A highly complex network of organ communication plays a key role in regulating metabolic homeostasis, specifically due to the modulation of the insulin signaling machinery. As a paradigm, the role of adipose tissue in organ crosstalk has been extensively investigated, but tissues such as muscles and the liver are equally important players in this scenario. Perturbation of organ crosstalk is a hallmark of insulin resistance, emphasizing the importance of crosstalk molecules in the modulation of insulin signaling, potentially leading to defects in insulin action. Classically secreted proteins are major crosstalk molecules and are able to affect insulin signaling in both directions. In this review, we aim to focus on some crosstalk mediators with an impact on the early steps of insulin signaling. In addition, we also summarize the current knowledge on the role of extracellular vesicles in relation to insulin signaling, a more recently discovered additional component of organ crosstalk. Finally, an attempt will be made to identify inter-connections between these two pathways of organ crosstalk and the potential impact on the insulin signaling network.

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The insulin receptor is associated with a protein kinase activity. This has been shown for the receptor of liver, fat, and some other tissues which are not primary targets of insulin action. Here kinase activity is demonstrated for the insulin receptor of rat skeletal and cardiac muscle with similar characteristics. Insulin (lo-' mol/l) stimulates phosphorylation of the 95kDa receptor subunit 3-to ll-fold. The effect is detectable at lO-'O mol/l insulin; the ED,, is approx. 3 x 10e9 mol/l. The kinase phosphorylates exogenous substrate as well, and it is recovered after immunoprecipitation of the receptor with antireceptor antibody suggesting that kinase activity is intrinsic to the muscle receptor. Insulin Receptor

There is an urgent need for developing effective drugs to combat the obesity and Type 2 diabetes mellitus epidemics. The endocannabinoid system plays a major role in energy homeostasis. It comprises the cannabinoid receptors 1 and 2 (CB1 and CB2), endogenous ligands called endocannabinoids and their metabolizing enzymes. Because the CB1 receptor is overactivated in metabolic alterations, pharmacological blockade of the CB1 receptor arose as a promising candidate to treat obesity. However, because of the wide distribution of CB1 receptors in the central nervous system, their negative central effects halted further therapeutic use. Although the CB2 receptor is mostly peripherally expressed, its role in metabolic homeostasis remains unclear. This review discusses the potential of CB1 and CB2 receptors at the peripheral level to be therapeutic targets in metabolic diseases. We focus on the impact of pharmacological intervention and/or silencing on peripheral cannabinoid receptors in organs/tissues relevant for energy homeostasis. Moreover, we provide a perspective on novel therapeutic strategies modulating these receptors. Targeting CB1 with peripherally restricted antagonists, neutral antagonists, inverse agonists, or monoclonal antibodies could represent successful strategies. CB2 agonism has shown promising results at preclinical level. Beyond classic antagonism and agonism targeting orthosteric sites, the recently described crystal structures of CB1 and CB2 open new possibilities for therapeutic interventions with negative and positive allosteric modulators. The challenge of simultaneously targeting CB1 and CB2 might be possible by developing dual-steric ligands. The future will tell whether these promising strategies result in a renaissance of the cannabinoid receptors as therapeutic targets in metabolic diseases.