Cold exposure has been proposed as a potential tool to face obesitysince it is able to increase energy expenditure (i.e., cold induced thermogenesis –CIT). This increase is partially mediated by brown adipose tissue (BAT). Nevertheless, little is known yet about how CIT (specially its non-shivering component) and BATmetabolic activityare regulated, and which are theclinical implicationsof harnessingthem in humans. Furthermore, most physiological functions in our organism are under the control of the biological clock, which shows a tight link with disease in humans. However, to date it remains unknown whether CIT and BAT activity follow a diurnal/circadian rhythmicity, and whether they are related to the general functioning of the circadian system. Furthermore, whether exercise and physical activity are efficient strategies to recruit and activate BATstill needto be explored.Therefore, theoverall aim of the present Doctoral Thesis wasto studythe role of cold and the biological clock on energy balance in humans as well ason BAT; and toinvestigate whether exercise and physical activity could be potential strategiesto recruit and activate BATin humans. Mild cold elicits a modest increase in CIT and prompts a fat oxidative metabolism, especially during the initial moments of cold exposure (Study I).In addition,subjectsexposed to the coldest ambient temperature during their daily life have 3-5 times more BAT volume and activity-measured as 18F-fluordeoxygelucose (18F-FDG) uptake -compared to subjects who are exposed to a warmer ambient temperature (Study II). CIT and BAT 18F-FDG uptake do not seem to have diurnal variations (Study III), and the relationship between the daily rhythm of distal skin temperature-an overall indicator of the circadian system functioning-and BAT 18F-FDG uptake, is masked by the environmental temperature (Study II). In addition, sleepduration and qualityare not related to human BAT metabolic activity (Study IV). Anacutebout ofaerobic exercise does not induce significant changes in the protein concentrations of UCP-1 (and therefore BAT activity) in mice (Study V). Accordingly, physicalactivity levels and sedentary time are not related to BAT 18F-FDG uptake in young human adults (Study VI), neither to the regulation of browning markers, suggesting a negligible role for exercise and physical activity as potential strategies to recruit and activate human BAT. The results from the present Doctoral Thesisincrease our knowledge on the effects of cold on energyand BATmetabolism in humans, and on how the biological clock and related factors might affect them. In addition, it provides novel information on the search of potential strategies to improve BATfunction and browning of specific adipose depots.