Search

Glucagon-like peptide-1 (GLP-1) is a polypeptide hormone secreted from enteroendocrine L cells and potentiates glucose-dependent insulin secretion in pancreatic [beta] cells. Recently the GLP-1 receptor (GLP-1 R) has been a focus for new anti-diabetic therapy with the introduction of GLP-1 analogues and DPP-IV inhibitors, and this has stimulated additional interest in the mechanisms of GLP-1 signaling. Here we identify a mechanism for GLP-1 action, showing that the scaffold protein [beta]-arrestin-1 mediates the effects of GLP-1 to stimulate cAMP production and insulin secretion in [beta] cells. Using a coimmunoprecipitation technique, we also found a physical association between the GLP-1 R and [beta]-arrestin-1 in cultured INS-1 pancreatic [beta] cells. [beta]-Arrestin-1 knockdown broadly attenuated GLpol signaling, causing decreased ERK and CREB activation and IRS-2 expression as well as reduced cAMP levels and impaired insulin secretion. However, [beta]-arrestin-1 knockdown did not affect GLP-1 R surface expression and ligand-induced GLP-1 R internalization/desensitization. Taken together, these studies indicate that [beta]-arrestin-1 plays a role in GLP-1 signaling leading to insulin secretion, defining a previously undescribed mechanism for GLP-1 action. CREB | IRS-2

Peroxisome proliferator-activated receptor-[gamma] (PPAR-[gamma]) plays a critical role in regulating insulin sensitivity and glucose homeostasis. In this study, we identified highly efficient small interfering RNA (siRNA) sequences and used lentiviral short hairpin RNA and electroporation of siRNAs to deplete PPAR-[gamma] from 3T3-LI adipocytes to elucidate its role in adipogenesis and insulin signaling. We show that PPAR-[gamma] knockdown prevented adipocyte differentiation but was not required for maintenance of the adipocyte differentiation state after the cells had undergone adipogenesis. We further demonstrate that PPAR-[gamma] suppression reduced insulin-stimulated glucose uptake without affecting the early insulin signaling steps in the adipocytes. Using dual siRNA strategies, we show that this effect of PPAR-[gamma] deletion was mediated by both GLUT4 and GLUT1. Interestingly, PPAR-[gamma]-depleted cells displayed enhanced inflammatory responses to TNF-[alpha] stimulation, consistent with a chronic anti-inflammatory effect of endogenous PPAR-[gamma]. In summary, 1) PPAR-[gamma] is essential for the process of adipocyte differentiation but is less necessary for maintenance of the differentiated state, 2) PPAR-[gamma] supports normal insulin-stimulated glucose transport, and 3) endogenous PPAR-[gamma] may play a role in suppression of the inflammatory pathway in 3T3-L1 cells. small interfering RNA; lentivirus; peroxisome proliferator activated-receptor-[gamma] doi:10.1152/ajpendo.00695.2006

Wavenumber spectra of the atmospheric potential energy of Mars at mesoscales (wavelengths of 64-957 km) were obtained as a function of latitude, season, and Martian year using infrared radiance data obtained by the Thermal Emission Spectrometer (TES) onboard the Mars Global Surveyor (MGS) spacecraft. Spectral slopes tend to be flatter at smaller scales, and the slopes are usually flatter than -1 near small-scale ends. Near large-scale ends, the spectra sometimes show prominent steepening with slopes from -2 to -3. The power peaks in the high latitudes in winter and equinoxes, suggesting that eddies are generated preferentially in baroclinic zones. The seasonal variation at each latitude band, on the other hand, tends to be obscured by large interannual variability. An enhancement in the power was observed around the storm tracks in the Southern Hemisphere. Spectra of the terrestrial stratosphere were also obtained with a similar method from data taken by the Aura satellite and compared to the results for Mars.

