Date of Award

8-2015

Level of Access Assigned by Author

Campus-Only Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

Advisor

Clifford Rosen

Second Committee Member

Leif Oxburgh

Third Committee Member

Peter Brooks

Additional Committee Members

Pradeep Sathyanarayana

Kevin Flurkey

Anne Breggia

Abstract

Osteopenia, a state of low bone mass, can lead to devastating fractures; a number of risk factors for the development of these fractures have been identified, but a further understanding of the effects of nutrition and environment on bone are required for proper risk assessment. I sought to identify the effects of diet and sympathetic nervous system (SNS) activation on body composition and bone density and to delineate the differences in response between adolescent and aging mice from two wildtype strains, C57BL/6J (B6) and C3H/HeJ (C3H).

I observed that consumption of a 30% calorie-restricted (CR) diet for 12 weeks starting at 3 weeks of age inhibited interstitial and appositional growth of the femur and resulted in dramatic reductions in areal bone mineral density (aBMD), bone mineral content (BMC), and bone microarchitecture. Decreased weight and body size in calorie- restricted mice were primarily due to decreases in body fat; however, marrow adipose tissue (MAT) was paradoxically increased. In aging mice maintained on a CR diet for 12 weeks starting at 40 weeks of age, I observed similar reductions in body weight, size, and fat, and an increase in MAT volume. However, aging B6 mice appeared to be resistant to calorie restriction-induced trabecular bone loss. On the other hand, consumption of a high-fat diet for 12 weeks beginning at wean resulted in increased body weight, size, and fat; however, there were no overt changes aBMD, BMC, or bone microarchitecture. In response to long-term cold exposure (1 week at 18°C, 3 weeks at 4°C) in adolescent and aging B6 and C3H mice, I observed that C3H, but not B6, mice had reduced MAT content and cortical bone microarchitecture. The C3H strain also demonstrated a greater propensity for browning of white adipose tissue (WAT).

In sum, these results suggest that calorie restriction is deleterious to bone development, but that the effects of high-fat diet feeding are less clear. In addition, strain-dependent effects of cold exposure may indicate a genetic predisposition for browning of white adipose tissue. These findings provide novel insight into the mechanisms of calorie restriction-induced bone loss and SNS-mediated cortical bone loss.

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