Organ Systems Involved
Central and Peripheral Systems Controlling Weight and Appetite
Homeostatic control maintains the body's stable weight and energy stores. The discovery of hormones and neuronal networks in regulating appetite, weight, and energy balance results from knowledge obtained from the study of monogenic syndromes and the product of their altered gene expressions.[2] The latest research since the discovery of the hormone leptin in 1994 has elevated adipocyte as a functioning organ vital to weight regulation and energy balance.[7]
Cortico-limbic System
Cortico- limbic system has been an essential neuronal system for weight and energy balance throughout evolution. In the past, this system had significance in providing cues about food procurement as a conservatory measure. In modern times these networks and their substrate are essential to understand food and drug reward centers. In addition, these networks and substrates are necessary for the pharmacologic treatment of obesity.[8][9]
Frontal Lobe
The frontal lobe is the regulatory and control center of food intake and behavior. Additionally, the frontal lobe also governs food choices made by individuals. Current evidence puts the prefrontal cortex in the center of behavioral control of food intake. Damage or pathology in this area is known to cause disinhibition. The prefrontal cortex has had the most considerable increase in size during evolution, accounting for representative behavioral differences in humans compared to other species. It modulates behavior with input from the sensory, limbic, and autonomic nervous systems. Studies have shown a crucial role of the prefrontal cortex in the weight regulation and pathogenesis of obesity. Gourmand syndrome manifests from damage to the right frontal cortex resulting in a passion for eating gourmet foods and talking about fine foods. In patients with frontotemporal dementia, right frontal atrophy is linked to hyperphagia and weight gain, whereas left frontal atrophy is associated with weight loss.[9]
Research into Klein-Levin syndrome (a rare syndrome with excessive sleepiness, compulsive overeating, and behavioral disturbance) has shown evidence of hypoperfusion of the right frontal lobe.[10] In patients with the right frontal lobe epilepsy, overactivity of this region leads to anorexia, and it resolves after therapy with antiepileptics.[11] Evidence also links the right prefrontal cortex with spontaneous physical activity, and reciprocally physical activity can affect the size and function of the prefrontal cortex. The right prefrontal cortex is vital in decision-making and judgment for the long-term consequences of the decision. Disturbance of this modality may explain poor food choices and non-adherence to therapeutic interventions in obesity.
Studies on mice show that the prefrontal cortex may be a site of action of leptin in appetite regulation. Chronic psychosocial stress may also have adverse regulatory effects on the prefrontal cortex by activating the hypothalamus-pituitary-adrenal axis, causing hypersecretion of cortisol.
Hypothalamus
The hypothalamus plays a vital role in maintaining energy balance by regulating food intake and energy expenditure. It collaborates with the cortex, limbic system, autonomic nervous system and receives inputs from the gastrointestinal tract, pancreas, liver, and adipocytes. Hypothalamus has bidirectional communication and coordination with these systems.[12]
The arcuate nucleus is vital to the energy homeostasis and regulation of weight and appetite. The arcuate nucleus is located adjacent to the median eminence and third ventricle. This area around the ventricle is rich in fenestrated capillaries. The anatomical location of the arcuate nucleus near these capillaries allows the passage of peripheral hormonal signals through the blood-brain barrier and receiving neuronal input. Two functional systems in the arcuate nucleus regulate appetite. These neuronal circuits maintain long-term and short-term energy balance. These functional antagonist systems include POMC (Pro-opiomelanocortin), which is appetite-suppressing (anorexigenic), and NPY-AgRP (Neuropeptide Y and Agouti Related Protein), which is appetite-stimulating (orexigenic).[13]
POMC in the arcuate nucleus is metabolized to alpha MSH and also beta-endorphins. POMC also produces ACTH in the pituitary. In addition, POMC is stimulatory for MC3R and MC4R receptors in the brain. The arcuate nucleus also has another system that is inhibitory to the POMC system. It includes AgRP, NPY (Neuropeptide-Y), and GABA, which are activated by energy deficit (e.g., starvation). POMC acts as a substrate for MC4R receptors. MC4R receptors in the hypothalamus are vital to appetite control. Stimulation of MC4R by POMC leads to satiety. MC4R receptors are also expressed in other parts of the brain and autonomic nervous system, including vagus nuclei.
