Exercise inhibits fat formation, and serves as a stimulus to form bone and muscle. While increased calorie use during strenuous activity helps to suppress fat accumulation, we have found that adipogenesis in vitro, and adiposity in vivo can also be inhibited in a calorie independent manner by mechanically biasing mesenchymal stem cells (MSCs) to favor differentiation towards a musculoskeletal, rather than an adipose fate. The ability to define stem cell lineage by mechanical signals suggests that a 'developmental'rather than a 'metabolic'strategy could be employed to prevent and/or treat diseases such as obesity, diabetes and osteoporosis. In marked contrast to bone/fat outcomes generated by prolonged exercise, we have shown that Low Intensity Vibration (LIV) produces an anabolic response in bone and a marked suppression of fat after short daily treatment time (<20 minutes per day) with high frequency (30-90Hz), extremely low intensity (<1.0g) mechanical signals. Translating this mechanosensitivity to the clinic, LIV can be delivered to the standing human with high efficiency (~70%), and is considered safe by both ISO and NIOSH for exposures up to 4 hours each day. This BRP is designed to improve our understanding of the physical and biological basis of regulating MSC fate with mechanical signals, and thereby improve our ability to translate this to the clinic as an """"""""optimized"""""""" non- drug based intervention to prevent or reverse obesity and diabetes, while simultaneously suppressing osteopenia. Through three integrated specific aims, this BRP will examine the: 1) Biologic Mechanism of LIV: using primary MSCs, we will define specific molecular pathways which control - and maximize - the biologic responsiveness of MSC populations to these mechanical signals (e.g., incorporating recovery periods between mechanical bouts allows for amplification of the biologic response), with efforts to define which components of cell architecture contribute to the response;2) Optimization of LIV Signal: by integrating finite element modeling with in vitro studies, we will work towards establishing the mechanical environment to which MSC are exposed during LIV, and identify those specific parameters that contribute to the efficacy of the LIV signal, providing the basis for optimizing the LIV signal. 3) Translational Potential of LIV: a the level of the whole animal, examine the degree to which optimized LIV signal and scheduling suppresses the fat phenotype in mouse models of diet-induced obesity and estrogen deficiency (ovariectomy), achieved through the regulation of MSC activity, and the extent to which downstream complications of diabesity, including insulin sensitivity, tissue steatosis, elevated triglycerides, free fatty acids and adipokines, are mitigated through exposure to LIV over extended periods of time. In sum, this BRP lies at the convergence of engineering, molecular biology, biophysics and medicine to understand how mechanical signals regulate MSC cell fate, with the ultimate goal of harnessing this sensitivity towards a bioengineering based, non-pharmacologic intervention for the suppression of diabesity, particularly excess visceral adiposity, in those at high risk for obesity and diabetes.

Public Health Relevance

This BRP is designed, through three interconnected specific aims, to better understand how low intensity vibration (LIV) effectively bias mesenchymal stem cell differentiation away from adipogenesis (fat formation) and towards osteoblastogenesis (bone formation), and to establish whether this science can translate to the clinic as a non-pharmacological intervention to suppress chronic diseases such as diabesity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB014351-03
Application #
8717417
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Hunziker, Rosemarie
Project Start
2012-09-17
Project End
2015-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
State University New York Stony Brook
Department
Biomedical Engineering
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Krishnamoorthy, D; Frechette, D M; Adler, B J et al. (2016) Marrow adipogenesis and bone loss that parallels estrogen deficiency is slowed by low-intensity mechanical signals. Osteoporos Int 27:747-56
Uzer, Gunes; Rubin, Clinton T; Rubin, Janet (2016) Cell Mechanosensitivity is Enabled by the LINC Nuclear Complex. Curr Mol Biol Rep 2:36-47
Pagnotti, Gabriel M; Chan, M Ete; Adler, Benjamin J et al. (2016) Low intensity vibration mitigates tumor progression and protects bone quantity and quality in a murine model of myeloma. Bone 90:69-79
Pongkitwitoon, Suphannee; Uzer, Gunes; Rubin, Janet et al. (2016) Cytoskeletal Configuration Modulates Mechanically Induced Changes in Mesenchymal Stem Cell Osteogenesis, Morphology, and Stiffness. Sci Rep 6:34791
Uzer, Gunes; Thompson, William R; Sen, Buer et al. (2015) Cell Mechanosensitivity to Extremely Low-Magnitude Signals Is Enabled by a LINCed Nucleus. Stem Cells 33:2063-76
Styner, Maya; Pagnotti, Gabriel M; Galior, Kornelia et al. (2015) Exercise Regulation of Marrow Fat in the Setting of PPARγ Agonist Treatment in Female C57BL/6 Mice. Endocrinology 156:2753-61
Thompson, William R; Uzer, Gunes; Brobst, Kaitlyn E et al. (2015) Osteocyte specific responses to soluble and mechanical stimuli in a stem cell derived culture model. Sci Rep 5:11049
Frechette, Danielle M; Krishnamoorthy, Divya; Adler, Benjamin J et al. (2015) Diminished satellite cells and elevated adipogenic gene expression in muscle as caused by ovariectomy are averted by low-magnitude mechanical signals. J Appl Physiol (1985) 119:27-36
Thompson, William R; Yen, Sherwin S; Rubin, Janet (2014) Vibration therapy: clinical applications in bone. Curr Opin Endocrinol Diabetes Obes 21:447-53
Adler, Benjamin J; Green, Danielle E; Pagnotti, Gabriel M et al. (2014) High fat diet rapidly suppresses B lymphopoiesis by disrupting the supportive capacity of the bone marrow niche. PLoS One 9:e90639

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