Responses of brown adipose tissue to diet-induced obesity, exercise, dietary restriction and ephedrine treatment
Introduction
Excess energy intake over expenditure results in obesity, and it has been estimated that more than 50% of the European population are overweight (Body Mass Index, BMI > 25 kg/m2) and 30% are obese (BMI > 30 kg/m2) (Groves, 2006, Information Centre, 2008). In the United States, adult obesity and overweight (combined) prevalence was 68.0% of the population during 2007–2008 (Flegal et al., 2010). Furthermore, complications related to obesity (e.g., cardiovascular disease, type 2 diabetes, hypertension, metabolic syndrome, nonalcoholic fatty liver disease and cancer) continue to burden the health care system (an estimated expense of $147 billion a year) in the United States (Finkelstein et al., 2009, Booth et al., 2011). Common strategies to obtain a healthy BMI include changes in diet and exercise. But these lifestyle changes are not easily achieved, and most importantly, results may be moderate and transient. Recently, brown adipose tissue (BAT) has been proposed as a target to modify energy expenditure. BAT has been shown to maintain core temperature via thermogenesis by dissipating stored energy as heat. Morphologically, brown adipocytes have granular eosinophilic cytoplasm due to high content of large mitochondria with abundant cristae. These adipocytes are densely innervated by the sympathetic nervous system, and sympathetic neuronal release of norepinephrine activates ß-adrenergic receptors (ßARs) expressed on the surface of brown adipocytes, ultimately leading to the production of heat. Heat is generated by uncoupling oxidative phosphorylation from ATP production via uncoupling protein-1 (UCP-1), a BAT-specific proton transporter located in the inner mitochondrial membrane. In rodents, UCP-1 has been shown to play an important role in the regulation of energy expenditure and body weight. BAT activation causes body weight loss in rodents, and is likely to be protective against obesity-associated diseases (Ghorbani et al., 1997, Guerra et al., 1998).
In the past, BAT was thought to exist only in small mammals and infants, but recent data from positron emission tomography and computerized tomography have confirmed the presence of BAT depots in adult humans (Virtanen et al., 2009, Cypess and Kahn, 2010). It is now clear that human BAT depots are activated by cold exposure and adrenergic drugs (Cypess and Kahn, 2010). Mounting evidence suggests that BAT is protective against obesity and weight gain in humans. It has been estimated that as little as 50 g of maximally stimulated human BAT could utilize up to 20% of basal caloric needs (Rothwell and Stock, 1983), and therefore, the ability to stimulate energy expenditure via BAT thermogenesis might have important implications for the treatment of obesity and concurrent diseases in humans. Targeting BAT thermogenesis by drugs is a novel anti-obesity approach; however, it is critical to compare this drug-induced weight loss strategy with weight loss approaches that are generally considered safe, such as diet and exercise. In this study, we examined BAT adaptation to exercise, diet restriction (DR) and ephedrine, a sympathomimetic drug, in diet-induced obese (DIO) mice. Our aim was to better elucidate efficacy and toxicity-driven mechanism of weight loss and to characterize the mechanistic differences among these weight loss strategies by evaluating changes in gene expression (mRNA), body composition, CLAMs (Comprehensive Laboratory Animal Monitoring system) and histopathology in DIO mice.
Section snippets
Materials and methods
All procedures involving animals conformed to the guidelines set forth in the Guide to the Use and Care of Laboratory Animals and were reviewed and approved by the GlaxoSmithKline Institutional Animal Care and Use Committee. 22–24 Weeks old, male DIO (C57Bl/6NTac) mice were obtained from Taconic (Germantown, NY). Except for the DR group, all animals were fed a standard obesity inducing high fat diet (60% kcal from fat; Research Diets, Inc., New Brunswick, NJ) ad libitum. Reverse osmosis-treated
Body weight and composition
Body weight and composition (absolute/percent fat and lean tissue masses) are summarized in Fig. 1, Fig. 2, Fig. 3, Fig. 4. All animals including the control group lost body weight by the end of the 7-day study. However, body weights in the exercise and DR groups were significantly decreased compared with control DIO mice (both p < 0.01). The body weight loss in DIO mice given ephedrine treatment was not statistically significant (p = 0.30) compared with control. Pre-study body composition
Discussion
Despite poor adherence and modest long term success, lifestyle interventions such as exercise and calorie restriction remain the most desirable weight loss management for obesity. Moreover, most anti-obesity drugs have had limited success in humans due to variable efficacy and/or undesirable side effects. Differentiating desirable from undesirable weight loss is therefore indispensable, and more importantly, will facilitate the distinction between efficacy and toxicity-driven mechanism of
Acknowledgments
The authors thank Drs. Christine Merrill, Richard Miller, Dan Kemp, Heidi Colton and Jeff Ambroso for critical review of the manuscript, and Lisa Gates, Crystal Woodlief, Teresa Wylie, Elizabeth McNeil, Dennie Frailey, Kerry Crabb for technical assistance.
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