**9. Hyperphagia: etiopathogenesis and treatment**

In the modern environment of plenty, obesity is favored by biological features that generally are advantageous in a restrictive environment, such as attraction to palatable and energy dense foods, slow satiety mechanisms and high metabolic efficiency [198].

The control of food intake and energy expenditure consists of a complex network of neural and hormonal systems that involving many genes [199]: in particular, the informations are collected at the peripheral level (intestine, stomach, adipose tissue); then, they are processed at the hypothalamic level and, finally, generate behavioral, endocrine and autonomic output [198].

In particular, much larger portions of the nervous system of animals and humans, including cortex, basal ganglia, and the limbic system, are concerned with the procurement of food as a basic and evolutionarily conserved survival mechanism to defend body weight [200]. These systems are directly and primarily involved in the interactions of the modern environment and lifestyle with the human body [198]. By focusing on the neural reward systems and the interaction between reward and homeostatic functions, it is possible to infer that the disturb‐ ance of this relationship determines obesity (**Figure 6**).

medical indications and treatment and appropriate treatment of psychological problems [190]. Also it is recommended that bariatric surgery be done only in centers that can provide a multidisciplinary pre‐ and post‐operative evaluation and psychological support both before

Currently, data on bariatric surgery in children and adolescents with genetic obesity are limited and still controversial [183]. To date, bariatric surgery experience in treating children and adolescents with monogenic and syndromic forms of obesity is limited, and different bariatric procedures have been used with varying success [194]. Some studies have demonstrated the efficacy of bariatric surgery (in terms of weight loss and reduction of comorbidities such as obstructive sleep apnea, dyslipidemia, hypertension, diabetes mellitus and poor mobility) in patients with monogenic obesity (such as LEPR‐deficient patients and patients with hetero‐ zygous *MC4R* mutations, but not in patients with homozygous *MC4R* mutation [195]) and syndromic obesity (such as PWS, BBS, Alström syndrome) but, due to the limited number of cases, the long‐term efficacy and safety of bariatric surgery in genetic forms of obesity need

Even more in the early days are studies that try to correlate specific polymorphisms with response to bariatric surgery: For example, a study tried to find the presence of an association between several polymorphisms (including the *FTO* and *MC4R* genes) with post‐operative weight loss [196]; another study found that a 15q26.1 locus is significantly associated with weight loss after Roux‐en‐Y gastric bypass surgery [197]. Thus, there is some evidence for the use of genomics to identify response to surgical procedures; the identification of genetic contributors could be useful to select those individuals who will obtain a greater benefit from

In the modern environment of plenty, obesity is favored by biological features that generally are advantageous in a restrictive environment, such as attraction to palatable and energy dense

The control of food intake and energy expenditure consists of a complex network of neural and hormonal systems that involving many genes [199]: in particular, the informations are collected at the peripheral level (intestine, stomach, adipose tissue); then, they are processed at the hypothalamic level and, finally, generate behavioral, endocrine and autonomic output

In particular, much larger portions of the nervous system of animals and humans, including cortex, basal ganglia, and the limbic system, are concerned with the procurement of food as a basic and evolutionarily conserved survival mechanism to defend body weight [200]. These systems are directly and primarily involved in the interactions of the modern environment and lifestyle with the human body [198]. By focusing on the neural reward systems and the interaction between reward and homeostatic functions, it is possible to infer that the disturb‐

a bariatric surgery. However, these results have yet to be confirmed.

foods, slow satiety mechanisms and high metabolic efficiency [198].

**9. Hyperphagia: etiopathogenesis and treatment**

ance of this relationship determines obesity (**Figure 6**).

and after the surgery [193].

242 Adiposity - Omics and Molecular Understanding

further evaluation [183].

[198].

**Figure 6.** Relationship between metabolic and hedonic controls of food intake and energy balance. Adapted with per‐ mission from Berthoud et al. [198].

This process can generate hedonic and metabolic consequences, which are independent from each other: in particular, the hedonic consequences are regulated by reward functions while the metabolic consequences of food (defined in terms of their input of energy and their effects on body composition, particularly increased fat accretion as in obesity) are regulated by homeostatic functions.

The alteration of reward functions may be a cause (i.e., excessive caloric intake modulated by hedonic value of food (1)) and/or a consequence (induced by obese state (3)) of obesity [198].

As schematically depicted in **Figure 6**, several potential interactions exist between food reward and obesity.

In particular, there are three fundamental mechanisms involved in the development of obesity, which are not mutually exclusive, but a combination of all three is operative in most individ‐ uals: excessive intake of palatable and energy dense foods, differences (genetic and other pre‐ existent) in reward functions and increase of obese state consequently to alterations of reward functions induced by obesity [198].

It is also important to realize that hyperphagia is not always necessary for obesity to develop, as the macronutrient composition of food can independently favor fat deposition.

In this regard, there is the "*gluttony hypothesis*" emerged from several studies in animals: in particular, although reward functions are not altered unlimited access to palatable food and food cues leads to excessive caloric intake (hedonic overeating) and, consequently, to obesity (defined as diet‐induce obesity) [198].

However, it is important to underline that not all individuals exposed to environment of plenty show an increased food intake and weight gain; this means that there are genetic and epigenetic pre‐existing alterations that make some individuals more vulnerable to the increased availa‐ bility of palatable food and food cues [198].

One of the key questions is how the motivation to get a reward will translate into action. In most cases, the motivation for something comes from the pleasure that this has generated in the past, or in other words, to obtain what has been helpful. The dopamine signal seems to be a critical component in this process [198].