MC3R is distributed in CNS, including the arcuate nucleus in the hypothalamus. It is expressed on NPY/AgRP neurons and is an inhibitory autoreceptor for the POMC pathway. POMC gene mutation leads to obesity syndrome in humans characterized by ACTH insufficiency (from lack of ACTH), red hair (from lack of melanocortin), and obesity. MC4R mutations in humans present with obesity, increased linear growth, hyperphagia, and hyperinsulinemia.
An MC4R agonist setmelanotide is under development for POMC deficiency. Hypothalamus receives peripheral signals of nutrient intake via gut hormones, leptin, and vagal afferents. These signals lead to POMC cleavage to alpha-MSH, which stimulates MC3/4R, sending satiety (anorexic) and energy expenditure signals. Starvation or caloric restriction activates AgRP/NPY, which has an anorexigenic effect and reduces energy expenditure. AgRP/NPY neurons also inhibit the POMC pathway via GABA ( gamma-aminobutyric acid )
CART (Cocaine and Amphetamine-regulated Transcript)
CART is a neuropeptide important in weight and appetite regulation. It is secreted proportional to nutrient information received by vagal afferents via gut hormones. It mediates its anorectic effects by its interaction with leptin, ghrelin, and the POMC pathway.[14]
Serotonin
Activation of central 5 HT receptors suppresses appetite. Activation of 5HT2C receptors activates POMC neuronal pathway, whereas activation of 5HT1B receptors inhibits NPY/AgRP neuronal pathway.[15]
Orexin (A and B)
Orexins are recently discovered peptide hormones secreted by the hypothalamus. They have been associated with the central control of energy balance and the sleep-wake cycle. Disorders of orexin signaling have been linked to obesity and narcolepsy. In addition, orexin may be linked to Klein–Levine syndrome.[6]
Hedonic Control of Appetite–Food and Drug Reward Pathway
A wide array of evidence shows that the food and drug reward pathway seem to converge within the limbic system. Furthermore, it appears to be mediated by the dopaminergic pathway. Increased dopaminergic stimulation by highly palatable foods (high sugar/high-fat content) seems similar to drug reward and addiction. There is an abundant supply of food and less incentive for physical activity in the modern world than during evolution's premodern era. Competition between homeostatic and hedonistic drive results in dysregulation of energy balance.[16]
The Adipocyte
The white adipose tissue is responsible for insulation, mechanical support, and energy balance. White adipose tissue is found in the subcutaneous region and visceral area. During times of surplus food and or low energy expenditure, it is stored as a triglyceride. During starvation and or increased energy expenditure, triglycerides are broken down to free fatty acids and glycerols. Brown adipose tissue is responsible for energy expenditure via adaptive thermogenesis. Brown tissue has an abundance of mitochondria consisting of uncoupling protein-1 (UCP -1). UCP-1 makes brown adipose tissue capable of oxidizing substrates to produce heat (thermogenesis ).
Adaptive thermogenesis can be in response to food or cold exposure. In adults, brown adipose tissue is found in the supraclavicular region and upper trunk. The sympathetic nervous system promotes brown tissue mediated thermogenesis. Research has shown that some white adipose tissue may be capable of expressing UCP-1 by a process called browning, which imparts brown adipose tissue-like capability for energy expenditure. The transitional adipose tissue is known as beige adipose tissue. Brown adipose tissue, when stimulated, is responsible for increased insulin sensitivity, improved glucose disposal, and free fatty acid oxidation. The transformation of white to beige adipose tissue is known as browning, a potential target for obesity pharmacotherapeutics. Physiologically browning is mediated by adrenergic stimulation, thyroid hormone, stress, and exercise.[17] Adipocyte has endocrine, immunologic, and energy balance regulatory functions making it a functional organ. Most important, adipocyte secretes leptin, which suppresses appetite and helps and weight loss.
