Despite daily fasting and feeding, plasma glucose levels are normally maintained within a narrow range owing to the hormones insulin and glucagon. Insulin increases glucose uptake into fat and muscle cells through the regulated trafficking of vesicles that contain glucose transporter type 4 (GLUT4). New insights into insulin signalling reveal that phosphorylation events initiated by the insulin receptor regulate key GLUT4 trafficking proteins, including small GTPases, tethering complexes and the vesicle fusion machinery. These proteins, in turn, control GLUT4 movement through the endosomal system, formation and retention of specialized GLUT4 storage vesicles and targeted exocytosis of these vesicles. Understanding these processes may help to explain the development of insulin resistance in type 2 diabetes and provide new potential therapeutic targets.

Ubiquitin fold modifier 1 (UFM1) is a small, metazoan-specific, ubiquitin-like protein modifier that is essential for embryonic development. Although loss-of-function mutations in UFM1 conjugation are linked to endoplasmic reticulum (ER) stress, neither the biological function nor the relevant cellular targets of this protein modifier are known. Here, we show that a largely uncharacterized ribosomal protein, RPL26, is the principal target of UFM1 conjugation. RPL26 UFMylation and de-UFMylation is catalyzed by enzyme complexes tethered to the cytoplasmic surface of the ER and UFMylated RPL26 is highly enriched on ER membrane-bound ribosomes and polysomes. Biochemical analysis and structural modeling establish that UFMylated RPL26 and the UFMylation machinery are in close proximity to the SEC61 translocon, suggesting that this modification plays a direct role in cotranslational protein translocation into the ER. These data suggest that UFMylation is a ribosomal modification specialized to facilitate metazoan-specific protein biogenesis at the ER.

Insulin stimulates glucose transport in muscle and adipose tissue by producing translocation of the glucose transporter Glut4. The exocyst, an evolutionarily conserved vesicle tethering complex, is crucial for targeting Glut4 to the plasma membrane. Here we report that insulin regulates this process via the G protein RalA, which is present in Glut4 vesicles and interacts with the exocyst in adipocytes. Insulin stimulates the activity of RalA in a PI 3-kinase-dependent manner. Disruption of RalA function by dominant-negative mutants or siRNA-mediated knockdown attenuates insulin-stimulated glucose transport. RalA also interacts with Myo1c, a molecular motor implicated in Glut4 trafficking. This interaction is modulated by Calmodulin, which functions as the light chain for Myo1c during insulin-stimulated glucose uptake. Thus, RalA serves two functions in insulin action: as a cargo receptor for the Myo1c motor, and as a signal for the unification of the exocyst to target Glut4 vesicles to the plasma membrane.

Obesity produces a chronic inflammatory state involving the NFκB pathway, resulting in persistent elevation of the noncanonical IκB kinases IKKε and TBK1. In this study, we report that these kinases attenuate β-adrenergic signaling in white adipose tissue. Treatment of 3T3-L1 adipocytes with specific inhibitors of these kinases restored β-adrenergic signaling and lipolysis attenuated by TNFα and Poly (I:C). Conversely, overexpression of the kinases reduced induction of Ucp1, lipolysis, cAMP levels, and phosphorylation of hormone sensitive lipase in response to isoproterenol or forskolin. Noncanonical IKKs reduce catecholamine sensitivity by phosphorylating and activating the major adipocyte phosphodiesterase PDE3B. In vivo inhibition of these kinases by treatment of obese mice with the drug amlexanox reversed obesity-induced catecholamine resistance, and restored PKA signaling in response to injection of a β-3 adrenergic agonist. These studies suggest that by reducing production of cAMP in adipocytes, IKKε and TBK1 may contribute to the repression of energy expenditure during obesity.DOI: http://dx.doi.org/10.7554/eLife.01119.001