The limited information available suggests that repeated sucrose access can upregulate dopamine release [201] and dopamine transporter [202] and change dopamine D1 and D2 receptor availability [201] in the nucleus accumbens.

As demonstrated by some observations, such pleasing foods have a high potential for addiction for which the withdrawal from it can cause symptoms such as anxiety, stress, depression resulting behavior of relapse because of occurring neural and molecular changes. Therefore, it is critical for switching the cycle of addiction and the prevention of a further spiral of addiction [198].

An issue on which to focus is that excessive caloric intake, as part of a disease, can gradually worsen: in fact at the beginning, there is overeating; then, the individual eats also in the absence of physiological hunger. Subsequently, there will be loss of control over eating (binge eating), and finally, hyperphagia defined as a hallmark of inherited disorders, in which obesity is present [203].

The term "hyperphagia" includes a series of conditions, such as binge eating disorder, hormonal imbalances such as glucocorticoid excess, leptin signaling abnormalities, syndromes associated with obesity and cognitive impairment (e.g., PWS) [203] and can be used in different situations: for example, to evaluate hunger and satiety through appropriate scales for patho‐ logical individuals compared to healthy individuals [203], to evaluate excessive caloric intake and the impact on body size and body composition in pathological individuals [203] or to evaluate preoccupation and psychological symptoms such as anxiety, stress due to hyperpha‐ gic behavior and the consequences that it determines (e.g., continuous search for food, night eating, ingestion of inedible food, theft of food, etc.) [203].

A person with hyperphagia has an obsessive and compulsive behavior towards food and often continues to eat for a long time, even if he/she feels full. This excessive nutriment can cause abdominal pain, guilt or drowsiness.

In particular, obesity is associated with dysregulated signaling systems, such as leptin and insulin resistance, as well as increased signaling through proinflammatory cytokines and pathways activated by oxidative and endoplasmatic reticulum stress [204] (**Figure 7**).

As schematically depicted in **Figure 7**, obesity and, in turn, neurodegenerative diseases may be caused by leptin resistance, central insulin and altered regulation of energy balance, con‐ New Thoughts on Pediatric Genetic Obesity: Pathogenesis, Clinical Characteristics and Treatment Approach http://dx.doi.org/10.5772/66128 245

food cues leads to excessive caloric intake (hedonic overeating) and, consequently, to obesity

However, it is important to underline that not all individuals exposed to environment of plenty show an increased food intake and weight gain; this means that there are genetic and epigenetic pre‐existing alterations that make some individuals more vulnerable to the increased availa‐

One of the key questions is how the motivation to get a reward will translate into action. In most cases, the motivation for something comes from the pleasure that this has generated in the past, or in other words, to obtain what has been helpful. The dopamine signal seems to be

The limited information available suggests that repeated sucrose access can upregulate dopamine release [201] and dopamine transporter [202] and change dopamine D1 and D2

As demonstrated by some observations, such pleasing foods have a high potential for addiction for which the withdrawal from it can cause symptoms such as anxiety, stress, depression resulting behavior of relapse because of occurring neural and molecular changes. Therefore, it is critical for switching the cycle of addiction and the prevention of a further spiral of

An issue on which to focus is that excessive caloric intake, as part of a disease, can gradually worsen: in fact at the beginning, there is overeating; then, the individual eats also in the absence of physiological hunger. Subsequently, there will be loss of control over eating (binge eating), and finally, hyperphagia defined as a hallmark of inherited disorders, in which obesity is

The term "hyperphagia" includes a series of conditions, such as binge eating disorder, hormonal imbalances such as glucocorticoid excess, leptin signaling abnormalities, syndromes associated with obesity and cognitive impairment (e.g., PWS) [203] and can be used in different situations: for example, to evaluate hunger and satiety through appropriate scales for patho‐ logical individuals compared to healthy individuals [203], to evaluate excessive caloric intake and the impact on body size and body composition in pathological individuals [203] or to evaluate preoccupation and psychological symptoms such as anxiety, stress due to hyperpha‐ gic behavior and the consequences that it determines (e.g., continuous search for food, night

A person with hyperphagia has an obsessive and compulsive behavior towards food and often continues to eat for a long time, even if he/she feels full. This excessive nutriment can cause

In particular, obesity is associated with dysregulated signaling systems, such as leptin and insulin resistance, as well as increased signaling through proinflammatory cytokines and

As schematically depicted in **Figure 7**, obesity and, in turn, neurodegenerative diseases may be caused by leptin resistance, central insulin and altered regulation of energy balance, con‐

pathways activated by oxidative and endoplasmatic reticulum stress [204] (**Figure 7**).

(defined as diet‐induce obesity) [198].

244 Adiposity - Omics and Molecular Understanding

bility of palatable food and food cues [198].

a critical component in this process [198].

addiction [198].

present [203].

receptor availability [201] in the nucleus accumbens.

eating, ingestion of inedible food, theft of food, etc.) [203].

abdominal pain, guilt or drowsiness.

**Figure 7.** Secondary effects of obesity on reward circuitry and hypothalamic energy balance regulation. Adapted with‐ permission from Berthoud et al. [198].

trolled by hypothalamus. About the latter, the literature shows that mitochondrial and oxida‐ tive stress increase due to high‐fat diets leading to neural/glial dysfunction and, consequently, cytotoxic effects [198].

However, these toxic effects do not stop at the level of the hypothalamus but can also affect brain areas involved in reward processing [198].
