Doctoral Dissertations

Date of Award


Degree Type


Degree Name

Doctor of Philosophy


Human Ecology

Major Professor

Michael B. Zemel

Committee Members

Jay Whelan, Jung Han Kim, Michael McEntee


Obesity is a disorder of energy balance in which energy intake exceeds energy expenditure. Methods to control obesity through limiting energy intake have had limited success, and it is widely recognized that energy expenditure must also be increased if long-term weight loss is to be achieved. Uncoupling proteins (UCPs) are a family of integral membrane proteins of mitochondrial inner membrane, where they uncouple the process of mitochondrial respiration from oxidative phosphorylation, diminishing the resulting production of ATP and decreasing the metabolic efficiency of the organism. Thus, UCPs provide new molecular targets for increasing energy expenditure. Unlike the other UCP family members, UCP2 is ubiquitously expressed, with the highest level in white adipose tissue. Stimulation of mitochondrial uncoupling in adipocytes in vitro demonstrates a direct inhibitory effect on lipogenesis and suppression on lipolysis via a calcium dependent mechanism, indicating a potential role of UCP2 in regulation of adiposity.

Previous studies demonstrate that intracellular Ca2+ ([Ca2+]i ) plays a key role in metabolic disorders associated with obesity. [Ca2+]i can clearly be modulated by the calcitrophic hormone 1α, 25-dihydroxyvitamin D3 (1α, 25-(OH)2-D3), which appears to have both genomic and non-genomic action in adipocytes. 1α, 25-(OH)2-D3 modulates adipocyte Ca2+ signaling directly, resulting in an increased lipogenesis and decreased lipolysis. In addition, 1α, 25-(OH)2-D3 plays a genomic role in regulating adipocyte UCP2 expression levels, indicating that the regulation of UCP2 and the resulting increased core temperature may contribute to increased rates of energy dissipation. Accordingly, the suppression of 1α, 25-(OH)2-D3 by increasing dietary calcium attenuates adiposity by decreasing triglyceride accumulation in the adipocytes: increasing dietary calcium results in a net reduction in fat mass in the absence of caloric restriction, a marked augmentation of body weight and fat loss during energy restriction, and an inhibition of weight and fat regain after food restriction in mice.

Although these anti-obesity effects of dietary calcium are due, in part, to enhanced metabolic rate and thermogenic processes, it is also possible that a loss of adipocytes would result in a deficit cells for lipid esterification as the body recovers. Physiological doses of 1α, 25-(OH)2-D3 inhibit apoptosis in differentiated 3T3-L1 adipocytes, and the suppression of 1α, 25-(OH)2-D3 in vivo by increasing dietary calcium stimulates adipocyte apoptosis in refeeding following energy restriction in aP2 transgenic mice, indicating that the stimulation of adipocyte apoptosis contributes to adiposity reduction after high calcium diet administration. UCP2 plays a direct role in modulating adipocyte apoptosis by inducing mitochondrial potential collapse and inhibiting ATP production. Overexpression of UCP2 in adipocyte stimulates apoptosis while inhibition of mitochondrial uncoupling either by chemical inhibitor GDP or by siRNA duplexes suppresses adipocyte apoptosis. Accordingly, suppression of UCP2 by physiologically low doses of 1α, 25-(OH)2-D3, which can be induced by low dietary calcium, decreases apoptosis. Although 1α, 25-(OH)2-D3 causes dose-dependent stimulation on [Ca2+]i levels, low doses of 1α, 25-(OH)2-D3 decrease mitochondrial calcium accumulation while a high dose of 1α, 25-(OH)2-D3 induces markedly greater increase in [Ca2+]i and stimulates calcium storage in mitochondria. Bay K 8644, which is a Ca2+ ionophore and can mimic the stimulatory effect of 1α, 25-(OH)2-D3 on [Ca2+]i without exerting effects on UCP2, causes a dose-dependent increases in apoptosis and mitochondrial calcium accumulation, indicating that stimulation of pharmaceutical high dose 1α, 25-(OH)2-D3 on apoptosis is a calcium-dependent effect.

In summary, present data support the concept that dietary calcium exerts antiobesity effects in aP2 transgenic mice under conditions of varying nutrient status. In addition, this study extended our observation that dietary calcium not only regulates adipocyte size by decreasing lipid accumulation, but also modulates adipocyte number by stimulating apoptotic death. These anti-obesity effects of dietary calcium are attributable to the up-regulation of UCP2, which stimulates energy expenditure, fat utilization and adipocyte apoptosis in white adipose tissue. Accordingly, these data indicate an important role of increasing dietary calcium in prevention and management of obesity.

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