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.

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