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.

Cancer-associated fibroblasts (CAF) comprise the majority of stromal cells in breast cancers, yet their precise origins and relative functional contributions to malignant progression remain uncertain. Local invasion leads to the proximity of cancer cells and adipocytes, which respond by phenotypical changes to generate fibroblast-like cells termed as adipocyte-derived fibroblasts (ADF) here. These cells exhibit enhanced secretion of fibronectin and collagen I, increased migratory/invasive abilities, and increased expression of the CAF marker FSP-1 but not a-SMA. Generation of the ADF phenotype depends on reactivation of the Wnt/b-catenin pathway in response to Wnt3a secreted by tumor cells. Tumor cells cocultivated with ADFs in two-dimensional or spheroid culture display increased invasive capabilities. In clinical specimens of breast cancer, we confirmed the presence of this new stromal subpopulation. By defining a new stromal cell population, our results offer new opportunities for stroma-targeted therapies in breast cancer. Cancer Res; 73(18); 5657-68. Ó2013 AACR.

A high-fat diet (HFD) induces metabolic disease and low-grade metabolic inflammation in response to changes in the intestinal microbiota through as-yet-unknown mechanisms. Here, we show that a HFD-derived ileum microbiota is responsible for a decrease in Th17 cells of the lamina propria in axenic colonized mice. The HFD also changed the expression profiles of intestinal antigen-presenting cells and their ability to generate Th17 cells in vitro. Consistent with these data, the metabolic phenotype was mimicked in RORγt-deficient mice, which lack IL17 and IL22 function, and in the adoptive transfer experiment of T cells from RORγt-deficient mice into Rag1-deficient mice. We conclude that the microbiota of the ileum regulates Th17 cell homeostasis in the small intestine and determines the outcome of metabolic disease.

Sarcopenia, the degenerative loss of skeletal muscle mass, quality and strength, lacks early diagnostic tools and new therapeutic strategies to prevent the frailty-to-disability transition often responsible for the medical institutionalization of elderly individuals. Herein we report that production of the endogenous peptide apelin, induced by muscle contraction, is reduced in an age-dependent manner in humans and rodents and is positively associated with the beneficial effects of exercise in older persons. Mice deficient in either apelin or its receptor (APLNR) presented dramatic alterations in muscle function with increasing age. Various strategies that restored apelin signaling during aging further demonstrated that this peptide considerably enhanced muscle function by triggering mitochondriogenesis, autophagy and anti-inflammatory pathways in myofibers as well as enhancing the regenerative capacity by targeting muscle stem cells. Taken together, these findings revealed positive regulatory feedback between physical activity, apelin and muscle function and identified apelin both as a tool for diagnosis of early sarcopenia and as the target of an innovative pharmacological strategy to prevent age-associated muscle weakness and restore physical autonomy.

Obesity favours the occurrence of locally disseminated prostate cancer in the periprostatic adipose tissue (PPAT) surrounding the prostate gland. Here we show that adipocytes from PPAT support the directed migration of prostate cancer cells and that this event is strongly promoted by obesity. This process is dependent on the secretion of the chemokine CCL7 by adipocytes, which diffuses from PPAT to the peripheral zone of the prostate, stimulating the migration of CCR3 expressing tumour cells. In obesity, higher secretion of CCL7 by adipocytes facilitates extraprostatic extension. The observed increase in migration associated with obesity is totally abrogated when the CCR3/CCL7 axis is inhibited. In human prostate cancer tumours, expression of the CCR3 receptor is associated with the occurrence of aggressive disease with extended local dissemination and a higher risk of biochemical recurrence, highlighting the potential benefit of CCR3 antagonists in the treatment of prostate cancer.

Apelin is a peptide known as the ligand of the G-protein-coupled receptor APJ. Several active apelin forms exist such as apelin-36, apelin-17, apelin-13, and the pyroglutamated form of apelin-13. Apelin and APJ are expressed in the central nervous system, particularly in the hypothalamus and in many peripheral tissues. Apelin has been shown to be involved in the regulation of cardiovascular and fluid homeostasis, food intake, cell proliferation, and angiogenesis. In addition to be an ubiquitous peptide, apelin is also produced and secreted by adipocytes and thus considered as an adipokine. This has opened a new field of investigation establishing a link between apelin and metabolic disorders (obesity, type 2 diabetes, etc.) which is the focus of the present review. Several studies, but not all, have reported an increase of plasma apelin concentrations in humans and in animal models with different metabolic pathologies. Moreover, important roles for apelin both in glucose and lipid metabolism have been highlighted as well as the associated signaling pathways. Apelin appears as a beneficial adipokine with anti-obesity and anti-diabetic properties and thus as a promising therapeutic target in metabolic disorders.

We have recently identified apelin as a novel adipokine up-regulated by insulin and obesity. Since obesity and insulin resistance are associated with chronically elevated levels of both insulin and TNFalpha, the present study was performed to investigate a putative regulation of apelin expression in adipocytes by TNFalpha. Herein, we report a tight correlation between apelin and TNFalpha expression in adipose tissue of lean and obese humans. Apelin regulation by TNFalpha was further studied in cultured explants of human adipose tissue. The endogenous expression of TNFalpha in adipocytes isolated from the explants was accompanied by a 6-9 h subsequent increase of apelin expression in adipocytes. This increase was reversed by inhibiting TNFalpha expression with 100 microM isobutylmethylxanthine. In different mouse models of obesity, expression of both TNFalpha and apelin was also significantly increased in adipocytes of obese mice. Furthermore, short-term exposure to an i.p. injection of TNFalpha in C57Bl6/J mice induced an increase of apelin expression in adipose tissue as well as apelin plasma levels. Finally, a direct positive effect of TNFalpha has been shown in differentiated 3T3F442A adipocytes on apelin expression and secretion. The signaling pathways of TNFalpha for the induction of apelin were dependent of PI3-kinase, c-Jun NH2-terminal kinase (JNK), and MAPK but not PKC activation. All together, these findings suggest that apelin might be a candidate to better understand potential links between obesity and associated disorders such as inflammation and insulin resistance.

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.