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The concept of 'critical nodes' has been used to define the main junctions in physiologically important, complex signalling networks. Several critical nodes of the insulin network have been identified and shown to have important roles in normal physiology and disease states.

Mutations in genes that regulate endocrine signalling pathways can increase the lifespans of worms, flies and mammals. Endocrine pathways might therefore serve as targets for the manipulation of the ageing process and prevention of age-related diseases.

Adipose tissue is a major source of circulating exosomal miRNAs, which contribute to the regulation of gene expression in distant tissues and organs.

Most current obesity therapies aim to reduce calorific intake or absorption and are limited by poor efficacy or unpleasant side effects. Here, Tseng and colleagues discuss the therapeutic potential of the alternative approach of increasing cellular energy expenditure, principally by stimulating adaptive thermogenesis, to prevent or treat this disorder.

The authors previously identified a family of viral insulin-like peptides (VILPs) with high homology to human insulin/IGF−1. Here, they report that one of these VILPs exhibits antagonist properties associated with a unique conformation of the IGF1R.

Despite being structurally similar, the insulin receptor (IR) and insulin growth factor I receptor (IGF1R) elicit distinct signalling pathways. Here the authors use receptor chimeras to unveil that IR and IGF1R signalling is related primarily to differences in their intracellular juxtamembrane region.

Insulin and insulin-like growth factor 1 signalling pathways have overlapping effects on adipose tissue and glucose homeostasis. Boucheret al.created fat-specific double knockouts of these pathways and demonstrated their crucial role for adipocyte development, metabolism and thermogenesis in mice.

Multiple mechanisms regulate adipose mass and body weight. In addition to factors controlling appetite and energy expenditure, mechanisms controlling adipocyte number, triglyceride synthesis and triglyceride breakdown have important functions. But recent studies challenge our concepts concerning each of these.

The transcriptional regulator Tbx15 has a role in organ development. Here Lee et al.show that Tbx15 influences fibre-type determination in murine skeletal muscles, explaining local and systemic metabolic derangements in heterozygous Tbx15 knockout mice.

Nagao et al. show that the insulin receptor can mediate receptor-dependent, but ligand- and tyrosine kinase-independent, events. These are associated with regulation of extracellular matrix, cell cycle, ATM signaling, senescence and apoptosis.

The sequencing of the human genome represents a major milestone that will have profound consequences for the practice of medicine. Many new disease genes will be identified, and this information may someday be used to predict a patient's risk of developing a specific disease or response to a particular drug. The following six News and Views articles discuss how The Human Genome Project will revolutionize the diagnosis and treatment of diseases including diabetes, asthma, cancer, autoimmunity and cardiac disease, as well as the potential for developing 'personalized therapies'. They also serve to remind us that although we have our 'genetic blueprint' in hand, a large amount of work remains before we fully understand how to best use it.

Insulin signals through phosphoinositide 3-kinase (PI3K) to induce cell growth, which often increases protein translation and stress of the endoplasmic reticulum (ER). In two new studies, Umut Ozcan and Ron Kahn and their colleagues now find that in response to insulin signaling, p85α and p85β, the heterodimeric regulatory subunits of PI3K, can increase the nuclear localization of a key transcription factor that resolves ER stress (pages 374–376 and pages 429–437).

Diabetes is associated with decreased PI3K activation in skeletal muscle. Here, the authors show that p110a is the predominant PI3K subunit in muscle, and show that its ablation in muscle, but not ablation of p110beta, leads to insulin resistance, increased proteosomal and autophagic activity, and altered mitochondria homeostasis in mice.

The origin of the heterogeneity of metabolic and inflammatory profiles exhibited by white adipocytes is little understood. Here, using scRNA-seq and computational methods, the authors show that differentiating preadipocytes exhibit gene expression differences and suggest underlying regulators.

Immune-mediated insulin resistance should be considered in patients with increasing hyperglycemia despite high-dose insulin treatment. This article illustrates the differential diagnosis of insulin resistance and describes the features and management of the type B insulin resistance syndrome.

Adipose tissue transplantation is increasingly being explored as a treatment strategy for metabolic disease—to promote the beneficial metabolic effects of subcutaneous white adipose tissue and brown adipose tissue, as well as those of adipose-derived stem cells. This Review summarizes the current available data on the biology of different adipose tissue depots and conceptualizes the future of adipose tissue transplantation and ongoing research.

MicroRNAs encode sorting sequences that determine whether they are secreted in exosomal vesicles to regulate gene expression in distant cells or retained in cells that produced them, with different sequences used by individual cell types.

Insulin signaling represses Forkhead transcription factor FoxO activity, which contributes to organismal metabolism. Here, the authors use proteomics to identify positively regulated insulin signaling targets FoxK1/K2 and demonstrate their role in lipid metabolism and mitochondrial regulation.

Authors present workflows for the analysis of metabolism phenotypes in mice and recommend analysis of covariance to asses body composition effects.