**1. Introduction: The brain and regulation of food intake**

Up until at least 1973, the brain was believed to act much like a thermostat in its regulation of food intake and body weight. Hundreds of studies had shown that damage to the ventromedial

© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

hypothalamus (VMH) resulted in hyperphagia and obesity in a wide variety of species including humans and that lesions of the adjacent lateral hypothalamus (LH) resulted in aphagia and weight loss [1]. Female rats with large VMH lesions frequently doubled their body weight within 30 days [2]. In 1954, Eliot Stellar used these two nuclei as the model example for his dual-center hypothesis for motivated behavior [3]. The LH was the "excitatory center," activation of which caused the organism to eat. Food intake provided some (unknown at that time) manner of glucostatic, lipostatic, and/or thermostatic feedback to the VMH, the "inhibitory center," which then inhibited the LH, resulting in cessation of feeding. The underlying principal was homeostasis, i.e., food intake decreased when body weight exceeded some stable state (set point) and increased when body weight fell below this set point (see [4] for a history of set point theory). The weight changes observed after lesions were generally attributed to a resetting of the set point [5].

So compelling was the evidence, and model, that the leading researchers of human obesity of that era directly compared obese humans to obese rats with VMH lesions [6–8]. Similarities in patterns of food intake, hyperreactivity to the sensory qualities of food (e.g., taste), and unwillingness to work for food were particularly noted. Researchers concluded that obese individuals had "a weak ventromedial hypothalamus" [6, p. 450] and that "the obesity of rats and men has a common physiological locus in the ventromedial hypothalamus" [8, p. 143].

The simplicity of the dual-center model was abandoned in the 1970s when, first, it was found that transection of the ventral noradrenergic bundle at the level of the midbrain resulted in overeating and obesity [9] and, second, when a few years later it was discovered that lesions of the hypothalamic paraventricular nucleus (PVN) also produced hyperphagia and obesity [10, 11]. The next 30 years of research (with lab rats) focused on the role of the PVN and arcuate nuclei [12] and circulating levels of leptin and insulin, hormones that are released in proportion to body fat content [13]. Mice that have mutations in the gene for leptin (ob/ob) become markedly obese [14]. Other brain structures were also found to play a role in the regulation of food intake and body weight, including the posterodorsal amygdala [15, 16]. The model had become more complex, but the underlying principal was still believed to be energy homeostasis [13, 17] and the related concept of set point (or settling point). Human obesity was explained, at least in part, as a malfunction of the system, e.g., resistance to leptin [18].

The studies with rats confined in small cages and fed a single standard lab chow diet have contributed greatly to our understanding of brain mechanisms regulating individual meal parameters [19], but how well do they explain regulation of body weight in free-living humans? The answer is not very well. Similar to lab rats, humans do not overeat when offered a bland diet ad libitum [20], but many researchers have noted that homeostatic controls appear to be absent in environments with an abundance of good-tasting foods [13, 18, 21–26]. In fact, in a long series of studies, de Castro and colleagues determined that only 14% of the variance in the daily food intake of free-living humans could be explained by brain homeostatic mechanisms [27]. As stated by Cameron and Doucet [21], "…when given a barrage of anorexigenic signals, humans still manage to overconsume even at gluttonous levels" (p. 183).

The prevalence of overweight and obese individuals in the United States has nearly tripled since 1980 [23]. One third of adults are overweight (BMI > 25 kg/m2 ), and over one third more are clinically obese (BMI > 30 kg/m2 ) [28]. Researchers have projected that at least 42–44% of Americans will be obese by 2030 [29, 30]. This is a substantial increase since 1960 when only about one in five Americans was overweight [31]. Any explanation for the regulation of body weight in humans must be able to account for this dramatic increase in obesity in just a fewdecade time. It is highly unlikely that the modern obesity pandemic is due to recent pathology in genetics, metabolism, or the brain homeostatic (inhibitory) controls of feeding behavior [22]. Two thirds of the American population could not suddenly have become leptin resistant.

In actuality, the brain is reacting to present-day environmental stimuli exactly in the manner in which it evolved during 2 million years of environmental selective pressures since the appearance of the genus *Homo* [23]. Considerable evidence has accrued that in obesity-prone individuals, it is the reward circuitry of the brain, not the hypothalamic homeostatic nuclei, that developed during human evolution which control feeding behavior when there is an abundance of good-tasting foods [21]. As expected, initial brain fMRI studies found activation of hypothalamic nuclei in response to changes in glucose and insulin levels [32–34]. However, more recent brain fMRI studies also reveal hyperactivation of the cortico-limbic-striatal structures in the reward circuitry of obese children and adults in response to pleasant food stimuli (see Refs. [35–37] for reviews). Genetically obesity-prone children display hyperactivation of the reward circuitry before they become obese [38, 39]. Previously obese adults who have dieted and lost their excess weight continue to show hyperactivity in the reward circuits in response to food [40]. It must be noted that brain fMRI studies of obesity are still in their initial stages, and attempts to identify the specific reward circuitry associated with obesity are inconsistent [37].

One thing is certain: the brain's reward circuitry is not homeostatic, i.e., there is no upper-level body weight set point at which it shuts down [41]. In short, the brain developed as an organ attracted to energy-dense rewards. For many people, the sensory/reward aspects of food simply overwhelm the homeostatic satiety signals [18, 23].
