SUMMARY Obesity is associated with a chronic, low-grade, systemic inflammation that may contribute to the development of insulin resistance and type 2 diabetes. Resveratrol, a natural compound with anti-inflammatory properties, is shown to improve glucose tolerance and insulin sensitivity in obese mice and humans. Here we tested the effect of a 2-year resveratrol administration on pro-inflammatory profile and insulin resistance caused by a high-fat, high-sugar (HFS) diet in white adipose tissue (WAT) from rhesus monkeys. Eighty mg/day of resveratrol for 12-month followed by 480 mg/day for the second year decreased adipocyte size, increased sirtuin 1 expression, decreased NF-κB activation and improved insulin sensitivity in visceral but not subcutaneous WAT from HFS-fed animals. These effects were reproduced in 3T3-L1 adipocytes cultured in media supplemented with serum from monkeys fed HFS +/− resveratrol diets. In conclusion, chronic administration of resveratrol exerts beneficial metabolic and inflammatory adaptations in visceral WAT from diet-induced obese monkeys.

Background: GLUT4 glucose transporters are trapped and sequestered intracellularly in adipocytes by TUG. Results: Insulin stimulates TUG cleavage, which separates regions of TUG that bind GLUT4 and Golgi matrix proteins. Cleavage is required for highly insulin-responsive GLUT4 translocation. Conclusion: TUG proteolysis liberates GLUT4 trapped at the Golgi matrix. Significance: Endoproteolytic cleavage is a novel biochemical mechanism for insulin action to regulate glucose uptake.

Background: Insulin stimulates endoproteolytic cleavage of TUG proteins to promote glucose uptake in cultured adipocytes, but the role of this pathway in muscle is uncharacterized. Results: Transgenic mice with constitutive and unregulated TUG cleavage in muscle had increased whole-body and musclespecific glucose uptake during fasting. Conclusion: Insulin acts through TUG to control glucose uptake in muscle. Significance: Understanding insulin action will elucidate diabetes pathogenesis.

Background: Insulin stimulates glucose uptake by triggering TUG proteolysis, which liberates intracellular storage vesicles containing GLUT4. Results: TUG acetylation modulates its interaction with Golgi matrix proteins and enhances its function to trap GLUT4 storage vesicles within unstimulated cells. SIRT2 modulates TUG acetylation and controls insulin sensitivity in vivo. Conclusion: TUG acetylation promotes GLUT4 accumulation in insulin-responsive vesicles. Significance: Nutritional status modulates insulin-stimulated glucose uptake.

Insulin regulates glucose uptake by controlling the subcellular location of GLUT4 glucose transporters. GLUT4 is sequestered within fat and muscle cells during low-insulin states, and is translocated to the cell surface upon insulin stimulation. The TUG protein is a functional tether that sequesters GLUT4 at the Golgi matrix. To stimulate glucose uptake, insulin triggers TUG endoproteolytic cleavage. Cleavage accounts for a large proportion of the acute effect of insulin to mobilize GLUT4 to the cell surface. During ongoing insulin exposure, endocytosed GLUT4 recycles to the plasma membrane directly from endosomes, and bypasses a TUG-regulated trafficking step. Insulin acts through the TC10α GTPase and its effector protein, PIST, to stimulate TUG cleavage. This action is coordinated with insulin signals through AS160/Tbc1D4 and Tbc1D1 to modulate Rab GTPases, and with other signals to direct overall GLUT4 targeting. Data support the idea that the N-terminal TUG cleavage product, TUGUL, functions as a novel ubiquitin-like protein modifier to facilitate GLUT4 movement to the cell surface. The C-terminal TUG cleavage product is extracted from the Golgi matrix, which vacates an “anchoring” site to permit subsequent cycles of GLUT4 retention and release. Together, GLUT4 vesicle translocation and TUG cleavage may coordinate glucose uptake with physiologic effects of other proteins present in the GLUT4-containing vesicles, and with potential additional effects of the TUG C-terminal product. Understanding this TUG pathway for GLUT4 retention and release will shed light on the regulation of glucose uptake and the pathogenesis of type 2 diabetes.