Chronic Exposure to TNFα Impairs Secretion of Glucagon-Like Peptide-1.

Obesity is associated with systemic inflammation and elevated levels of TNFα, leading to impaired glucose tolerance. In humans, obesity is also associated with reduced nutrient-stimulated secretion of the intestinal incretin hormone, glucagon-like peptide-1 (GLP-1). We hypothesized that TNFα plays a direct role in the impairment of GLP-1 secretion from the enteroendocrine L-cell and that blocking TNFα can restore both GLP-1 secretion and glucose homeostasis. Expression of the TNFα receptor subytpe-1 was detected in the human NCI-H716 and murine GLUTag L-cell models and in mouse ileal sections. Although TNFα acutely increased GLP-1 release from NCI-H716 cells (P < .05-.001), preincubation with TNFα for 24 hours reduced proglucagon mRNA (P < .05) and GLP-1 cellular (P < .05) levels without affecting cell viability. Furthermore, both NCI-H716 and GLUTag cells pretreated with TNFα for 24 hours no longer responded to known GLP-1 secretagogues, an effect that was reversed by coincubation with the Nuclear Factor Kappa B inhibitor, 5-aminosalicylic acid, in the NCI-H716 cells. Mice given a high-fat diet (HFD) for 12 weeks developed impaired glucose tolerance, hyperinsulinemia, and increased TNFα mRNA expression in fat and ileal tissue. Hyperglycemia and hyperinsulinemia were reduced in HFD mice treated with the anti-TNFα biological, etanercept, for 2 weeks. In primary intestinal cultures from these animals, HFD control mice had impaired GLP-1 secretion, and this was not observed in the HFD etanercept-derived cultures (P < .05). In conclusion, chronic exposure to TNFα directly impairs GLP-1 secretion at the level of the intestinal L-cell, an effect that is reversed by anti-TNFα therapy in association with improved glucose tolerance.

Acute mechanoadaptation of vascular smooth muscle cells in response to continuous arteriolar vasoconstriction: implications for functional remodeling.

Arterioles exposed to norepinephrine (NE) for 4 h exhibit incomplete relaxation on removal of the agonist. We hypothesized that this is due to a mechanoadaptation process associated with active repositioning of vascular smooth muscle cells (VSMCs) within the vascular wall. Isolated arterioles were exposed to NE (10(-5.5) M) for either 5 min (n = 7) or 4 h (n = 13). During the 5-min exposure, vessel diameter was reduced to 61 +/- 2.6%, and cells shortened to 76.3 +/- 3.8% of control. After NE removal, vessel diameter and cell length returned to control values, which indicated that during acute vasoconstriction cells shorten and relengthen in a reversible fashion. In contrast, when NE exposure lasted 4 h, vessels did not return to control diameter, but VSMCs returned to control length after NE removal. During the 4-h constriction, 56% of the VSMCs began returning to control length, and the overlap between VSMCs increased, which indicated that cellular repositioning had occurred in the presence of the maintained constriction. Thus, in response to prolonged constriction, VSMCs undergo a mechanoadaptation process involving "length autoregulation" that would be energetically favorable for maintenance of a reduced diameter and may provide a mechanism for the development of eutrophic remodeling of the vascular wall.