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. [1]
This field of research had been almost unapproached until the leptin gene was discovered in 1994 by J. M. Friedman's laboratory. [2] 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. [3] 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, as well as many other mediators have been studied. The adipokines are mediators produced by adipose tissue; their action is thought to modify many obesity-related diseases.
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. [4] 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. [1]
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. [1] 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. [5]
The arcuate nucleus contains two distinct groups of neurons. [1] 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. [1]
Obesity has been associated with an inflammatory state, which is chronic and low-grade inflammation, known as meta-inflammation. [6] [7] Meta-inflammation is subclinical meaning that while there is an increase in circulating pro-inflammatory factors, no clinical signs of inflammation, heat, pain, and redness, are seen with meta-inflammation. [8] Based on the immune system cells involved, both innate and adaptive immunity are involved in meta-inflammation. [8]
There are different types of obesity depending on where fat cells are stored. Abdominal obesity, excess fat cell accumulation in adipose tissue of the abdomen, is associated more strongly with meta-inflammation. [9]
Evolutionarily, adipose tissue has been shown to function as an immune organ. [8] The immune cells located in adipose tissue are important for maintaining metabolic homeostasis. With obesity, the immune cells important for maintaining metabolic homeostasis are suppressed because immune cell function and immune cell amount are affected by excess fat accumulation in adipose tissue. [7] [8] Excess fat accumulation can lead to insulin resistance, and insulin resistance has been linked to meta-inflammation. [8] With insulin resistance, there is an increase in macrophages, mast cells, neutrophils, T lymphocytes, and B lymphocytes, and a decrease in eosinophils and some T lymphocytes. [8]
Obesity has also been shown to induce hypoxic conditions in adipose cells. [6] [9] Hypoxic conditions result from fat cells expanding, and this decreases vascularization to surrounding fat cells. [6] [7] [8] Decreased vascularization results in decreased amounts of oxygen in adipose tissue so adipose cells have to switch to anaerobic metabolism for energy production. [9] Anaerobic metabolism stimulates inflammation caused by macrophages. [9] There are two types of macrophages, classically activated M1 macrophages that increase inflammation and alternatively activated M2 macrophages that decrease inflammation. In animal studies, obesity has been shown to cause a shift from M2 to M1 macrophages in adipose tissue, causing an increase in inflammation. [7] [8] [9]
Pro-opiomelanocortin (POMC) is a precursor polypeptide with 241 amino acid residues. POMC is synthesized in corticotrophs of the anterior pituitary from the 267-amino-acid-long polypeptide precursor pre-pro-opiomelanocortin (pre-POMC), by the removal of a 26-amino-acid-long signal peptide sequence during translation. POMC is part of the central melanocortin system.
Leptin is a protein hormone predominantly made by adipose cells and its primary role is likely to regulate long-term energy balance.
Appetite is the desire to eat food items, usually due to hunger. Appealing foods can stimulate appetite even when hunger is absent, although appetite can be greatly reduced by satiety. Appetite exists in all higher life-forms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. Appetite has a relationship with every individual's behavior. Appetitive behaviour also known as approach behaviour, and consummatory behaviour, are the only processes that involve energy intake, whereas all other behaviours affect the release of energy. When stressed, appetite levels may increase and result in an increase of food intake. Decreased desire to eat is termed anorexia, while polyphagia is increased eating. Dysregulation of appetite contributes to anorexia nervosa, bulimia nervosa, cachexia, overeating, and binge eating disorder.
Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular endothelial cells and a variety of immune cells such as adipose tissue macrophages. Adipose tissue is derived from preadipocytes. Its main role is to store energy in the form of lipids, although it also cushions and insulates the body. Far from being hormonally inert, adipose tissue has, in recent years, been recognized as a major endocrine organ, as it produces hormones such as leptin, estrogen, resistin, and cytokines. In obesity, adipose tissue is also implicated in the chronic release of pro-inflammatory markers known as adipokines, which are responsible for the development of metabolic syndrome, a constellation of diseases, including type 2 diabetes, cardiovascular disease and atherosclerosis. The two types of adipose tissue are white adipose tissue (WAT), which stores energy, and brown adipose tissue (BAT), which generates body heat. The formation of adipose tissue appears to be controlled in part by the adipose gene. Adipose tissue – more specifically brown adipose tissue – was first identified by the Swiss naturalist Conrad Gessner in 1551.
Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. In cell culture, adipocyte progenitors can also form osteoblasts, myocytes and other cell types.
Resistin also known as adipose tissue-specific secretory factor (ADSF) or C/EBP-epsilon-regulated myeloid-specific secreted cysteine-rich protein (XCP1) is a cysteine-rich peptide hormone derived from adipose tissue that in humans is encoded by the RETN gene.
The arcuate nucleus of the hypothalamus is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence. The arcuate nucleus includes several important and diverse populations of neurons that help mediate different neuroendocrine and physiological functions, including neuroendocrine neurons, centrally projecting neurons, and astrocytes. The populations of neurons found in the arcuate nucleus are based on the hormones they secrete or interact with and are responsible for hypothalamic function, such as regulating hormones released from the pituitary gland or secreting their own hormones. Neurons in this region are also responsible for integrating information and providing inputs to other nuclei in the hypothalamus or inputs to areas outside this region of the brain. These neurons, generated from the ventral part of the periventricular epithelium during embryonic development, locate dorsally in the hypothalamus, becoming part of the ventromedial hypothalamic region. The function of the arcuate nucleus relies on its diversity of neurons, but its central role is involved in homeostasis. The arcuate nucleus provides many physiological roles involved in feeding, metabolism, fertility, and cardiovascular regulation.
