Mesenchymal stem cells (MSCs) are defined by their ability to self-renew and differentiate into the cells that form mesodermal tissues such as bone and fat. Low magnitude mechanical signals (LMMS) have been shown to be anabolic to bone and have been recently reported to suppress the development of fat in normal animals fed a regular diet. Using male C57BL/6J mice, the ability of LMMS (0.2g, 90-Hz signal applied for 15 min/d, 5 d/wk) to simultaneously promote bone formation and prevent diet-induced obesity was correlated to mechanical influences on the molecular environment of the bone marrow, as indicated by the population dynamics and lineage commitment of MSCs. Six weeks of LMMS increased the overall marrowbased stem cell population by 37% and the number of MSCs by 46%. Concomitant with the increase in stem cell number, the differentiation potential of MSCs in the bone marrow was biased toward osteoblastic and against adipogenic differentiation, as reflected by upregulation of the transcription factor Runx2 by 72% and downregulation of PPAR␥ by 27%. The phenotypic impact of LMMS on MSC lineage determination was evident at 14 wk, where visceral adipose tissue formation was suppressed by 28%, whereas trabecular bone volume fraction in the tibia was increased by 11%. Translating this to the clinic, a 1-yr trial in young women (15-20 yr; n ס 48) with osteopenia showed that LMMS increased trabecular bone in the spine and kept visceral fat at baseline levels, whereas control subjects showed no change in BMD, yet an increase in visceral fat. Mechanical modulation of stem cell proliferation and differentiation indicates a unique therapeutic target to aid in tissue regeneration and repair and may represent the basis of a nonpharmacologic strategy to simultaneously prevent obesity and osteoporosis.
Obesity, a global pandemic that debilitates millions of people and burdens society with tens of billions of dollars in health care costs, is deterred by exercise. Although it is presumed that the more strenuous a physical challenge the more effective it will be in the suppression of adiposity, here it is shown that 15 weeks of brief, daily exposure to high-frequency mechanical signals, induced at a magnitude well below that which would arise during walking, inhibited adipogenesis by 27% in C57BL/6J mice. The mechanical signal also reduced key risk factors in the onset of type II diabetes, nonesterified free fatty acid and triglyceride content in the liver, by 43% and 39%, respectively. Over 9 weeks, these same signals suppressed fat production by 22% in the C3H.B6 -6T congenic mouse strain that exhibits accelerated age-related changes in body composition. In an effort to understand the means by which fat production was inhibited, irradiated mice receiving bone marrow transplants from heterozygous GFP ؉ mice revealed that 6 weeks of these low-magnitude mechanical signals reduced the commitment of mesenchymal stem cell differentiation into adipocytes by 19%, indicating that formation of adipose tissue in these models was deterred by a marked reduction in stem cell adipogenesis. Translated to the human, this may represent the basis for the nonpharmacologic prevention of obesity and its sequelae, achieved through developmental, rather than metabolic, pathways. mesenchymal stem cells ͉ obesity ͉ therapeutics ͉ diabetes ͉ vibration
IQGAPs are multidomain scaffolding proteins that integrate Rho GTPase and Ca2؉ /calmodulin signals with cell adhesive and cytoskeletal reorganizational events. Targeted disruption of the murine Iqgap2 gene resulted in the age-dependent development of apoptosis and hepatocellular carcinoma (HCC), characterized by the overexpression of IQGAP1, the loss of membrane E-cadherin expression, the cytoplasmic translocation (and activation) of ␤-catenin, and the overexpression of a nuclear target of ␤-catenin, cyclin D1. In normal hepatocytes, IQGAP2 was found to exist as one component of a multifunctional scaffolding complex comprising IQGAP1, ␤-catenin, and E-cadherin, with no evidence for direct IQGAP1-IQGAP2 interactions. Interbreeding of Iqgap2 ؊/؊ mice into the Iqgap1 ؊/؊ background resulted in the phenotypic correction of the preexisting hepatopathy, decreases in the incidence and sizes of HCC tumors, and the normalization of overall survival rates compared to those of Iqgap2 ؊/؊ mice, suggesting that maximal penetrance of the Iqgap2 ؊/؊ HCC phenotype requires the coordinate expression of IQGAP1. These results identify Iqgap2 as a novel tumor suppressor gene specifically linked to the development of HCC and the activation of the Wnt/␤-catenin signaling pathway, while also suggesting that IQGAP1 and IQGAP2 retain functionally divergent roles in hepatocellular carcinogenesis.
