Appetite control and energy balance regulation in the modern world: reward-driven brain overrides repletion signals

Abstract

Powerful biological mechanisms evolved to defend adequate nutrient supply and optimal levels of body weight/adiposity. Low levels of leptin indicating food deprivation and depleted fat stores have been identified as the strongest signals to induce adaptive biological actions such as increased energy intake and reduced energy expenditure. In concert with other signals from the gut and metabolically active tissues, low leptin levels trigger powerful activation of multiple peripheral and brain systems to restore energy balance. It is not just neurons in the arcuate nucleus, but many other brain systems involved in finding potential food sources, smelling and tasting food, and learning to maximize rewarding effects of foods, that are affected by low leptin. Food restriction and fat depletion thus lead to a 'hungry' brain, preoccupied with food. By contrast, because of less (adaptive thrifty fuel efficiency) or lost (lack of predators) evolutionary pressure, the upper limits of body weight/adiposity are not as strongly defended by high levels of leptin and other signals. The modern environment is characterized by the increased availability of large amounts of energy-dense foods and increased presence of powerful food cues, together with minimal physical procurement costs and a sedentary lifestyle. Much of these environmental influences affect cortico-limbic brain areas concerned with learning and memory, reward, mood and emotion. Common obesity results when individual predisposition to deal with a restrictive environment, as engraved by genetics, epigenetics and/or early life experience, is confronted with an environment of plenty. Therefore, increased adiposity in prone individuals should be seen as a normal physiological response to a changed environment, not in the pathology of the regulatory system. The first line of defense should ideally lie in modifications to the environment and lifestyle. However, as such modifications will be slow and incomplete, it is equally important to gain better insight into how the brain deals with environmental stimuli and to develop behavioral strategies to better cope with them. Clearly, alternative therapeutic strategies such as drugs and bariatric surgery should also be considered to prevent or treat this debilitating disease. It will be crucial to understand the functional crosstalk between neural systems responding to metabolic and environmental stimuli, i.e. crosstalk between hypothalamic and cortico-limbic circuitry.

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.