Ghrelin is a hormone produced by enteroendocrine cells of the gastrointestinal tract, especially the stomach, and is often called a "hunger hormone" because it increases the drive to eat. Blood levels of ghrelin are highest before meals when hungry, returning to lower levels after mealtimes. Ghrelin may help prepare for food intake by increasing gastric motility and stimulating the secretion of gastric acid.
Neuropeptide Y (NPY) is a 36 amino-acid neuropeptide that is involved in various physiological and homeostatic processes in both the central and peripheral nervous systems. It is secreted alongside other neurotransmitters such as GABA and glutamate.
Agouti-related protein (AgRP), also called agouti-related peptide, is a neuropeptide produced in the brain by the AgRP/NPY neuron. It is synthesized in neuropeptide Y (NPY)-containing cell bodies located in the ventromedial part of the arcuate nucleus in the hypothalamus. AgRP is co-expressed with NPY and acts to increase appetite and decrease metabolism and energy expenditure. It is one of the most potent and long-lasting of appetite stimulators. In humans, the agouti-related peptide is encoded by the AGRP gene.
The melanocortins are a family of neuropeptide hormones which are the ligands of the melanocortin receptors The melanocortin system consists of melanocortin receptors, ligands, and accessory proteins. The genes of the melanocortin system are found in chordates. Melanocortins were originally named so because their earliest known function was in melanogenesis. It is now known that the melanocortin system regulates diverse functions throughout the body, including inflammatory response, fibrosis, melanogenesis, steroidogenesis, energy homeostasis, sexual function, and exocrine gland function.
Nesfatin-1 is a neuropeptide produced in the hypothalamus of mammals. It participates in the regulation of hunger and fat storage. Increased nesfatin-1 in the hypothalamus contributes to diminished hunger, a 'sense of fullness', and a potential loss of body fat and weight.
The central melanocortin system is defined anatomically as a collection of central nervous system circuits which include:
Chemerin, also known as retinoic acid receptor responder protein 2 (RARRES2), tazarotene-induced gene 2 protein (TIG2), or RAR-responsive protein TIG2 is a protein that in humans is encoded by the RARRES2 gene.
Hunger is a sensation that motivates the consumption of food. The sensation of hunger typically manifests after only a few hours without eating and is generally considered to be unpleasant. Satiety occurs between 5 and 20 minutes after eating. There are several theories about how the feeling of hunger arises. The desire to eat food, or appetite, is another sensation experienced with regards to eating.
Sleep is important in regulating metabolism. Mammalian sleep can be sub-divided into two distinct phases - REM and non-REM (NREM) sleep. In humans and cats, NREM sleep has four stages, where the third and fourth stages are considered slow-wave sleep (SWS). SWS is considered deep sleep, when metabolism is least active.
Ingestive behaviors encompass all eating and drinking behaviors. These actions are influenced by physiological regulatory mechanisms; these mechanisms exist to control and establish homeostasis within the human body. Disruptions in these ingestive regulatory mechanisms can result in eating disorders such as obesity, anorexia, and bulimia.
Michael Warren Schwartz is Robert H. Williams Endowed Chair, Professor of Medicine in the Division of Metabolism, Endocrinology and Nutrition at the University of Washington and Director of the UW Medicine Diabetes and Obesity Center of Excellence. He is the Director of the NIH-funded Nutrition Obesity Research Center (NORC) at the University of Washington. His research investigates brain mechanisms governing energy balance and glucose metabolism and how obesity and diabetes result from impairment of these brain systems. He has published more than 200 articles and book chapters related to these topics and his research has been continuously funded by the NIH since joining the faculty of UW 18 years ago. Dr. Schwartz is a member of the Association of American Physicians, the Western Association of Physicians, and the American Society for Clinical Investigation, is the recipient of the 2007 Williams-Rachmiel Levine Award for Outstanding Mentorship from the Western Society for Clinical Investigation, the 2006 Naomi Berrie Award for Outstanding Achievement in Diabetes Research from Columbia University, and was the 2012 Solomon A. Berson Lecturer for the American Physiological Society, among other awards. He is a member of the editorial boards of the Journal of Clinical Investigation, American Journal of Physiology, Endocrine Reviews, Molecular Metabolism and Frontiers in Neuroendocrinology.
Adipose tissue macrophages comprise tissue resident macrophages present in adipose tissue. Adipose tissue apart from adipocytes is composed of the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular endothelial cells and variety of immune cells. The latter ones are composed of mast cells, eosinophils, B cells, T cells and macrophages. The number of macrophages within adipose tissue differs depending on the metabolic status. As discovered by Rudolph Leibel and Anthony Ferrante et al. in 2003 at Columbia University, the percentage of macrophages within adipose tissue ranges from 10% in lean mice and humans up to 50% in extremely obese, leptin deficient mice and almost 40% in obese humans. Increased number of adipose tissue macrophages correlates with increased adipose tissue production of proinflammatory molecules and might therefore contribute to the pathophysiological consequences of obesity.
Asprosin is a protein hormone produced by mammals in tissues that stimulates the liver to release glucose into the blood stream. Asprosin is encoded by the gene FBN1 as part of the protein profibrillin and is released from the C-terminus of the latter by specific proteolysis. In the liver, asprosin activates rapid glucose release via a cyclic adenosine monophosphate (cAMP)-dependent pathway.