PFI-2 br Metabolic effects of apelin in obesity

Metabolic effects of apelin in obesity and type 2 diabetes Mice fed a high fat diet (HFD) for several weeks become obese, hyperglycemic, hyperinsulinemic and insulin resistant. Acute apelin treatment by intravenous injection or by infusion during a hyperinsulinemic–euglycemic clamp in obese and insulin resistant mice improves glucose tolerance and insulin sensitivity respectively (Dray et al., 2008). Thus, despite elevated plasma apelin concentrations in obese and insulin resistant mice, exogenous apelin is still efficient. During chronic apelin treatment (28 days), a marked improvement in insulin sensitivity has also been observed in obese and insulin resistant mice as well as a decrease in body fat mass gain (Attane et al., 2012). This improved insulin sensitivity throughout the body seems to be due to a better muscle metabolic function. Indeed, the complete oxidation of fatty acids was increased in the soleus muscle of obese and insulin resistant mice treated with apelin. In addition, the rate of long chain acylcarnitines generated during incomplete oxidation known to be associated with insulin resistance (Koves et al., 2008, Mihalik et al., 2010) was reduced. This could explain the fact that the insulin-stimulated glucose transport was significantly increased in muscle of apelin-treated mice (Attane et al., 2012). This better use of lipids in the muscle was coupled with an increase in mitochondrial oxidative capacity and mitochondrial biogenesis (Attane et al., 2012). This last effect was associated with an increase in the PFI-2 of peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α), nuclear respiratory factor-1 and mitochondrial transcription factor A, factors that act in concert to increase mitochondrial oxidative phosphorylation and mitochondrial biogenesis (Scarpulla, 2008). In addition, apelin treatment reduces the adverse alterations of the ultra-structure of muscle mitochondria, usually seen in T2D (Bonnard et al., 2008). Similar results on mitochondrial biogenesis have also been obtained in transgenic mice over-expressing apelin (Tg-apelin). Tg-apelin mice fed a HFD had similar food intake than wild type mice without gaining weight and display higher oxygen consumption and increased mitochondrial biogenesis in skeletal muscle (Yamamoto et al., 2011). However, the increased mitochondrial DNA content in skeletal muscles was not due to changes in PGC-1α expression (Yamamoto et al., 2011). Interestingly, the resistance to obesity of Tg-apelin mice was correlated with an increase in vessel formation in skeletal muscle due to increased gene expression of angiopoietin-1 and its receptor (Yamamoto et al., 2011). The importance of vessels integrity in both blood and lymph vasculature has more recently been demonstrated in apelin deficient mice (apelin KO mice) (Sawane et al., 2013). Indeed, besides the fact that apelin KO mice fed a HFD present an obese phenotype, they have abnormal lymphatic and blood vessel enlargement. In addition, HFD fed apelin KO mice, treated with an inhibitor of cyclooxygenase-2, have improved vascular function and decreased fat mass (Sawane et al., 2013). These data led the authors to hypothesize that this increased vascular permeability would allow greater fatty acids uptake by adipose tissue. Thus, this study highlights the importance of apelin in the maintenance of vascular integrity that would prevent the development of obesity. The role of apelin in energy metabolism has also been recently shown in obesity-related decline of cardiac function (Alfarano et al., 2014). HFD-fed mice subjected to aortic banding exhibit impaired cardiac contractile function. Chronic apelin treatment (28 days) not only reversed cardiac hypertrophy but also prevented aortic banding-induced reduction of fatty acid and glucose oxidation. It has also been shown that in isolated cardiomyocytes from HFD-fed mice, apelin increased fatty acid oxidation depending of the sirtuin 3 activation. Moreover, PGC-1α, nuclear respiratory factor-1 and mitochondrial transcription factor A genes expression was also increased in apelin-treated cardiomyocytes in accordance with the effect of apelin on mitochondrial biogenesis described in skeletal muscles. Thus apelin exerts also beneficial cardiac and metabolic effects in a model of obesity-associated heart failure.