Pathophysiology

4. Pathophysiology of Obesity

Energy Balance: Intake Versus Expenditure

The control of body weight requires the accurate matching of caloric intake to caloric expenditure over time. Despite dramatic fluctuations in caloric intake, normal animals are able to maintain a very stable body weight. Long-term regulation of energy balance is dependent on the coordination and interpretation of peripheral signals indicating the level of energy stores. The best known signals are leptin and insulin. Short-term regulation depends on meal-related signals such as cholecystokinin (CCK) or gastrin related peptide (GRP) (Strader & Woods, 2005). Therefore, the central nervous system receives uninterrupted information about body energy stores through metabolic, neural and endocrine factors. Some are from central origin; some originate from the gastrointestinal tract or adipose cells. However, the elementary distinction between central and peripheral mechanisms tends to give way to a more integrated concept. In fact, each peripheral factor acts independently from central control and central factors modulate the secretion of peripheral factors by adjusting the response to ingested nutrients and modifying appetite behavior.

Weight Gain and Appetite Control

A wide range of central neuroendocrine factors have been linked to the control of energy balance. At a mechanistic level, identification of those factors that control appetite remains a challenge and is an important physiological basis to develop new pharmacological treatment strategies. Among new strategies developed against obesity, appetite manipulation is one of the most attractive. The aim is to block endogenous signals that stimulate appetite.

Appetite is composed of three phases: hunger, satiation and satiety.

Hunger is defined as a biological drive impelling the ingestion of food.

"Satiation" and satiety are defined by some investigators as intra- and intermeal satiety, respectively:

- Satiation refers to processes that promote meal termination. A sensation of fullness develops, thus limiting meal size;

- Satiety refers to postprandial events that affect the interval to the next meal, so regulating meal frequency, which is also influenced by learned habits (Cummings & Overduin, 2007). Satiety is considered a motivation not to eat between episodes of eating. The state of satiety delays the onset of a meal and may reduce the amount of food consumed in a forthcoming meal.

Hunger has cognitive and environmental components, such that the feeling of hunger could develop despite physiological satiety. In this circumstance, there is disruption of the relationship between appetite and food intake and abnormal appetite control is common in obese subjects. Among factors leading a cat to eat in the absence of hunger, there is boredom, availability of palatable food, or emotional stress (Mattes et al., 2005).

Many pharmacologic approaches have been considered to control hunger and to modify the secretion of peptides implicated in its regulation (Table 3).

One of the most recently identified signals of food intake is the gut peptide ghrelin (Cummings et al., 2006). Ghrelin is the unique enteric peptide known to increase food intake. There is a net rise of plasma ghrelin concentration after a period of fasting and it declines in the post-prandial period. In addition, it appears that ghrelin is not only a short-term signal of hunger since, in obesity, its concentration was increased by 24% in a group of subjects who had lost weight (Cummings et al., 2002). Thus, the increased concentration of ghrelin, an orexigenic signal, counteracts the effect of the regimen and tends to promote the regain of lost weight after a period of energy restriction. Future research should focus on dietary interventions that could reduce ghrelin concentration and food intake.

CCK controls satiety. It is released in response to the ingestion of fat and protein in the diet, although its appetite suppression effect is strongly increased by stomach distension (Kissileff et al., 2003). Central administration of CCK reduces meal size in animals including humans. However, despite promising results showing that CCK acts to limit energy intake, it appears that long-term chronic administration has no effect on body weight loss. Therefore, the best method to control CCK release seems to be modifying the composition of the diet via protein levels. In cats, it has been demonstrated that dietary protein and amino acids raise plasma CCK concentration (Backus et al., 1997). Among amino acids, tryptophan, phenylalanine, leucine and isoleucine were found to be the most effective.