It is shown that planetary-scale waves are inherently accompanied by latitudinal momentum transport when they propagate vertically in vertically sheared zonal flows. Because of the dependence of the wave's latitudinal scale on the intrinsic phase speed, positive (negative) vertical shear should force prograde (retrograde) waves to focus equatorward and retrograde (prograde) waves to expand poleward in the course of upward propagation. Consequently, Eliassen-Palm (EP) flux vectors are tilted from the vertical and nonzero latitudinal momentum fluxes occur. The direction of momentum transport should always be equatorward (poleward) in positive (negative) vertical shear irrespective of the zonal propagation direction. The idea was applied to upwardly propagating waves in the Venusian middle atmosphere, where vertical shear of strong midlatitude jets and equatorial superrotation exist. Numerical solutions showed that Kelvin and prograde inertio-gravity waves focus equatorward and mixed Rossby gravity and Rossby waves expand poleward below the cloud top. The former is attributed primarily to the vertical shear of the superrotation, while the latter to the vertical shear beneath the midlatitude jets. Such characteristics of planetary-scale waves will cause angular momentum separation between high and low latitudes and, at least partly, contribute to the maintenance of the superrotation.

A modified, equatorial Kelvin wave solution is obtained in the presence of the zonal-mean meridional circulation. The modified Kelvin wave solution, which is obtained via a perturbation expansion of the linearized, primitive equations on an equatorial [beta] plane, possesses a nonzero meridional wind component. This meridional wind component is absent when the background flow is at rest. The combination of the meridional and zonal winds induces a meridional flux of zonal momentum in the upstream direction of the background north south flow. This flux is divergent in latitude and produces a nonzero wave-induced force even though the waves are linear, steady, and conservative. It is shown that, although such a force violates the traditional nonacceleration theorem in which the mean meridional circulation is negligible at leading order, the result is in accord with a more general nonacceleration theorem obtained from the exact generalized Lagrangian-mean theory in which the mean meridional circulation is nonzero. The meridional circulation, in effect, attempts to advect wave pseudomomentum off the equator, resulting in a nonzero acceleration in the Eulerian reference frame. The meridional flux of momentum for any equatorially trapped mode is derived from the generalized Lagrangian-mean theory. Those modes with eastward (westward) intrinsic phase velocity transport eastward (westward) zonal momentum in the upstream direction of the background meridional flow in the neighborhood of the equator. It is also shown that the vertical flux of zonal momentum is not constant with altitude in a steady vertical flow since diabatic heating/cooling is needed to sustain the vertical wind. Implications of the results for the terrestrial and Venusian atmospheres are discussed.

Growth factors, cell-surface receptors, adhesion molecules, an extracellular matrix proteins play critical roles in vascular pathophysiology by affecting growth, migration, differentiation, and survival of vascular cells. In a search for secreted and cell-surface molecules expressed in the cardiovascular system, by using a retrovirus-mediated signal sequence trap method, we isolated a cell-surface protein named vasorin. Vasorin is a typical type membrane protein, containing tandem arrays of a characteristic leucine-rich repeat motif, an epidermal growth factor-like motif, and a fibronectin type III-like motif at the extracellular domain. Expression analyses demonstrated that vasorin is predominantly expressed in vascular smooth muscle cells, and that its expression is developmentally regulated, To clarify biological functions of vasorin, we searched for its binding partners and found that vasorin directly binds to transforming growth factor (TGF)-[beta] and attenuates TGF-[beta] signaling in vitro. Vasorin expression was down-regulated during vessel repair after arterial injury, and reversal of vasorin down-regulation, by using adenovirus-mediated in vivo gene transfer, significantly diminished injury-induced vascular lesion formation, at least in part, by inhibiting TGF-[beta] signaling in vivo. These results suggest that down-regulation of vasorin expression contributes to neointimal formation after vascular injury and that vasorin modulates cellular responses to pathological stimuli in the vessel wall. Thus, vasorin is a potential therapeutic target for vascular fibroproliferative disorders.