Leptin (Greek "lepto" meaning thin)
Leptin is a peptide hormone discovered in 1994, is relatively newer compared to other hormones. It is produced by adipocytes mainly and also by gastric mucosa and enterocytes. Jeffrey Friedman discovered leptin. Produced in white adipocytes in proportion to fat mass, leptin is a marker of energy stores. Triglyceride stores in fat cells determine the level of leptin secretion. Leptin receptor sites are located in the central nervous system, including the hypothalamus (arcuate nucleus). Leptin signals satiety. Leptin level is decreased in starvation, and it sends signals for food intake by increasing appetite.
Long-term starvation and low leptin levels also lead to decreased sympathetic nervous system output and thyroid function. Obese individuals have elevated leptin levels despite high-fat mass signaling leptin resistance (similar to insulin resistance). Congenital leptin deficiency is a rare syndrome characterized by hyperphagia, obesity, and hypogonadotropic hypogonadism. Leptin therapy can reverse obesity, increased appetite, and hypogonadism seen in congenital leptin deficiency syndrome.
Leptin receptor deficiency syndrome presents similar to congenital leptin deficiency in children but does not respond to leptin therapy. It is treated by the novel therapeutic agent setmelanotide. Lipodystrophy comprises loss of functional adipocytes, which leads to low leptin levels resulting in increased appetite and insulin resistance that reverses with leptin therapy. Leptin needs to cross the blood-brain barrier to signal neuronal networks, including the hypothalamus. The arcuate nucleus in the hypothalamus is an essential site of action for leptin in weight and appetite regulation. The therapeutic effect of leptin administration in healthy obese subjects hasn't shown promising weight loss. Leptin works through OB receptors.[18]
Other Adipokines
Adiponectin, also secreted by adipocytes, reduces insulin resistance and inflammation. Resistin secreted by adipocytes is responsible for insulin resistance and inflammation. Adipocyte also plays a role in the immune system by secreting inflammatory cytokines (e.g., TNF alpha and interleukin-6).[19]
Cannabinoid receptors
Cannabinoid receptors (CB-1 and CB-2) have garnered considerable attention as potential targets for obesity treatment. This is because CB-1 and CB-2 receptors are involved in the browning of white adipose tissue. CB-1 is mainly expressed in the central nervous system, inhibition of which leads to weight loss and appetite suppression. Unfortunately, CB-1 antagonist rimonabant had significant psychotropic side effects, which led to its discontinuation. These psychotropic side effects can be eliminated if a peripherally acting CB-1 receptor antagonist is developed.
CB-2 receptors are predominantly found in the immune system, including the spleen and thymus. However, it is also found in the musculoskeletal system, including white adipose tissue. Stimulation of CB2 receptors leads to the browning of white adipose tissue by expressing UCP-1, making it a potential therapeutic target.[20]
Pancreatic Hormones
Insulin
Insulin also is secreted in proportion to body fat. Leptin and insulin need to cross the blood-brain barrier to signal neuronal networks, including the hypothalamus. Insulin suppresses appetite by inhibiting AgRP/NPY neurons. It is not as potent as leptin in appetite suppression. Obese subjects do not experience this central weight loss effect despite higher levels of insulin owing to insulin resistance.[21]
Pancreatic Polypeptide
Pancreatic polypeptide is secreted by F cells in response to calorie intake; low levels are seen in caloric restriction. In addition, it slows gastric emptying and suppresses appetite by inhibiting NPY/AgRP system in the hypothalamus. Pathologically low levels are seen in obesity and Prader Willi syndrome.
Amylin
Amylin is co-secreted with insulin from pancreatic beta cells. It increases leptin and insulin sensitivity, slows gastric emptying, and inhibits hepatic gluconeogenesis by suppressing glucagon production.
Estrogen
Decreased estrogen levels after menopause are associated with obesity and central fat accumulation. Hypoenstrogenemia causes increased food intake and decreasing energy expenditure. Estrogen receptor alpha has been implicated in mediating estrogen's effect on weight regulation. Estrogen acting through estrogen receptor isoform alpha has been shown to mediate satiety in animal models, and estrogen receptor alpha is expressed in the arcuate nucleus, paraventricular nucleus, ventromedial nucleus in the hypothalamus, and parts of the brain stem like the nucleus of the solitary tract. These areas have been implicated in estrogen's role in regulating energy expenditure by decreasing physical activity.
