Excess caloric intake can lead to insulin resistance. The underlying reasons are complex but likely related to ectopic lipid deposition in nonadipose tissue. We hypothesized that the inability to appropriately expand subcutaneous adipose tissue may be an underlying reason for insulin resistance and beta cell failure. Mice lacking leptin while overexpressing adiponectin showed normalized glucose and insulin levels and dramatically improved glucose as well as positively affected serum triglyceride levels. Therefore, modestly increasing the levels of circulating full-length adiponectin completely rescued the diabetic phenotype in ob/ob mice. They displayed increased expression of PPARgamma target genes and a reduction in macrophage infiltration in adipose tissue and systemic inflammation. As a result, the transgenic mice were morbidly obese, with significantly higher levels of adipose tissue than their ob/ob littermates, leading to an interesting dichotomy of increased fat mass associated with improvement in insulin sensitivity. Based on these data, we propose that adiponectin acts as a peripheral "starvation" signal promoting the storage of triglycerides preferentially in adipose tissue. As a consequence, reduced triglyceride levels in the liver and muscle convey improved systemic insulin sensitivity. These mice therefore represent what we believe is a novel model of morbid obesity associated with an improved metabolic profile.

Compromised immunoregulation contributes to obesity and complications in metabolic pathogenesis. Here, we demonstrate that the nuclear factor of activated T cell (NFAT) group of transcription factors contributes to glucose and insulin homeostasis. Expression of two members of the NFAT family (NFATc2 and NFATc4) is induced upon adipogenesis and in obese mice. Mice with the Nfatc2 ؊/؊ Nfatc4 ؊/؊ compound disruption exhibit defects in fat accumulation and are lean. Nfatc2 ؊/؊ Nfatc4 ؊/؊ mice are also protected from diet-induced obesity. Ablation of NFATc2 and NFATc4 increases insulin sensitivity, in part, by sustained activation of the insulin signaling pathway. Nfatc2 ؊/؊ Nfatc4 ؊/؊ mice also exhibit an altered adipokine profile, with reduced resistin and leptin levels. Mechanistically, NFAT is recruited to the transcription loci and regulates resistin gene expression upon insulin stimulation. Together, these results establish a role for NFAT in glucose/insulin homeostasis and expand the repertoire of NFAT function to metabolic pathogenesis and adipokine gene transcription.

Studies were conducted to determine whether maternal substrate utilization during pregnancy affects fetal growth and predisposes offspring to metabolic disease. Female wild-type (WT) and glucose transporter 4 heterozygous mice (G4Ϯ, a model of altered peripheral substrate utilization) were fed high-fat diet (HFD, 35.5% fat) or control chow (C, 9.5% fat) for 2 wk before mating, throughout pregnancy and lactation (IU/L). WT HFD females exhibited increased serum nonesterified fatty acid and lactate levels and increased hepatic mRNA expression of peroxisome proliferatoractivated receptor ␥ coactivator-1-␤ and SREBP-1c, consistent with increased lipogenesis. G4Ϯ HFD females exhibited enhanced lipid clearance, and exposure to HFD did not increase hepatic gene expression. HFD independent of maternal genotype decreased fetal growth and birth weight. WT offspring were weaned onto a low-fat diet (5.6% fat). Male offspring of WT mothers exposed to HFD exhibited "catch-up" growth accompanied by increased adiposity, impaired glucose tolerance, and insulin sensitivity. In contrast, male offspring of G4Ϯ HFD mothers did not exhibit any characteristics of metabolic syndrome. These data suggest that differences in maternal substrate utilization influence offspring metabolic phenotype. (Pediatr Res 66: 368-373, 2009)

Objective-Adiponectin is an adipocyte-derived, secreted protein that is implicated in protection against a cluster of related metabolic disorders. Mice lacking adiponectin display impaired hepatic insulin sensitivity and respond only partially to peroxisome proliferator-activated receptor ␥ agonists. Adiponectin has been associated with antiinflammatory and antiatherogenic properties; however, the direct involvement of adiponectin on the atherogenic process has not been studied. Methods and Results-We crossed adiponectin knockout mice (Adn Ϫ/Ϫ ) or mice with chronically elevated adiponectin levels (Adn Tg ) into the low-density lipoprotein receptor-null (Ldlr Ϫ/Ϫ ) and the apoliprotein E-null (Apoe Ϫ/Ϫ ) mouse models. Adiponectin levels did not correlate with a suppression of the atherogenic process. Plaque volume in the aortic root, cholesterol accumulation in the aorta, and plaque morphology under various dietary conditions were not affected by circulating adiponectin levels. In light of the strong associations reported for adiponectin with cardiovascular disease in humans, the lack of a phenotype in gain-and loss-of-function studies in mice suggests a lack of causation for adiponectin in inhibiting the buildup of atherosclerotic lesions. Conclusion-These data indicate that the actions of adiponectin on the cardiovascular system are complex and multifaceted, with a minimal direct impact on atherosclerotic plaque formation in preclinical rodent models.

A novel passive microfluidic silicon mixer has been designed, optimized and fabricated. The architecture of the mixer consists of a simple “T” junction, made up by a 20 μm wide by 82 μm deep channel, followed by three repeats of an alcove, each with a triangular obstruction, arranged in a zigzag fashion. Numerical simulations were employed to optimize the geometry, particularly the dimensions of the alcoves, the relative orientation and the spacing between them, and the degree of intrusion associated with them. The simulation results demonstrate that chaotic flow due to recirculation within the alcoves results in transverse velocity that promotes effective fluid mixing. The microfluidic mixer with the simulation-optimized geometry was fabricated with photolithographic techniques and characterized by optical imaging, fluorescence and Raman microscope spectroscopy. At a sample flow rate of 20 μL/s, the mixer exhibits a short mixing deadtime of ~22 μs and a high mixing efficiency under both low and high viscosity conditions. The alcove-based microfluidic silicon mixer offers unique advantages for its short deadtime and slow sample consumption rate. In addition, it provides a valuable component for lab-on-a-chip applications for its ease of development into multiple networks for massively parallel analytical processes.