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PPARγ (peroxisome proliferator-activated receptor gamma) is a nuclear receptor whose activation is dependent on a ligand. PPARγ activation by exogenous ligands, such as thiazolidinediones (TZDs), is a strategy in the treatment of type 2 diabetes for the improvement of insulin sensitivity. In addition to a ligand, PPARγ function is also regulated by posttranslational modifications, such as phosphorylation, sumoylation, and ubiquitination. Here, we report that PPARγ protein is modified by acetylation, which induces the PPARγ function in the absence of an external ligand. We observed that histone deacetylase 3 (HDAC3) interacted with PPARγ to deacetylate the protein. In immunoprecipitation, the HDAC3 protein was associated with the PPARγ protein. Inhibition of HDAC3 using RNAi-mediated knockdown or HDAC3 inhibitor increased acetylation of the PPARγ protein. Furthermore, inhibition of HDAC3 enhanced expression of PPARγ target genes such as adiponectin and aP2. The expression was associated with an increase in glucose uptake and insulin signaling in adipocytes. HDAC3 inhibition enhanced lipid accumulation during differentiation of adipocytes. PPARγ acetylation was also induced by pioglitazone and acetylation is required for PPARγ activation. In the absence of TZDs, the acetylation from HDAC3 inhibition was sufficient to induce the transcriptional activity of PPARγ. Treating the Dio mice with HDAC3 inhibitor or pioglitazone for 2 weeks significantly improved high fat diet induced–insulin resistance. Our data suggest that acetylation of PPARγ is a ligand-independent mechanism of PPARγ activation. HDAC3 inhibitor is a potential PPARγ activator for improvement of insulin sensitivity.

SUMMARYA two-parameter model has been proposed previously for predicting the response of laterally loaded single piles in homogenous soil. A disadvantage of the model is that at high Poisson's ratio, unreliable results may be obtained. In this paper, a new load transfer approach is developed to simulate the response of laterally loaded single piles embedded in a homogeneous medium, by introducing a rational stress "eld. The approach can overcome the inherent disadvantage of the two-parameter model, although developed in a similar way. Generalized solutions for a single pile and the surrounding soil under various pile-head and base conditions were established and presented in compact forms. With the solutions, a load transfer factor, correlating the displacements of the pile and the soil, was estimated and expressed as a simple equation. Expressions were developed for the modulus of subgrade reaction for a Winkler model as a unique function of the load transfer factor. Simple expressions were developed for estimating critical pile length, maximum bending moment, and the depth at which the maximum moment occurs. All the newly established solutions and/or expressions, using the load transfer factor, o!er satisfactory predictions in comparison with the available, more rigorous numerical approaches. The current solutions are applicable to various boundary conditions, and any pile}soil relative sti!ness.

An experimental apparatus was developed to investigate the behaviour of vertically loaded free-head piles in sand undergoing lateral soil movement (wf). A large number of tests have been conducted to date. Presented here are 14 typical model pile tests concerning two diameters, two vertical pile loading levels, and varying sliding depths with the movement wf driven by a triangular loading block. Results are provided for driving force as well as for induced shear force (T), bending moment (M), and deflection ( y) along the piles with wf / normalized sliding depth. The tests enable simple expressions to be proposed, drawn from the theory for a laterally loaded pile. The new expressions well capture the evolution of M, T, and y with soil movement observed in current model tests, and the three to five times difference in maximum bending moment (Mmax) from the two modes of loading. They further offer a good estimate of Mmax for eight in situ pile tests and one centrifuge test pile. The study quantifies the sliding resistance offered by a pile for the given wf profiles, pile location (relative to the boundary), and vertical load. It establishes the linear correlation between the maximum thrust (resistance T) and Mmax, regardless of the magnitudes of wf.

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