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

AIMS/HYPOTHESIS: Lysophosphatidic acid (LPA) is a lipid mediator produced by adipocytes that acts via specific G-protein-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 mg kg(-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 glucose-induced 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.

Apelin stimulates glucose uptake but not lipolysis in human adipose tissue ex vivo.

Apelin is a peptide present in different cell types and secreted by adipocytes in humans and rodents. Apelin exerts its effects through a G-protein-coupled receptor called APJ. During the past years, a role of apelin/APJ in energy metabolism has emerged. Apelin was shown to stimulate glucose uptake in skeletal muscle through an AMP-activated protein kinase (AMPK)-dependent pathway in mice. So far, no metabolic effects of apelin have been reported on human adipose tissue (AT). Thus, the effect of apelin on AMPK in AT was measured as well as AMPK-mediated effects such as inhibition of lipolysis and stimulation of glucose uptake. AMPK and acetyl-CoA carboxylase phosphorylation were measured by western blot to reflect the AMPK activity. Lipolysis and glucose uptake were measured, ex vivo, in response to apelin on isolated adipocytes and explants from AT of the subcutaneous region of healthy subjects (body mass index: 25.6 ± 0.8 kg/m(2), n = 30 in total). APJ mRNA and protein are present in human AT and isolated adipocytes. Apelin stimulated AMPK phosphorylation at Thr-172 in a dose-dependent manner in human AT, which was associated with increased glucose uptake since C compound (20  µM), an AMPK inhibitor, completely prevented apelin-induced glucose uptake. However, in isolated adipocytes or AT explants, apelin had no significant effect on basal and isoprenaline-stimulated lipolysis. Thus, these results reveal, for the first time, that apelin is able to act on human AT in order to stimulate AMPK and glucose uptake.

Altered food consumption in mice lacking lysophosphatidic acid receptor-1

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The release of lysophosphatidic acid (LPA) by adipocytes has previously been proposed to play a role in obesity and associated pathologies such as insulin resistance and diabetes. In the present work, the sensitivity to diet-induced obesity was studied in mice lacking one of the LPA receptor subtype (LPA1R). Conversely to what was observed in wild type (WT) mice, LPA1R-KO-mice fed a high fat diet (HFD) showed no significant increase in body weight or fat mass when compared to low fat diet (LFD). In addition, in contrast to what was observed in WT mice, LPA1R-KO mice did not exhibit over-consumption of food associated with HFD. Surprisingly, when fed a LFD, LPA1R-KO mice exhibited significant higher plasma leptin concentration and higher level of adipocyte leptin mRNA than WT mice. In conclusion, LPA1R-KO mice were found to be resistant to diet-induced obesity consecutive to a resistance to fat-induced over-consumption of food that may result at least in part from alterations in leptin expression and production (AU)

Altered food consumption in mice lacking lysophosphatidic acid receptor-1.

The release of lysophosphatidic acid (LPA) by adipocytes has previously been proposed to play a role in obesity and associated pathologies such as insulin resistance and diabetes. In the present work, the sensitivity to diet-induced obesity was studied in mice lacking one of the LPA receptor subtype (LPA1R). Conversely to what was observed in wild type (WT) mice, LPA1R-KO-mice fed a high fat diet (HFD) showed no significant increase in body weight or fat mass when compared to low fat diet (LFD). In addition, in contrast to what was observed in WT mice, LPA1R-KO mice did not exhibit over-consumption of food associated with HFD. Surprisingly, when fed a LFD, LPA1R-KO mice exhibited significant higher plasma leptin concentration and higher level of adipocyte leptin mRNA than WT mice. In conclusion, LPA1R-KO mice were found to be resistant to diet-induced obesity consecutive to a resistance to fat-induced over-consumption of food that may result at least in part from alterations in leptin expression and production.