Novak, Colleen M., Catherine M. Kotz, and James A. Levine. Central orexin sensitivity, physical activity, and obesity in diet-induced obese and diet-resistant rats. Am J Physiol Endocrinol Metab 290: E396-E403, 2006. First published September 27, 2005 doi:10.1152/ajpendo.00293.2005.-Nonexercise activity thermogenesis (NEAT), the most variable component of energy expenditure, can account for differential capacities for human weight gain. Also highly variable, spontaneous physical activity (SPA) may similarly affect weight balance in animals. In the following study, we utilized the rat model of obesity, the diet-induced obese (DIO) rat, as well as the diet-resistant (DR) rat strain, to investigate how access to a high-fat diet alters SPA and the associated energy expenditure (i.e., NEAT). DIO and DR rats showed no differences in the amount of SPA before access to the high-fat diet. After 29 days on a high-fat diet, the DIO rats showed significant decreases in SPA, whereas the DR rats did not. Next, we wanted to determine whether the DIO and DR rats showed differential sensitivity to microinjections of orexin into the paraventricular nucleus of the hypothalamus (PVN). Unilateral guide cannulae were implanted, aimed at the PVN. Orexin A (0, 0.125, 0.25, and 1.0 nmol in 500 nl) was microinjected through the guide cannula into the PVN, then SPA and energy expenditure were measured for 2 h. Using the response to vehicle as a baseline, the DR rats showed significantly greater increase in NEAT compared with the DIO rats. These data indicate that diet-induced obesity is associated with decreases in SPA and a lack of increase in NEAT. A putative mechanism for changes in NEAT that accompany obesity is a decreased sensitivity to the NEAT-activating effects of neuropeptides such as orexin.nonexercise activity thermogenesis; paraventricular nucleus of the hypothalamus; high-fat diet; hypocretin OBESITY IS AN EPIDEMIC associated with the increased prevalence of many diseases, increased mortality, and decreased quality of life (1, 8, 16 -20, 23, 26, 27, 31, 32, 55, 56, 58, 62, 67, 70). One major contributor to the rise in obesity is the sedentary lifestyle of many individuals, leading to decreased energy expenditure and increased body weight, as well as decreased health quality (3,6,11,22, 29, 30, 34, 36,65,77,82). In fact, energy expended through physical activity is the single most variable component of energy expenditure, and in the majority of individuals, daily physical activity is composed primarily of nonexercise activity (47, 48, 52). Nonexercise activity thermogenesis, or NEAT, differs between obese and lean individuals: lean subjects show significantly more ambulation and less sitting compared with obese subjects (50). Moreover, this difference is not altered after weight gain in lean individuals or weight loss in obese individuals, indicating that increased sedentariness is not secondary to the increased body mass in the obese subjects (50). Last, increases in NEAT in nonobese subjects after overfeeding are correlate...