Intestinal lymph as a readout of meal-induced GLP-1 release in an unrestrained rat model.

Intestinal lymph supposedly provides a readout for the secretion of intestinal peptides. We here assessed how mesenteric lymph duct (MLD) lymph levels of glucagon-like peptide (GLP-1), insulin, and metabolites [glucose and triglycerides (TG)] evolve after isocaloric high- and low-fat diet (HFD and LFD) meals and how they compare with hepatic portal vein (HPV) plasma levels. Moreover, we examined the effects of intraperitoneally administered GLP-1 (1 or 10 nmol/kg) on these parameters. At 20 min after the HFD meal onset, GLP-1 levels were higher in MLD lymph than in HPV plasma. No such difference occurred with the LFD meal. Intraperitoneal injections of 10 nmol/kg GLP-1 before meals enhanced the meal-induced increases in MLD lymph and HPV plasma GLP-1 levels except for the MLD lymph levels after the HFD meal. Intraperitoneal injection of 1 nmol/kg GLP-1 only increased HPV plasma GLP-1 levels at 60 min after the HFD meal. GLP-1 injections did not increase the MLD lymph or HPV plasma GLP-1 concentrations beyond the physiological range, suggesting that intraperitoneal GLP-1 injections can recapitulate the short-term effects of endogenous GLP-1. Dipeptidyl peptidase IV (DPP-IV) activity in MLD lymph was lower than in HPV plasma, which presumably contributed to the higher levels of GLP-1 in lymph than in plasma. Insulin and glucose showed similar profiles in MLD lymph and HPV plasma, whereas TG levels were higher in lymph than in plasma. These results indicate that intestinal lymph provides a sensitive readout of intestinal peptide release and potential action, in particular when fat-rich diets are consumed.

A New Caged-Glutamine Derivative as a Tool To Control the Assembly of Glutamine-Containing Amyloidogenic Peptides.

We present the design, synthesis, and characterization of a novel photocaged glutamine derivative (modified on the side chain of glutamine), and describe its use in enhancing peptide stability and solubility. Our results demonstrate that this approach can be used to develop molecular switches to control the folding and ß-sheet formation of amyloidogenic peptides.

Limiting glucocorticoid secretion increases the anorexigenic property of Exendin-4.

OBJECTIVE: Glucagon-like peptide-1 (GLP-1) analogs are attractive options for the treatment of type II diabetes and obesity because of their incretin and anorexigenic effects. Peripheral administration of the GLP-1R agonist Exendin-4 (Ex-4) also increases glucocorticoid secretion in rodents and humans, but whether the released glucocorticoids interact with Ex-4's anorexigenic effect remains unclear. METHODS: To test this, we used two experimental approaches that suppress corticosterone secretion and then assessed Ex-4 effects on eating in adult male rats. First, we combined acute and chronic low dose dexamethasone treatment with Ex-4. Second, we ablated hindbrain catecholamine neurons projecting to the hypothalamus with anti-dopamine-ß-hydroxylase-saporin (DSAP) to block Ex-4-induced corticosterone secretion. RESULTS: Combining dexamethasone and Ex-4 produced a larger acute anorexigenic effect than Ex-4 alone. Likewise, chronic dexamethasone and Ex-4 co-treatment produced a synergistic effect on eating and greater body weight loss in diet-induced obese rats than Ex-4 alone. DSAP lesions not only blunted Ex-4's ability to increase corticosterone secretion, but potentiated the anorexigenic effect of Ex-4, indicating that Ex-4-dependent corticosterone secretion opposes Ex-4's actions. Consistent with the enhancement of Ex-4's anorexigenic effect, DSAP lesion altered Ex-4-dependent changes in neuropeptide Y, preproglucagon, and corticotropin releasing hormone gene expression involved in glucocorticoid feedback. CONCLUSIONS: Our findings demonstrate that limiting glucocorticoid secretion and actions with low dose dexamethasone or DSAP lesion increases Ex-4's ability to reduce food intake and body weight. Novel glucocorticoid receptor based mechanisms, therefore, may help enhance GLP-1-based obesity therapies.