Physiology of Obesity
INTRODUCTION
Obesity is a chronic disease that is increasing in prevalence since 1980 in the United States and other arts of Western World. It poses a serious risk for the development of diabetes mellitus along with insulin resistance, cardiovasculardisease, non-alcoholic fatty liver disease, endocrine problems and certain forms of cancer, modestly increasing the risk of overall mortality. Obesity varies by age and sex,and by race-ethnic group. In 2003-2004, 32.9% of adults 20-74 years old were obese and more than 17% of teenagers (age, 12-19 years) of North America were overweight.
The most widely used formula for relating the height and weight of an individual is body mass index (BMI). BMI is defined as a ratio of weight (kilograms) and height2 (square meters). A BMI between 20-25 kg/m2 is normal and associated with lowest mortality, whereas a BMI of 25-30
kg/m2 is considered overweight. In adults a BMI above 30-40 kg/m2 is defined as obesity and BMI above 40 kg/m2 is severe obesity. Among the children and adolescent population with a BMI above the 95th percentile for age belong to the obese group. However, BMI does not discriminate between muscle and adipose tissue and does not directly assess regional adiposity. Still, BMI rimarily due to its simplicity often serves a guide in treatment selection.
Obesity could be viewed as a consequence of the interaction of environmental factors and the individual genetic predisposition. A child of two obese parents has about 80% chance of becoming obese, whereas the risk is only 15% for the offspring of two parents of normal weight. In addition,
obesity is strongly conditioned by available food and sedentary life style. Treatment of obesity should be undertaken with a clear understanding of the realities of the problem and its outcome. Both, obesity and high visceral fat increase health risks even when total body weight and fat are not significantly elevated. Weight regain is common in obesity upon discontinuation of any treatment. Failure of diet and exercise in the long-term treatment of obesity is quite frequent and creates an obvious need for pharmacotherapy. The regulation of energy uptake and expenditure are controlled by complex systems, thus an improved understanding of pathophysiology is a prerequisite for selection of treatment option of obesity.
ENERGY BALANCE IN THE BODY
Fat accounts for 21-37 % of the body weight of middleaged men and women. In case of obese individual more calories are consumed than expended and appetite does not subsequently reduced to compensate for the increase in energy stores. The amount of the adipose tissue is tightly regulated through neural and humoral signals transmitted to the brain. Failure of fat cells to send adequate signals or failure of the brain to respond to appropriate signals causes obesity [9]. An effective system for the regulation of energy balance require sensors of energy stores in adipose tissue, mechanisms of relay of information to central control sites (hypothalamus) for subsequent integration, which in turn will determine food intake and energy expenditure.
Leptin is a peptide hormone that provides signals to the brain about the amount of fat stores and is secreted mainly by the adipose tissue. Leptin is found in the blood of normal mice but not of genetically obese ob/ob mice. If recombinant leptin is injected into the third or the lateral ventricle of the ob/ob mouse, it reduces food intake and weight gain, acting on neural networks of the brain involved in the control of food intake and energy expenditure. In addition, leptin increases the level of activity in the recipient mice, normalizes body temperature and restores reproductive function. Leptin mRNA is expressed exclusively in fat cells. The concentration of leptin in the circulation is proportional to fat stores and BMI in normal subjects, and its secretion is pulsatile and inversely related to hydrocortisone levels. The generation of leptin is enhanced by glucocorticoids, estrogens and insulin and is reduced by adrenergic agonists. From fat storage sites leptin reaches the brain and enters by saturable transport to hypothalamus.
In contrast to leptin, leptin receptor is found in several forms. The leptin receptor, OB-R, is the product of the db gene and it belongs to the class I cytokine receptor family. At least six OB-R splice variants have been identified. The most abundant one has the longest cytoplasmic tail, and it interacts with the Jak/Stat (Janus Kinase – Signal Transducer and Activator of Transcription) signaling pathway. The long form leptin receptor belongs to the cytokine receptor superfamily. This pathway is essential for the regulation of energy homeostasis by leptin but not for the leptin-dependent control of reproductive function and glucose homeostasis. Activation of PI3-K/Akt pathway as well as the downstream mTOR pathway is also involved in the control of appetite and weight loss by leptin.
Mutations in leptin and in leptin receptor have been described at least in some obese patients. Since large populations of obese individuals have normal leptin and OB-R genes, likely obesity has multiple causes, including environmental factors and association of alleles of various genes
implicated in the regulation of energy metabolism.