Administration of amylin, bombesin and related-peptides (GRP, neuromedin B, glucagon-like peptide [GLP]-1, glucagon and related peptides (glicentin, GLP-2, oxyntomodulin), peptide tyrosine-tyrosine (PYY) and related peptides (pancreatic polypeptide, neuropeptide Y), gastric leptin and apolipoprotein AIV reduces food intake. Leptin is an orexigenic factor that leads to glucose intolerance, insulin resistance and hyperinsulinemia; further, chronic hyperleptinemia induces obesity (Kopelman, 2000). With the exception of the pancreatic hormones and leptin, all such peptides are synthesized in the brain. This underlines the complexity of the system and shows how difficult it is to understand all the mechanisms implicated in food intake. Therefore, the use of pharmacologic therapies should be extremely cautious and may have strong side effects due to the high complexity of the regulation on a long-term basis.

Neutering and Obesity

How neutering leads to weight gain has been the subject of some debate. The main factor seems to be an alteration in feeding behavior leading to increased food intake (Flynn et al., 1996; Fettman et al., 1997; Harper et al., 2001; Hoenig & Ferguson, 2002; Kanchuk et al., 2003; see also Figure 6), and decreased activity (Flynn et al., 1996; Harper et al., 2001).

Figure 6. Effect of neutering on food intake. (From Calvert, 2003).  

The metabolic consequences observed after neutering are likely to be secondary to the specific hormonal changes that occur after this procedure. Studies in other species have shown that estrogens can suppress appetite (Czaja & Goy, 1975). Thus, removal of the metabolic effects of estrogens and androgens by gonadectomy may lead to increased food consumption. However, the exact mechanism by which this occurs is not known and, in this respect, a recent study has refuted the hypothesis that gonadal hormones may interact with CCK, the gastrointestinal hormone that can influence appetite (Backus et al., 2005; Asarian & Geary, 2006). Ghrelin is probably implicated in this mechanism.

In studies conducted by one of the authors, plasma concentrations of various hormones were monitored in seven male and six female cats, before and after neutering (Martin et al., 2004; 2006a). All cats were neutered after they had reached sexual maturity, at 11 months of age. By modifying endocrine homeostasis, neutering induces a new state of equilibrium in which the hormones involved in obesity and the dysregulation of glucose metabolism predominate. The earliest hormonal change was a rapid increase in the plasma concentration of IGF-1. This increase was noticeable as soon as the first week after neutering and tended to stabilize over time. Although studies about the regulation of the somatotropic axis in obesity report contradictory results on the secretion of IGF-1, receptors for this molecule have nevertheless been identified in pre-adipocyte and adipocyte cells lines (Louveau & Gondret, 2004). Thus, the increase in IGF-1 secretion following neutering may have a primary role in the onset of obesity in the cat, since it promotes the multiplication and even the growth of adipocytes.

Increase in prolactin concentration varied between the males and females (p <0.0001) (Martin & Siliart, 2005).

• Female cats (with the exception of one cat) demonstrated hyperprolactinemia prior to neutering, that was probably linked to their sexual activity at the time of neutering (heat period). Hyperprolactinemia was maintained over time and by 24 weeks post-neutering, the mean concentration was about 60 ng/mL.
• In male cats, results were markedly different. Prior to castration, the mean plasma concentration was below 20 ng/mL; after 12 weeks it reached about 30 ng/mL.

Two years after castration, the mean prolactin concentration was about 70 ng/mL for both gender. We conclude that neutering induces a persistent hyperprolactinemia, regardless of gender and initial concentrations.

Prolactin has a role in the production and maintenance of adipose tissue (Flint et al., 2003). Additionally, it is possible that an elevated prolactin concentration could also have a deleterious effect on glucose metabolism in the cat in the short or long term.

When energy expenditure is expressed on a lean mass basis, no difference in metabolic rate was noted between entire individuals and individuals that are neutered (Fettman et al., 1997; Martin et al., 2001; Kanchuk et al., 2003; Nguyen et al., 2004). However, neutered cats are more obese than intact ones (Figure 7) and they are reported to have resting metabolic rates 20-33% below those of intact cats (Flynn et al., 1996; Root et al., 1996; Harper et al., 2001; Hoenig & Ferguson, 2002). Coupled with reduced physical activity, this lower metabolic rate highlights the necessity to decrease the caloric intake of neutered cats to limit the increase in body weight.

Figure 7. Effect of neutering on body weight. (From Calvert, 2003).