Accurate and precise techniques that identify the quantity and distribution of adipose tissue in vivo are critical for investigations of adipose development, obesity, or diabetes. Here, we tested whether in vivo micro-computed tomography (microCT) can be used to provide information on the distribution of total, subcutaneous and visceral fat volume in the mouse. Ninety C57BL/6J mice (weight range: 15.7-46.5 g) were microCT scanned in vivo at 5 months of age and subsequently sacrificed. Whole body fat volume (base of skull to distal tibia) derived from in vivo microCT was significantly (p<0.001) correlated with the ex vivo tissue weight of discrete perigonadal (R(2)=0.94), and subcutaneous (R(2)=0.91) fat pads. Restricting the analysis of tissue composition to the abdominal mid-section between L1 and L5 lumbar vertebrae did not alter the correlations between total adiposity and explanted fat pad weight. Segmentation allowed for the precise discrimination between visceral and subcutaneous fat as well as the quantification of adipose tissue within specific anatomical regions. Both the correlations between visceral fat pad weight and microCT determined visceral fat volume (R(2)=0.95, p<0.001) as well as subcutaneous fat pad weight and microCT determined subcutaneous fat volume (R(2)=0.91, p<0.001) were excellent. Data from these studies establish in vivo microCT as a non-invasive, quantitative tool that can provide an in vivo surrogate measure of total, visceral, and subcutaneous adiposity during longitudinal studies. Compared to current imaging techniques with similar capabilities, such as microMRI or the combination of DEXA with NMR, it may also be more cost-effective and offer higher spatial resolutions.
In mammals, glucose transporter (GLUT)-4 plays an important role in glucose homeostasis mediating insulin action to increase glucose uptake in insulin-responsive tissues. In the basal state, GLUT4 is located in intracellular compartments and upon insulin stimulation is recruited to the plasma membrane, allowing glucose entry into the cell. Compared with mammals, fish are less efficient restoring plasma glucose after dietary or exogenous glucose administration. Recently our group cloned a GLUT4-homolog in skeletal muscle from brown trout (btGLUT4) that differs in protein motifs believed to be important for endocytosis and sorting of mammalian GLUT4. To study the traffic of btGLUT4, we generated a stable L6 muscle cell line overexpressing myc-tagged btGLUT4 (btGLUT4myc). Insulin stimulated btGLUT4myc recruitment to the cell surface, although to a lesser extent than rat-GLUT4myc, and enhanced glucose uptake. Interestingly, btGLUT4myc showed a higher steady-state level at the cell surface under basal conditions than rat-GLUT4myc due to a higher rate of recycling of btGLUT4myc and not to a slower endocytic rate, compared with rat-GLUT4myc. Furthermore, unlike rat-GLUT4myc, btGLUT4myc had a diffuse distribution throughout the cytoplasm of L6 myoblasts. In primary brown trout skeletal muscle cells, insulin also promoted the translocation of endogenous btGLUT4 to the plasma membrane and enhanced glucose transport. Moreover, btGLUT4 exhibited a diffuse intracellular localization in unstimulated trout myocytes. Our data suggest that btGLUT4 is subjected to a different intracellular traffic from rat-GLUT4 and may explain the relative glucose intolerance observed in fish.
In mammals and birds, several isoforms of facilitative glucose transporters have been identified (GLUT1-4), but no information is available regarding the molecules involved in glucose transport in other vertebrates. Here we report the cloning of a GLUT molecule from fish muscle with high sequence homology to GLUT4 and containing features characteristic of a functional GLUT. Fish GLUT is expressed predominantly in skeletal muscle, kidney and gill, which are tissues with known high glucose utilization. These results indicate that fish GLUT is structurally, and perhaps functionally, similar to the other known GLUTs expressed in muscle in mammalian and avian species.
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