Lysophosphatidic acid receptor mRNA levels in heart and white adipose tissue are associated with obesity in mice and humans

Abstract

BackgroundLysophosphatidic acid (LPA) receptor signaling has been implicated in cardiovascular and obesity-related metabolic disease. However, the distribution and regulation of LPA receptors in the myocardium and adipose tissue remain unclear.ObjectivesThis study aimed to characterize the mRNA expression of LPA receptors (LPA1-6) in the murine and human myocardium and adipose tissue, and its regulation in response to obesity.MethodsLPA receptor mRNA levels were determined by qPCR in i) heart ventricles, isolated cardiomyocytes, and perigonadal adipose tissue from chow or high fat-high sucrose (HFHS)-fed male C57BL/6 mice, ii) 3T3-L1 adipocytes and HL-1 cardiomyocytes under conditions mimicking gluco/lipotoxicity, and iii) human atrial and subcutaneous adipose tissue from non-obese, pre-obese, and obese cardiac surgery patients.ResultsLPA1-6 were expressed in myocardium and white adipose tissue from mice and humans, except for LPA3, which was undetectable in murine adipocytes and human adipose tissue. Obesity was associated with increased LPA4, LPA5 and/or LPA6 levels in mice ventricles and cardiomyocytes, HL-1 cells exposed to high palmitate, and human atrial tissue. LPA4 and LPA5 mRNA levels in human atrial tissue correlated with measures of obesity. LPA5 mRNA levels were increased in HFHS-fed mice and insulin resistant adipocytes, yet were reduced in adipose tissue from obese patients. LPA4, LPA5, and LPA6 mRNA levels in human adipose tissue were negatively associated with measures of obesity and cardiac surgery outcomes. This study suggests that obesity leads to marked changes in LPA receptor expression in the murine and human heart and white adipose tissue that may alter LPA receptor signaling during obesity.

Relative expression and regulation by short‐term fasting of lysophosphatidic acid receptors and autotaxin in white and brown adipose tissue depots

“…In all depots examined, expression of Lpar6 predominated. This is different from a prior report in mouse perigonadal WAT, cultured 3 T3‐L1 adipocytes, and human subcutaneous adipose tissue, where Lpar6 was among the more abundant Lpar expressed, but was detected at comparable levels to other lysoPtdOH ‐receptors (Brown et al, ). The next most abundant Lpar in all WAT depots we examined was Lpar1 that was ~3–15 fold less abundant than Lpar6 .…”

“…). Our findings are in agreement with a prior report on perigonadal WAT, showing that expression of Lpar1–6 were not significantly altered by fasting when mice are fed chow (Brown et al, ). However, in that report, fasting did significantly induce perigonadal Lpar3 and Lpar5 when mice were fed a high‐fat and high‐sucrose diet for 16 weeks prior to testing, suggesting that Lpar may become responsive to hormonal or energetic signals of nutritional status under some conditions.…”

Lysophosphatidic Acid Signaling in Obesity and Insulin Resistance

“…Our understanding of the relationship between the ATX-LPA pathway and obesity can be improved by examining circulating LPA levels in human cohorts, in addition to ATX expression and activity. Brown et al [ 16 ] demonstrated that mRNA levels of distinct LPA receptors in insulin sensitive mouse and human tissues are associated with obesity. For example, LPA4, LPA5, and/or LPA6 are significantly increased in myocardial tissue and cells from HFHS-fed mice and humans with preobesity or obesity [ 16 ].…”

“…Brown et al [ 16 ] demonstrated that mRNA levels of distinct LPA receptors in insulin sensitive mouse and human tissues are associated with obesity. For example, LPA4, LPA5, and/or LPA6 are significantly increased in myocardial tissue and cells from HFHS-fed mice and humans with preobesity or obesity [ 16 ]. These data suggest that changes in tissue LPA receptor expression may also contribute to alterations in ATX-LPA signaling during obesity.…”

“…The diversity of cellular responses to LPA is likely mediated by distinct LPA receptor tissue expression patterns, receptor–ligand kinetics, and substrate/acyl chain specificity of LPA receptors. For example, while all six LPA receptors are expressed in the murine and human heart and cardiomyocytes, LPA3 mRNA is undetectable in murine cardiomyocytes and human subcutaneous adipose tissue [ 16 ]. However, a comprehensive understanding of LPA receptor expression at baseline and under pathophysiological conditions is still lacking in many tissues.…”