Lysophosphatidic acid impairs glucose homeostasis and inhibits insulin secretion in high-fat diet obese mice

Abstract

Aims/hypothesis Lysophosphatidic acid (LPA) is a lipid mediator produced by adipocytes that acts via specific Gprotein-coupled receptors; its synthesis is modulated in obesity. We previously reported that reducing adipocyte LPA production in high-fat diet (HFD)-fed obese mice is associated with improved glucose tolerance, suggesting a negative impact of LPA on glucose homeostasis. Here, our aim was to test this hypothesis. Methods First, glucose tolerance and plasma insulin were assessed after acute (30 min) injection of LPA (50 mg/kg) or of the LPA1/LPA3 receptor antagonist Ki16425 (5 mgkg −1 day −1 , i.p.) in non-obese mice fed a normal diet (ND) and in obese/prediabetic (defined as glucose-intolerant) HFD mice. Glucose and insulin tolerance, pancreas morphology, glycogen storage, glucose oxidation and glucose transport were then studied after chronic treatment (3 weeks) of HFD mice with Ki16425. Results In ND and HFD mice, LPA acutely impaired glucose tolerance by inhibiting glucose-induced insulin secretion. These effects were blocked by pre-injection of Ki16425 (5 mg/kg, i.p.). Inhibition of glucoseinduced insulin secretion by LPA also occurred in isolated mouse islets. Plasma LPA was higher in HFD mice than in ND mice and Ki16425 transiently improved glucose tolerance. The beneficial effect of Ki16425 became permanent after chronic treatment and was associated with increased pancreatic islet mass and higher fasting insulinaemia. Chronic treatment with Ki16425 also improved insulin tolerance and increased liver glycogen storage and basal glucose use in skeletal muscle. Conclusions/interpretation Exogenous and endogenous LPA exerts a deleterious effect on glucose disposal through a reduction of plasma insulin; pharmacological blockade of LPA receptors improves glucose homeostasis in obese/prediabetic mice.

Lysophosphatidic Acid Inhibits Insulin Signaling in Primary Rat Hepatocytes via the LPA3 Receptor Subtype and is Increased in Obesity

“…These findings reveal that modulation of LPA 3 could be considered as a new therapeutic strategy for obesity-induced insulin resistance. Moreover, Rancoule et al have shown that treatment of high fat diet fed mice with Ki16425 increased glycogen content in hepatocytes which is also in agreement with our findings demonstrating the negative effect of LPA 3 in modulation of insulin-induced glycogen synthesis [11]. However, it should be mentioned that an opposite role of LPA on glucose mobilization has been reported in muscle and adipose tissue.…”

“…In agreement with these findings, Rancoule et al demonstrated that exogenous injection of LPA in mice induced an acute failure in glucose tolerance. A reduced insulin secretion in response to LPA was discussed as a possible mechanism for the hyperglycemic condition after LPA supply [11]. Nevertheless, our results provide evidence that the effect of LPA on insulin signaling in hepatocytes is a considerable determinant that also contributes to an impaired glucose utilization after LPA injection.…”

Gα13 ablation reprograms myofibers to oxidative phenotype and enhances whole-body metabolism

“…However, modulations of a specific GPCR have limits, as diseases are commonly driven by the simultaneous involvement of multiple receptors. Our study identifies Gα13 as the signaling node that regulates metabolic adaptation to extracellular stimuli, as supported by our findings that Gα13 levels in skeletal muscle were repressed by exercise, but increased under metabolic disease conditions, and that the genetic KO facilitated the reprogramming vides metabolic benefits such as the attenuation of diet-induced obesity and atherosclerosis development in mice (51,52). Inhibitors selectively targeting Rock2 or Ser243 phosphorylation of NFATc1 can also be attractive therapeutic candidates for metabolic diseases, as has already been observed in part with a nonselective Rock inhibitor (53).…”

LPA receptor signaling: pharmacology, physiology, and pathophysiology

“…LPA has been shown to lower glucose levels in normal and type I diabetic mice, though LPA production was unaltered (276). Furthermore, administration of LPA to obese prediabetic glucoseintolerant mice inhibited insulin secretion and lowered glucose tolerance (277,278). This effect was prevented by the antagonist Ki16425.…”