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]
Excessive fat tissue has a direct effect on the productivity of the immune system by slowing it down or interrupting the activity of the cells. It can alter the number of leukocytes, neutrophils, monocytes, and lymphocytes an individual has, while also lowering T and B cell mitogen-induced production. [10] The growth of fat tissue is followed by metabolic stress and inflammation in the adipose tissue. The dysregulation causes apoptosis in adipose tissue cells, then activating an influx of inflammatory leukocytes, ultimately resulting in chronic inflammation. There begin to be too many pro-inflammatory mediators, like cytokines and macrophages, that start blocking anti-inflammatory cytokines, weakening the ability to maintain stable levels of fat in the blood (high cholesterol) and desensitizing the body’s reaction to insulin. [11] Extracellular vesicles are diminished in the adipose tissue, and they help assist in cell communication, growth, and other functions. [12] Additionally, obesity can irregulate the hormone levels in a person’s body that are initially supported through nutrition. These hormones control metabolic functions like appetite, energy usage, and adipose tissue distribution in the body. [12] Leptin, an appetite and energy-controlling hormone, is increased in obese individuals, potentially causing infections within the cells because of the hormone's ability to regulate immune cells, like CD4+T cells. [12]
Maintaining a healthy diet and consuming substantial nutrition will help ensure that a person has a stronger immune system. Malnutrition can impact inflammatory responses in the innate immune system. [13] Consuming certain vitamins like vitamin A can help promote cell division and growth, while a deficiency could result in irregular innate and adaptive immune cell functions. Vitamins B1, B2, B3, and B12, have been linked to helping general functions within cells. [13] This includes foods like fruits, nuts, eggs, meats, fish, and many other foods. [14] A dangerous diet includes processed foods, “fast food”, and sugary beverages, all of which are characterized as having low nutritional value. [15] This diet can be described as a “western diet” which is defined by containing high levels of sugar, salt, white flour, processed meat, and food additives. Thus, allowing for spikes in glucose and insulin, while also not giving enough nutrients to be absorbed in the adipose tissue. [15]
Insulin resistance (IR) is a pathological condition in which cells in insulin-sensitive tissues in the body fail to respond normally to the hormone insulin or downregulate insulin receptors in response to hyperinsulinemia.
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, also known as obese protein, is a protein hormone predominantly made by adipocytes. 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 ARFID, anorexia nervosa, bulimia nervosa, cachexia, overeating, and binge eating disorder.
Adipose tissue is a loose connective tissue composed mostly of adipocytes. It also 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. Its main role is to store energy in the form of lipids, although it also cushions and insulates the body.
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 (ARH), or ARC, is also known as the infundibular nucleus to distinguish it from the arcuate nucleus of the medulla oblongata in the brainstem. The arcuate nucleus 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 primarily 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.
Weight gain is an increase in body weight. This can involve an increase in muscle mass, fat deposits, excess fluids such as water or other factors. Weight gain can be a symptom of a serious medical condition.
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.
Adipose tissue is an endocrine organ that secretes numerous protein hormones, including leptin, adiponectin, and resistin. These hormones generally influence energy metabolism, which is of great interest to the understanding and treatment of type 2 diabetes and obesity.
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 regard 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.
Adipose tissue macrophages (ATMs) comprise resident macrophages present in adipose tissue. Besides adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells that includes pre-adipocytes, fibroblasts, vascular endothelial cells, and a large 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 obese leptin deficient mice, and up to 40% in obese humans. ATMs comprise nearly 50% of all immune cells in normal conditions, suggesting an important role in supporting normal functioning of the adipose tissue. Increased number of adipose tissue macrophages may correlate with increased production of pro-inflammatory molecules and might therefore contribute to the pathophysiological consequences of obesity, although is becoming recognized that in healthy conditions tissue-resident macrophages actively support a variety of critical physiological functions in nearly all organs and tissues, including adipose tissue.
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.
Obesity is defined as an abnormal accumulation of body fat, usually 20% or more over an individual's ideal body weight. This is often described as a body mass index (BMI) over 30. However, BMI does not account for whether the excess weight is fat or muscle, and is not a measure of body composition. For most people, however, BMI is an indication used worldwide to estimate nutritional status. Obesity is usually the result of consuming more calories than the body needs and not expending that energy by doing exercise. There are genetic causes and hormonal disorders that cause people to gain significant amounts of weight but this is rare. People in the obese category are much more likely to suffer from fertility problems than people of normal healthy weight.