Pathophysiology of obesity is the study of disordered physiological processes that cause, result from, or are otherwise associated with obesity. A number of possible pathophysiological mechanisms have been identified which may contribute in the development and maintenance of obesity. Obesity results from a complex interplay of genetic, hormonal, neural, and environmental factors that dysregulate energy balance.
Research This field of research had been almost unapproached until the leptin gene was discovered in 1994 by J. M. Friedman's laboratory. These investigators postulated that leptin was a satiety factor. In the ob/ob mouse, mutations in the leptin gene resulted in the obese phenotype opening the possibility of leptin therapy for human obesity. However, soon thereafter J. F. Caro's laboratory could not detect any mutations in the leptin gene in humans with obesity. On the contrary, leptin expression was increased, proposing the possibility of leptin-resistance in human obesity. Since this discovery, many other hormonal mechanisms have been elucidated that participate in the regulation of appetite and food intake, storage patterns of adipose tissue, and development of insulin resistance. Since leptin's discovery, ghrelin, insulin, orexin, PYY 3-36, cholecystokinin, adiponectin, GLP-1, as well as many other mediators have been studied. In particular, obesity is associated with impaired L-cell secretion of GLP-1. The adipokines are mediators produced by adipose tissue; their action is thought to modify many obesity-related diseases. Recent research has also implicated western-diet-induced alterations to the duodenal mucosa as an early step in the pathophysiology of obesity, via altered neurohormonal signaling.
Appetite Leptin and ghrelin are considered to be complementary in their influence on appetite, with ghrelin produced by the stomach modulating short-term appetitive control (i.e. to eat when the stomach is empty and to stop when the stomach is stretched). Leptin is produced by adipose tissue to signal fat storage reserves in the body, and mediates long-term appetitive controls (i.e. to eat more when fat storages are low and less when fat storages are high). Although administration of leptin may be effective in a small subset of obese individuals who are leptin-deficient, most obese individuals are thought to be leptin resistant and have been found to have high levels of leptin. This resistance is thought to explain in part why administration of leptin has not been shown to be effective in suppressing appetite in most obese people. While leptin and ghrelin are produced peripherally, they control appetite through their actions on the central nervous system. In particular, they and other appetite-related hormones act on the hypothalamus, a region of the brain central to the regulation of food intake and energy expenditure. There are several circuits within the hypothalamus that contribute to its role in integrating appetite, the melanocortin pathway being the most well understood. The circuit begins with an area of the hypothalamus, the arcuate nucleus, that has outputs to the lateral hypothalamus (LH) and ventromedial hypothalamus (VMH), the brain's feeding and satiety centers, respectively. Recent studies have identified the duodenal mucosa as an important site for nutrient sensing, influencing hormonal and neuronal pathways that regulate appetite and metabolism. The duodenum contains enteroendocrine cells that detect dietary macronutrients and release hormones such as cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and peptide YY (PYY), which signal satiety and help regulate energy intake. In obesity, morphological changes in the duodenal mucosa, including mucosal hyperplasia and increased enteroendocrine cell density, have been observed, potentially leading to altered hormone secretion and impaired nutrient sensing. These alterations in the secretion and action of duodenal hormones, including potential resistance to their effects, may reduce satiety perception, leading to increased food intake. Impaired duodenal vagal afferent signaling may also reduce satiety perception, leading to increased food intake.
Arcuate nucleus The arcuate nucleus contains two distinct groups of neurons. The first group coexpresses neuropeptide Y (NPY) and agouti-related peptide (AgRP) and has stimulatory inputs to the LH and inhibitory inputs to the VMH. The second group coexpresses pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) and has stimulatory inputs to the VMH and inhibitory inputs to the LH. Consequently, NPY/AgRP neurons stimulate feeding and inhibit satiety, while POMC/CART neurons stimulate satiety and inhibit feeding. Both groups of arcuate nucleus neurons are regulated in part by leptin. Leptin inhibits the NPY/AgRP group while stimulating the POMC/CART group. Thus a deficiency in leptin signaling, either via leptin deficiency or leptin resistance, leads to overfeeding and may account for some genetic and acquired forms of obesity. In addition to hypothalamic pathways, gut-brain signaling originating from the duodenum influences feeding behavior. The duodenum communicates with the brain via the vagus nerve, transmitting nutrient-sensing signals that modulate hypothalamic activity. In obesity, resistance to duodenal-derived satiety hormones like CCK and GLP-1 has been linked to disrupted vagal signaling, impairing the brain's ability to regulate food intake effectively. This suggests that obesity-related changes in peripheral nutrient sensing mechanisms contribute to the dysregulation of central appetite control.
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