Apelin Treatment Increases Complete Fatty Acid Oxidation, Mitochondrial Oxidative Capacity, and Biogenesis in Muscle of Insulin-Resistant Mice

Abstract

Both acute and chronic apelin treatment have been shown to improve insulin sensitivity in mice. However, the effects of apelin on fatty acid oxidation (FAO) during obesity-related insulin resistance have not yet been addressed. Thus, the aim of the current study was to determine the impact of chronic treatment on lipid use, especially in skeletal muscles. High-fat diet (HFD)-induced obese and insulin-resistant mice treated by an apelin injection (0.1 μmol/kg/day i.p.) during 4 weeks had decreased fat mass, glycemia, and plasma levels of triglycerides and were protected from hyperinsulinemia compared with HFD PBS-treated mice. Indirect calorimetry experiments showed that apelin-treated mice had a better use of lipids. The complete FAO, the oxidative capacity, and mitochondrial biogenesis were increased in soleus of apelin-treated mice. The action of apelin was AMP-activated protein kinase (AMPK) dependent since all the effects studied were abrogated in HFD apelin-treated mice with muscle-specific inactive AMPK. Finally, the apelin-stimulated improvement of oxidative capacity led to decreased levels of acylcarnitines and enhanced insulin-stimulated glucose uptake in soleus. Thus, by promoting complete lipid use in muscle of insulin-resistant mice through mitochondrial biogenesis and tighter matching between FAO and the tricarboxylic acid cycle, apelin treatment could contribute to insulin sensitivity improvement.

Apelin Enhances Brown Adipogenesis and Browning of White Adipocytes

“…Mitochondrial biogenesis and morphological change (from tubular to spherical) accompany thermogenic activation in brown adipocytes (14,57). We and others have shown that apelin increases mitochondrial biogenesis in white adipocytes and skeletal muscle cells (31,34). As shown in Fig.…”

“…Mice were divided into apelin-treated and non-treated (100 l of saline, control) groups. Based on the previous studies (30,31), apelin was given at a dose of 0.1 mol/kg/day (dissolved in 100 l of saline) by intraperitoneal injection for 12 days. Animals were sacrificed 24 h after the last dose, and body and fat tissue weights were measured in all animals.…”

“…Apelin also suppresses white adipocyte differentiation and lipolysis (28,29). The antagonistic effects of apelin on dietinduced obesity and insulin resistance are attributable to its stimulation on UCP1 expression in BAT and body energy expenditure (30,31). Because apelin production in adipocytes and its plasma level are elevated in obesity (24), we speculate that apelin may provide a beneficial feedback control on both brown and white adipocytes.…”

The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis

“…Apelin KO mice have reduced insulin sensitivity, are glucose intolerant and are hyperinsulinaemic (Yue et al 2010). The peripheral administration of apelin reduces peak plasma glucose concentrations by increasing glucose uptake in skeletal muscle and adipose tissue ) and improves insulin sensitivity in both apelin KO (Yue et al 2010) and obese high-fat diet fed (Attane et al 2012) mice, with the insulin-sensitising effects continuing for up to 4 weeks, with no tolerance to the actions of apelin. Apelin increases glucose uptake, both in vitro (Zhu et al 2011) and in vivo, through both insulin-dependent and -independent pathways ).…”

Apelin Attenuates Oxidative Stress in Human Adipocytes

“…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).…”