**2. The environment and obesity**

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

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

), and over one third more

since 1980 [23]. One third of adults are overweight (BMI > 25 kg/m2

attributed to a resetting of the set point [5].

58 Adiposity - Epidemiology and Treatment Modalities

Until about 8000 BC, all humans lived in small nomadic, hunter-gatherer tribes [42, 43]. King [23] has reviewed the anthropological research showing that for the previous 2 million years, there were certainly periods (short and/or prolonged) of food shortages. It would have been advantageous to store energy as fat to survive periods of deprivation and have energy to hunt and thus, when food was plentiful, to consume more calories than was required just to satisfy short-term inter-meal deficits in energy [21, 25, 44]. In a restricted environment, this would have resulted, at most, in a moderately overweight phenotype.

In short, the modern societal practice of "three meals plus snacks every day is abnormal from an evolutionary perspective" [45, p. 16,647]. Interestingly, recent research has shown that intermittent fasting not only reduces body weight [45–48] but improves clinical health indicators [45, 47, 48] and may reduce processes leading to diseases such as diabetes, heart disease, and certain cancers [45, 47].

What has changed is not the brain, but the environment [23, 26]. The anthropological record reveals that the switch from hunting-gathering to farming as the primary source of food (with a greater reliance on carbohydrates than lean meat) began 10,000 years ago [49, 50]. The use of salt (and probably herbs and spices) to flavor foods dates back to at least the Bronze Age [51], but sugar was not widely available until the 1500s [52]. However, it was the industrialization of the food supply (i.e., the processing and distribution of food) in the last half of the twentieth century that has had the most dramatic impact on how today's humans eat [26, 53, 54].

The availability of high-calorie foods (e.g., carbohydrates and fats) has markedly increased in the United States since the 1970s [55]. One of the most obvious changes that began in the 1970s, at about the same time as the prevalence of obesity began to rapidly increase, was the proliferation of fast-food restaurants. McDonald's opened in 1955, had 1000 restaurants in 1968, and today has over 36,000 restaurants in over 100 countries. Burger King opened in 1954, had 275 restaurants in 1967, and today has 13,000 restaurants in 79 countries. Wendy's opened in 1969 and today has over 6850 restaurants. Similarly, today, Kentucky Fried Chicken has over 19,400 restaurants, Pizza Hut over 11,000, Taco Bell over 6500, Arby's over 3300, Chick-fil-A over 1950, and Church's Chicken nearly 1700 restaurants. Most of them have drive-up windows. Altogether, sales at the US fast-food restaurants increased from \$16.2 billion in 1975 to about \$110 billion by 2004 [56] with a corresponding increase in American's proportional consumption of calories in the form sweetened drinks and such foods as cheeseburgers and pizza [57, 58]. Add to fast-food restaurants an increase in cafeteria and full-menu restaurants, convenience stores, and dispensing machines, and the end result is an obesogenic environment: a high density of high-calorie food sources that require little energy expenditure for consumers to access.

Numerous studies have found a positive association between the geographical density of fastfood restaurants and prevalence of obesity [59–64] or obesity and the frequency with which individuals eat at restaurants [65–70; see also 71]. Compared to normal-weight persons, overweight and obese individuals consume larger meals when eating away from home [72]. Many studies have also found that when groups of people move from areas of the world where the prevalence of obesity is low to an obesogenic environment (e.g., the United States), they gain weight and eventually display the same prevalence of obesity as is found among those who were born in the obesogenic environment [73; see 24 for a review]. Freshman students often gain excess weight during the first few weeks of attending college [74]. One third of American adults may not (yet) be overweight, but many of them live in areas (e.g., very rural) that are not obesogenic.

As with any genetic trait (e.g., height), there is diversity, and some people are more obesity prone than others [18, 75–77]. Obese individuals are less responsive to homeostatic satiety mechanisms [76–78] and are much more responsive to external feeding stimuli than are normal-weight people [7, 24, 27, 77, 79]. The latter includes not only the taste and texture of food but also social cues (e.g., number of others eating, the sight of and variety of foods, portion size, time of day). Compared to others, obese individuals have a strong tendency to discount delayed food rewards in favor of immediate rewards [80–83].

Studies with twins reveal that appetite (responsiveness to food cues) and satiety responsiveness are highly heritable behavioral characteristics [27, 76, 77, 79], as is cognitive restraint, which is generally less for obese individuals [27, 84, 85]. These heritable behavioral characteristics emerge early in life [76], and while they do not cause obesity directly, they result in individuals being more susceptible to overeating in an obesogenic environment [18, 77, 86]. Not everyone has these heritable traits, but based on the obesity statistics, a large majority of humans do have them. At present, at least 32 genetic loci associated with BMI have been identified [87].

In summary, obesity is the result of interaction between genetic risks and the environment. The brain reward circuitry that evolved during 2 million years of our hunter-gatherer ancestry has resulted in many humans being more responsive to environmental food stimuli than they are to caloric/homeostatic stimuli [7, 21, 23, 24, 27, 75–77]. In the words of one group of researchers, humans have "fat brains [and] greedy genes" [79].
