Lysophosphatidic Acid: A Key Player in Obesity

Abstract

LPA receptor signaling has been implicated in severe non communicable diseases including cardiovascular disease, cancer, bone development and disease, fibrosis, reproductive disorders, schizophrenia and obesity [1-3]. It has also been implicated in the regulation of glucose homeostasis and obesity-related metabolic disease in mice and humans [4]. LPA activates multiple rhodopsin like G protein coupled receptors (LPA1-6) [5], which are expressed in heart and adipose tissue at distinct levels with a significant increase in levels of LPA 4, 5 and 6 in the heart of obese mice, although undetectable levels of LPA3 have been observed in adipocytes of mice and subcutaneous adipose tissue in humans [5,6]. Some other studies have reported LPA1, LPA2, LPA3 and LPA6 expression in primary rat hepatocytes with the highest expression of the LPA3 receptor subtype [7]. LPA4, LPA5, and/or LPA6 are significantly increased in myocardial tissue and cells from HFHS-fed mice and humans with pre obesity or obesity. Recently it has been suggested that plasma LPA positively correlates well with body mass index (BMI), an indicator of nutritional imbalance [8]. Evidences have proven that in human atrial tissue, LPA4 and LPA5 mRNA levels correlate well with BMI and waist circumference besides LPA3 stimulation is involved in attenuation of insulin-dependent signaling in hepatocytes in mice with obesity. Although LPA3 is not significantly expressed in mice and human heart but it is the crucial receptor subtype involved in the inhibitory effect of LPA on insulin signaling associated with obesity [9]. LPA1 is abundantly expressed in kidney cortex, playing a vital role in glomerular injury in diabetic mice [10]. Even if very little is known about the regulation of LPA receptor expression in obesity and heart disease, however, specific receptor targeting of the LPA signaling network thus may provide novel avenues for further therapeutic development in obesity and associated disorders.