Apelin Stimulates Glucose Utilization in Normal and Obese Insulin-Resistant Mice

Abstract

Adipose tissue (AT) secretes several adipokines that influence insulin sensitivity and potentially link obesity to insulin resistance. Apelin, a peptide present in different tissues, is also secreted by adipocytes. Apelin is upregulated in obese and hyperinsulinemic humans and mice. Although a tight relation exists between the regulation of apelin and insulin, it remains largely unknown whether apelin affects whole-body glucose utilization. Herein, we show that in chow-fed mice, acute intravenous injection of apelin has a powerful glucose-lowering effect associated with enhanced glucose utilization in skeletal muscle and AT. Through in vivo and in vitro pharmacological and genetic approaches, we demonstrate the involvement of endothelial NO synthase, AMP-activated protein kinase, and Akt in apelin-stimulated glucose uptake in soleus muscle. Remarkably, in obese and insulin-resistant mice, apelin restored glucose tolerance and increased glucose utilization. Apelin could thus represent a promising target in the management of insulin resistance.

Apelin Attenuates Oxidative Stress in Human Adipocytes

“…It also explains the previous observations in mice that apelin treatment leads to a significant decrease in plasma lipid hydroperoxide (an index of systemic oxidative stress) (23), and improves glucose uptake in adipose tissue (18). Dray et al has demonstrated that intravenous injection of apelin has a powerful effect to enhance glucose utilization in skeletal muscle and adipose tissue in high-fat fed obese and insulin-resistant mice (20). As reported in this study, endothelial NO synthase (eNOS) activation is essential to apelin's effect on skeletal muscle (20).…”

“…Dray et al has demonstrated that intravenous injection of apelin has a powerful effect to enhance glucose utilization in skeletal muscle and adipose tissue in high-fat fed obese and insulin-resistant mice (20). As reported in this study, endothelial NO synthase (eNOS) activation is essential to apelin's effect on skeletal muscle (20). eNOS activity is also important for glucose uptake in adipocytes (71,72).…”

“…Through interaction with G-protein coupled APJ receptors, apelin plays important roles in regulating energy metabolism, and has been recognized with its anti-obesity and anti-diabetic properties (18). Apelin, for examples, promotes glucose utilization and fatty acid oxidation in muscles of insulin-resistant mice (19,20), stimulates insulin signaling pathways and glycogen synthesis in hepatocytes and liver tissues of mice (21), and suppresses adipogenesis and lipolysis (22). Interestingly, apelin has also been shown to alleviate oxidative stress in cardiomyocytes and vascular smooth muscle cells (23,24).…”

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

“…Glucose transport in ex vivo muscle Glucose transport was measured as previously described [29]. Soleus muscles were isolated and preincubated for 10 min in KH buffer, pH 7.4, containing BSA (2 mg/ml), 2 mmol/l sodium pyruvate and 20 mmol/l HEPES.…”

Once fat was fat and that was that : our changing perspectives on adipose tissue

“…Circulating apelin increases in obesity 56 and has been show to lower glucose in normal and obese mice. 57 Homozygous apelin knockout mice have severe heart failure in response to pressure overload and diminished heart contractility in aged mice, 58 indicating a role for the adipokine in maintaining cardiac function. Visfatin is an adipokine that is predominantly expressed in visceral adipose tissue and has been attributed to having insulin-like properties, 59 although this has since been disputed, 60,61 and recently visfatin has been shown to have pro-inflammatory effects.…”