Among other targets, in the brain, leptin acts on neurons within arcuate nucleus of hypothalamus and signals them to reduce neuropeptide Y (NPY) production. Food deprivation enhances production of NPY by the hypothalamus. NPY stimulates food intake and decreases sympathetic outflow, and through these ways lowers energy expenditure. It also promotes storage and synthesis of fat by an action on lipoprotein lipase in adipose tissue. Although NPY is an important component of the response, its absence can be compensated by other mechanisms. The appetite-inducing hormone ‘ghrelin’ is derived from its prohormone proghrelin by posttranslational processing. The presence of another peptide hormone called ‘obestatin’ was initially predicted on basis of the bioinformatics data
and later isolated from rat stomach. Ghrelin is a ligand for growth hormone secretagogue receptor and it is synthesized in stomach. Interestingly, both ghrelin and obestatin are biosynthesized from the same precursor protein but possess opposing biological properties. For instance injections of ghrelin stimulate feeding in mice, whereas injections of obestatin inhibit it. Similarly, ghrelin increases gastric emptying but obestatin slows it down. Ghrelin regulates the pituitary hormone axis, metabolism of carbohydrates and different functions of the kidney, heart, adipose tissue, pancreas,
and gonads as well. Chronic ghrelin administration increases food intake in addition to decrease in energy expenditure. These effects lead to weight gain and possible development of obesity. In contrast obestatin seems to work as anorexic hormone and thus prevent weight gain. Ghrelin and obestatin differ in their effects on growth hormone, obestatin does not seem to have any effect on growth hormone axis. This fact undermines the importance of their posttranslational modification.
The most widely used formula for relating the height and weight of an individual is body mass index (BMI). BMI is defined as a ratio of weight (kilograms) and height2 (square meters). A BMI between 20-25 kg/m2 is normal and associated with lowest mortality, whereas a BMI of 25-30
kg/m2 is considered overweight. In adults a BMI above 30-40 kg/m2 is defined as obesity and BMI above 40 kg/m2 is severe obesity. Among the children and adolescent population with a BMI above the 95th percentile for age belong to the obese group. However, BMI does not discriminate between muscle and adipose tissue and does not directly assess regional adiposity. Still, BMI rimarily due to its simplicity often serves a guide in treatment selection.
Obesity could be viewed as a consequence of the interaction of environmental factors and the individual genetic predisposition. A child of two obese parents has about 80% chance of becoming obese, whereas the risk is only 15% for the offspring of two parents of normal weight. In addition,
obesity is strongly conditioned by available food and sedentary life style. Treatment of obesity should be undertaken with a clear understanding of the realities of the problem and its outcome. Both, obesity and high visceral fat increase health risks even when total body weight and fat are not significantly elevated. Weight regain is common in obesity upon discontinuation of any treatment. Failure of diet and exercise in the long-term treatment of obesity is quite frequent and creates an obvious need for pharmacotherapy. The regulation of energy uptake and expenditure are controlled by complex systems, thus an improved understanding of pathophysiology is a prerequisite for selection of treatment option of obesity.
ENERGY BALANCE IN THE BODY
Leptin is a peptide hormone that provides signals to the brain about the amount of fat stores and is secreted mainly by the adipose tissue. Leptin is found in the blood of normal mice but not of genetically obese ob/ob mice. If recombinant leptin is injected into the third or the lateral ventricle of the ob/ob mouse, it reduces food intake and weight gain, acting on neural networks of the brain involved in the control of food intake and energy expenditure. In addition, leptin increases the level of activity in the recipient mice, normalizes body temperature and restores reproductive function. Leptin mRNA is expressed exclusively in fat cells. The concentration of leptin in the circulation is proportional to fat stores and BMI in normal subjects, and its secretion is pulsatile and inversely related to hydrocortisone levels. The generation of leptin is enhanced by glucocorticoids, estrogens and insulin and is reduced by adrenergic agonists. From fat storage sites leptin reaches the brain and enters by saturable transport to hypothalamus.
In contrast to leptin, leptin receptor is found in several forms. The leptin receptor, OB-R, is the product of the db gene and it belongs to the class I cytokine receptor family. At least six OB-R splice variants have been identified. The most abundant one has the longest cytoplasmic tail, and it interacts with the Jak/Stat (Janus Kinase – Signal Transducer and Activator of Transcription) signaling pathway. The long form leptin receptor belongs to the cytokine receptor superfamily. This pathway is essential for the regulation of energy homeostasis by leptin but not for the leptin-dependent control of reproductive function and glucose homeostasis. Activation of PI3-K/Akt pathway as well as the downstream mTOR pathway is also involved in the control of appetite and weight loss by leptin.
Mutations in leptin and in leptin receptor have been described at least in some obese patients. Since large populations of obese individuals have normal leptin and OB-R genes, likely obesity has multiple causes, including environmental factors and association of alleles of various genes
implicated in the regulation of energy metabolism.
and later isolated from rat stomach. Ghrelin is a ligand for growth hormone secretagogue receptor and it is synthesized in stomach. Interestingly, both ghrelin and obestatin are biosynthesized from the same precursor protein but possess opposing biological properties. For instance injections of ghrelin stimulate feeding in mice, whereas injections of obestatin inhibit it. Similarly, ghrelin increases gastric emptying but obestatin slows it down. Ghrelin regulates the pituitary hormone axis, metabolism of carbohydrates and different functions of the kidney, heart, adipose tissue, pancreas,
and gonads as well. Chronic ghrelin administration increases food intake in addition to decrease in energy expenditure. These effects lead to weight gain and possible development of obesity. In contrast obestatin seems to work as anorexic hormone and thus prevent weight gain. Ghrelin and obestatin differ in their effects on growth hormone, obestatin does not seem to have any effect on growth hormone axis. This fact undermines the importance of their posttranslational modification.
