Fig. 1.

Schematic diagram showing major factors determining food intake and energy balance in restrictive and modern environments. The availability of nutrients (internal millieu) is detected by a plethora of distributed sensors and controls food intake directly through classical hypothalamic-brainstem pathways and indirectly through modulation of food reward processes in cortico-limbic structures (blue arrows). Low nutrient availability as, for example, signaled by low leptin levels, produces very strong sensitization of cognitive and hedonic mechanisms enabling procurement and ingestion of food as well as generating high reward and satisfaction. This system evolved in order to guarantee adequate nutrient supply in restrictive environments requiring a high physical activity level. The modern environment and lifestyle are characterized by high food availability, abundant food cues, and high food palatability (red arrows), all enhancing food intake either directly or through the same cortico-limbic systems easily sensitized by nutrient depletion signals. In addition, the built environment, sedentary lifestyle, and low procurement costs lead to decreased physical activity and in turn, increased nutrient availability (green arrows). Obesity develops in prone individuals that either efficiently translate exaggerated hedonic, cognitive, and/or emotional pressure exerted by the modern environment and lifestyle into increased eating, or individuals in which energy repletion signals are not able to suppress hedonic eating, or both.