derived autotaxin was a potential diagnostic marker and therapeutic target for obesity-related cardiomyopathy.

Autotaxin-LPA-LPP3 Axis in Energy Metabolism and Metabolic Disease

“…In agreement with a prohypertrophic effect of the ATX-LPA axis on cardiomyocytes, high fat-fed (60% kcal fat) obese mice with lentiviral ATX silencing in epididymal adipose tissue showed reduced cardiac hypertrophy, which was accompanied by diminished cardiac fibrosis and steatosis [58] (Table 1). ATX silencing in WAT resulted in a drastic decline in ATX levels in adipose tissue, serum, and cardiac tissue, as well as reduced circulating LPA levels [58]. These changes were not accompanied by alterations in body weight [58].…”

“…Interestingly, in humans, circulating ATX levels correlated inversely with ejection fraction and positively with the hypertrophy marker, NT-proBNP, indicating that the ATX-LPA axis may also contribute to obesity-induced cardiomyopathy in humans [35]. In agreement with a prohypertrophic effect of the ATX-LPA axis on cardiomyocytes, high fat-fed (60% kcal fat) obese mice with lentiviral ATX silencing in epididymal adipose tissue showed reduced cardiac hypertrophy, which was accompanied by diminished cardiac fibrosis and steatosis [58] (Table 1). ATX silencing in WAT resulted in a drastic decline in ATX levels in adipose tissue, serum, and cardiac tissue, as well as reduced circulating LPA levels [58].…”

“…ATX mRNA levels in intra-abdominal adipose tissue were also higher in obese women with impaired glucose tolerance or diabetes than women with normal glucose tolerance [55]. Most, but not all, studies using mice with high fat diet-induced obesity demonstrate ATX upregulation, either through increased ATX expression in adipose tissue or circulating ATX protein/activity [18,33,35,[55][56][57][58][59][60]. Similarly, ATX mRNA levels were increased in adipose tissue from obese-diabetic db/db mice but not gold-thioglucose-treated mice [55].…”

“…ATX silencing in WAT resulted in a drastic decline in ATX levels in adipose tissue, serum, and cardiac tissue, as well as reduced circulating LPA levels [58]. These changes were not accompanied by alterations in body weight [58]. High fat diet feeding induced a time-dependent increase in cardiac ATX levels and ATX levels correlated inversely with systolic function parameters, ejection fraction, and fractional shortening [58].…”

Molecular Mechanisms of Obesity-Linked Cardiac Dysfunction: An Up-Date on Current Knowledge

“…In mice fed HFD, autotaxin accumulation was associated with cardiac dysfunction in obese mice. On the other hand, autotaxin blockade protected obese mice against structural cardiac disorders, hypertrophy, and LV dysfunction [32].…”