Moderate Daily Exercise Activates Metabolic Flexibility to Prevent Prenatally Induced Obesity

ENERGY BALANCE-OBESITY Moderate Daily Exercise Activates Metabolic Flexibility to Prevent Prenatally Induced Obesity Jennifer L. Miles, Korinna Huber, Nichola M. Thompson, Michael Davison, and Bernhard H. Breier Liggins Institute (J.L.M., N.M.T., M.D., B.H.B.), National Research Centre for Growth and Development (J.L.M., B.H.B.), Department of Surgery (N.M.T.), Faculty of Medical and Health Sciences, and Department of Psychology (M.D.), Faculty of Science, The University of Auckland, 1142 Auckland, New Zealand; and Department of Physiology (K.H.), School for Veterinary Medicine, 30625 Hannover, Germany Obesity and its associated comorbidities are of major worldwide concern. It is now recognized that there are a number of metabolically distinct pathways of obesity development. The present paper investigates the effect of moderate daily exercise on the underlying mechanisms of one such pathway to obesity, through interrogation of metabolic flexibility. Pregnant Wistar rats were either fed chow ad libitum or undernourished throughout pregnancy, generating control or intrauterine growth restricted (IUGR) offspring, respectively. At 250 d of age, dualemission x-ray absorptiometry scans and plasma analyses showed that moderate daily exercise, in the form of a measured amount of wheel running (56 m/d), prevented the development of obesity consistently observed in nonexercised IUGR offspring. Increased plasma C-peptide and hepatic atypical protein kinase C␨ levels explained increased glucose uptake and increased hepatic glycogen storage in IUGR offspring. Importantly, whereas circulating levels of retinol binding protein 4 were elevated in obese, nonexercised IUGR offspring, indicative of glucose sparing without exercise, retinol binding protein 4 levels were normalized in the exercised IUGR group. These data suggest that IUGR offspring have increased flexibility of energy storage and use and that moderate daily exercise prevents obesity development through activation of distinct pathways of energy use. Thus, despite a predisposition to develop obesity under sedentary conditions, obesity development was prevented in IUGR offspring when exercise was available. These results emphasize the importance of tailored lifestyle changes that activate distinct pathways of metabolic flexibility for obesity prevention. (Endocrinology 150: 179 –186, 2009) O ptimal health requires the body to adapt effectively to cyclic changes in energy supply and energy expenditure through appropriate metabolic adjustments. Metabolic flexibility is the term that describes the ability to coordinate the homeorhetic regulation of energy metabolism during periods of energy replenishment and periods of energy expenditure (1). The capacity to switch substrate use between carbohydrates in times of abundance and lipids in times of scarcity, and the ability to shift substrate sources for energy use, are critical features of effective metabolic flexibility (1). Tissue sensitivity to hormones, in addition to the activity and expression of a host of intracellular pathways, influences preferential substrate use (2). Disharmony of this dynamic system is a critical feature of obesity development and its associated comorbidities, which are now major public health concerns in both developing and developed societies. It is well established that obesity leads to an impairment of lipid oxidation. Obese individuals require a higher fat mass to maintain lipid balance in comparison to lean people with effective energy use (3). The mechanism behind this reduction in lipid oxidation in obesity is unclear. In contrast, regular exercise is known to reduce body fat (4), with the majority of research focused on exercise-induced fatty acid oxidation (5). It is now recognized that exercise may also reduce the availability of lipid precursors and fatty acids for lipogenesis through the down- ISSN Print 0013-7227 ISSN Online 1945-7170 Printed in U.S.A. Copyright © 2009 by The Endocrine Society doi: 10.1210/en.2008-1035 Received July 11, 2008. Accepted August 25, 2008. First Published Online September 4, 2008 Abbreviations: AD, Ad libitum; CPT, carnitine palmitoyltransferase; DEXA, dual-emission x-ray absorptiometry; FAS, fatty acid synthase; GLUT2, glucose transporter 2; IUGR, intrauterine growth restriction; PC, pyruvate carboxylase; PEPCK, phosphoenolpyruvate carboxykinase; PI, phosphatidylinositol; PKC, protein kinase C; PLSD, projected least significant difference; PTP, protein tyrosine phosphatase; RBP4, retinol binding protein 4. Endocrinology, January 2009, 150(1):179 –186 endo.endojournals.org 179 180 Miles et al. Obesity Prevention in IUGR Offspring regulation of hepatic lipogenic enzymes such as fatty acid synthase (FAS) (6, 7). Moreover, it has recently been shown that regular exercise training decreases hepatic FAS activity in obese Zucker rats, thus preventing the elevated de novo lipogenesis usually observed in this strain of rats (8). There is a general perception that lipid oxidation is determined by free fatty acid availability. This notion has been challenged recently, with Wolfe (9) postulating that it is in fact the availability of glucose that dictates the nature of substrate oxidation. This proposal is supported by a number of studies that have found that increased glycogen stores and elevated plasma glucose levels favor glucose oxidation and limit fat oxidation (10 –12). Furthermore, a model proposed by Flatt (11, 12) suggests that a gradual increase in the maintenance range of glycogen storage may be related to the increasing prevalence of obesity. Although it is known that regular exercise progressively reduces glycogen and blood glucose use in favor of lipid use, results of research investigating the effect of exercise on substrate use in obese subjects are at present inconclusive (3). It is now recognized that there are a number of different pathways of obesity development. However, the means by which these pathways can be modified for obesity prevention require further investigation. Recently we described a metabolic pathway to obesity that is mechanistically distinct from that of dietinduced obesity. Such obesity, induced by intrauterine growth restriction (IUGR) through prenatal undernutrition and observed in IUGR rat offspring, is associated with enhanced insulin secretion and action (13), whereas diet-induced obesity is characterized by insulin resistance and an increase in fat deposition at nonphysiological ectopic locations like liver and muscle. In prenatally induced obesity, fat deposition was restricted to physiological fat depots and insulin sensitivity was conserved (13). Body mass index was significantly higher in IUGR offspring, indicative of the higher fat deposition in these rats. Concomitantly, plasma triglyceride levels were increased, but liver triglyceride concentrations were not influenced by prenatal undernutrition. Hepatic FAS mRNA was increased, indicating that increased (...truncated)