**4. Non-exercise activity thermogenesis (NEAT) and obesity**

Many previous studies have shown that sedentary lifestyle and daily physical inactivity contribute to obesity [31–35]. A recent systematic review and meta-analysis showed that obesity was associated with higher all-cause mortality than normal weight [36], and physical inactivity is a crucial problem for the prevention and treatment of obesity. Increasing energy expenditure in daily life is essential. NEAT is the main determinant of variability in total daily energy expenditure [37]. It is defined as the energy expenditure due to physical activities besides volitional exercise and includes various activities in daily life such as walking for pleasure, going to work, gardening, doing housework, singing, and dancing [38]. NEAT covers a wide range of intensity that at times reaches to the recommended level for obese individuals [39]. The energy expenditure by sitting and watching television is no more than 9 kcal per hour, but gardening and cleaning reach higher levels of energy expenditure; 100–150 kcal per hour and 500 kcal/day, respectively [40]. Steeves et al. [41] conducted a randomized controlled pilot study to examine the 6-month effects of two interventions; stepping in house during TV commercials vs. walking 30 minutes per day in sedentary and obese individuals. Although no significant difference between groups were observed, daily steps increased, and time of TV viewing, dietary intake, body fat percentage, waist and hip circumference significantly decreased after both interventions. Only stepping during watching TV could be a feasible approach for improving obesity. In the modern world, walking in a break during work is effective for weight loss. Levine and Miller [42] investigated whether the change of work environment affect individuals' energy expenditure at workplace. The vertical workstation that allows obese workers to use a personal computer while walking on a treadmill was established. The mean energy expenditure while walking at workplace was 191 kcal per hour, which was significantly higher than energy expenditure while seated at work (72 kcal per hour). This amount of energy expenditure could be equal to a weight loss of 20–30 kg per year. Furthermore, they assessed the effect of using an office-place stepping device housed under a desk on workers' energy expenditure [43]. The mean increase of energy expenditure in obese office workers was 335 kcal per hour, which could be equal to a weight loss of 20 kg per year. Changing living environments to change sedentary behavior will increase NEAT and decrease body weight. Each NEAT is small; however, "Many a little makes a mickle." To increase NEAT should be effective for improving obesity (**Figure 1**). NEAT is intricately regulated by endocrine, genetic, and sociological factors [39]. Sarcolipin [44] and ventromedial hypothalamic melanocortin receptor [45] have been of current interest as new mediators of NEAT. Sarcolipin, which consists of 31 amino acids and is highly expressed in skeletal muscle, plays a role in energy expenditure. Sopariwala et al. [44] showed that sarcolipin overexpression mice are more resistant to fatigue and more physically active compared with wild type. This newly identified regulator may increase non-shivering thermogenesis in humans [45] and could be effective to increase energy expenditure and control weight gain in obese individuals [46]. The ventromedial hypothalamus also has an important role in regulating energy balance, and the brain melanocortin system not only decreases appetite but increases physical activity [45, 47]. Gavini et al. [48] showed that intra-ventromedial hypothalamus melanocortin receptor activation increased physical activity and induced the elevation of mRNA expression of mediators of energy expenditure such as uncoupling proteins, peroxisome proliferator-activated receptors, peroxisome proliferatoractivated receptor gamma coactivator 1-α, and AMP-activated protein kinase. Modulating melanocortin receptors in the ventromedial hypothalamus may contribute to increase of NEAT. Identifying such novel mechanisms to increase energy expenditure is expected to be applied in the treatment of obesity. Moreover, the significant associations of NEAT with metabolic diseases such as type 2 diabetes, hypertension, and dyslipidemia have been identified [49–53]. NEAT intervention in addition to structured exercise prescription certainly improves obesity and metabolic diseases. To elucidate the effectiveness of NEAT for metabolic diseases, and further CVD, as well as obesity, well-designed longitudinal studies in humans are warranted. On the other hand, how to measure NEAT accurately under freeliving (accelerometry, doubly labeled water method, or a completely new method?) and how to intervene NEAT (recommendation or supervised program?) are still unknown. The development of measurement and intervention method of NEAT will be needed to conduct such clinical studies.

**Figure 1.** Obesity is treated with diet, physical activity, and pharmacologic therapy. Diet appears to be more effective for treating obesity than physical activity; therefore, physical activity intervention should be combined with dietary intervention in the management of obesity. Non-exercise activity thermogenesis (NEAT) beyond structured exercise may play a pivotal role in weight loss in obese individuals.
