SUMMARY Growth factors, such as insulin, can induce both acute and long-term glucose uptake into cells. Apart from the rapid, insulin-induced fusion of glucose transporter(GLUT)4 storage vesicles with the cell surface that occurs in muscle and adipose tissues, the mechanism behind acute induction has been unclear in other systems. Thioredoxin interacting protein (TXNIP) has been shown to be a negative regulator of cellular glucose uptake. TXNIP is transcriptionally induced by glucose and reduces glucose influx by promoting GLUT1 endocytosis. Here, we report that TXNIP is a direct substrate of protein kinase B (AKT) and is responsible for mediating AKT-dependent acute glucose influx after growth factor stimulation. Furthermore, TXNIP functions as an adaptor for the basal endocytosis of GLUT4 in vivo, its absence allows excess glucose uptake in muscle and adipose tissues, causing hypoglycemia during fasting. Altogether, TXNIP serves as a key node of signal regulation and response for modulating glucose influx through GLUT1 and GLUT4.

The combination of zinc dyshomoeostasis and oxidative damage has been linked to a number of human disease pathologies. A common pathway of oxidative damage centers on tyrosine with the generation of 3,4-dihydroxyphenylalanine (L-dopa). Once formed this catecholic moiety can be involved in metal binding. Herein, an L-dopa residue is incorporated into a peptide designed to adopt a -hairpin configuration. Variation of the cross strand partner to L-dopa introduces an aromatic pair to enhance structure. Mass spectrometry indicates successful zinc binding, consistent with a 1:1 peptide:zinc complex. NMR and spectrophotometric investigations reveal the L-dopa as the binding locus with association energies ranging between 4.3 and 5.2 kcalmol-1 .

The intestine plays a pivotal role in regulating systemic metabolism. It is the portal and sensor for incoming nutrients and the origin of neural and endocrine signals that determine responses to diet. Importantly, the intestine is the location where host, diet, and gut microbiota interact. We have discovered that acyl CoA:monoacylglycerol acyltransferase 2 (MGAT2) catalyzes triacylglycerol synthesis in enterocytes, mediates fat absorption in the intestine, and regulates whole body energy balance. Mice without a functional gene encoding the enzyme (Mogat2−/−) absorb a normal amount of dietary fat. However, they exhibit delayed fat absorption, altered gut hormone secretion, and increased energy expenditure. As a result, they are resistant to obesity and related metabolic disorders induced by a high‐fat diet. Using tissue‐specific gain‐ and loss‐of‐function models, we showed that intestinal MGAT2 enhances metabolic efficiency and promotes weight gain. When fed a fat‐free diet, Mogat2−/− mice still exhibit increased energy expenditure, suggesting the effects are not limited to calories from fat. Accordingly, MGAT2 deficiency protects the genetically hyperphagic Agouti mouse fed a regular chow from excessive weight gain, hepatic steatosis, and glucose intolerance. We also found that inactivation of MGAT2 in adult mice decreases weight gain and enhances glucose regulation, even in already obese mice. Surprisingly, Mogat2−/− mice are also protected from both chemical and genetic insults to the pancreatic beta‐cells. We hypothesize that loss of MGAT2 may act on beta‐cells through its effect on bile acid‐modifying gut microbiota. Some of these findings and approaches we are taking to test this hypothesis will be discussed in this presentation.Support or Funding InformationWe gratefully acknowledge our funding support from the U.S. National Institutes of Health (DK088210) and U.S. Department of Agriculture (WIS01442).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.