Brain-Gut Connection
After food intake, the central nervous system, including the hypothalamus, gets nutrient signals from hormones (such as leptin, insulin) that transcend through the blood-brain barrier and vagal afferent signals. In addition, the brain stem receives information from taste receptors when food enters the oral cavity. Finally, mechanoreceptors from the gastrointestinal tract also signal the brain via vagal stretch receptors about the potential arrival of nutrients. Different parts of the brain also receive olfactory signals of food odor which are important in the hedonic drive of eating.[21]
Ghrelin
The mucosa of the empty stomach secretes ghrelin, and ingestion of food suppresses its release. It has also been called the hunger hormone (orexigenic). Its actions are both central and peripheral. Ghrelin suppression also varies with the type of food ingested (protein versus fat versus carbohydrate) and fluctuates with circadian rhythm. Ghrelin may be partly responsible for the hedonistic drive of eating through the food reward mechanism by involving the dopaminergic pathway.
Ghrelin also has other functions and effects beyond appetite stimulation. It increases insulin secretion and its sensitivity, increases thermogenesis, and has a role in the sleep-wake cycle. Research is ongoing for its connection to the immune system and its relationship with obesity (stress and sleep deprivation increases Ghrelin levels). Patients with Prader Willi syndrome have elevated ghrelin levels.[22]
Cholecystokinin
Cholecystokinin (CCK) is released from the upper small intestine (duodenum and jejunum) in response to protein and fat (not glucose). It suppresses food intake by sending a central signal via the bloodstream to the hypothalamus, slows gastric emptying, and stimulates gallbladder contraction. It works through CCK–1 receptors primarily located in the gastrointestinal tract and CCK-2 receptors located mainly in the central nervous system.
Incretins
GLP-1 (Glucagon-like Peptide -1)
GLP-1 is secreted from L cells in the ileum and colon by direct contact with nutrients (fat, protein, and glucose) and neuronal input from the upper intestine. GLP-1 has a variety of peripheral and central effects. It has a satiety effect manifested by its blood-borne transfer to the hypothalamus and paracrine fashion action on vagal afferents. It stimulates glucose-dependent insulin release from the pancreas, slows gastric emptying, and inhibits inappropriate glucagon release (inhibits hepatic gluconeogenesis by suppressing glucagon).
Naturally secreted GLP-1 has a short half-life (around 5 minutes) owing to its rapid breakdown by DPP-4 (dipeptidyl peptidase 4) enzyme. GLP-1 and DPP 4 are novel therapeutic targets in the treatment of diabetes and obesity. GLP-1 levels are lower in obesity, prediabetes, and diabetes. Patients with type 2 diabetes experience immediate improvement in glycemic control after gastric bypass surgery before weight loss owing to the rise in GLP-1, which is because of bypassing of the small intestine.[23]
PYY (Peptide YY)
PYY, also secreted by L cells in the ileum and colon, has a similar effect on suppressing food intake. It is also degraded by the DPP 4 enzyme.
GIP (Glucose-dependent insulinotropic polypeptide)
An incretin similar to GLP-1 is secreted from K cells in the proximal duodenum in response to glucose and fat (fat more than glucose). GIP promotes fat storage in the form of triglycerides. GIP is also degraded by DPP-4. Research into the combination of GLP-1 and GIP as a therapeutic option (e.g., Tirzepatide ) for diabetes and obesity is ongoing and promising.[20]
Oxyntomodulin
Oxyntomodulin is secreted from L cells in the ileum and colon postmeal and has been shown to activate GLP-1 and glucagon receptors. In addition, it is known to suppress appetite and is also involved in glucose metabolism. These traits make it a potential target for diabetes and obesity therapy.
Sleep
Sleep disorders increase the risk of obesity and diabetes. Sleep deprivation and poor sleep quality lead to reduced leptin, increased ghrelin, and orexin, leading to increased appetite. The sleep-deprived individuals also have reduced thyroid-stimulating hormone leading to decreased energy expenditure and weight gain.
The Gut Microbiome
There has been considerable research emphasis linking the gut microbiome to health and disease, and obesity is no exception. Research has shown an association between the diversity of gut bacterial species and obesity. Obese individuals tend to have higher firmicutes to bacteroids ratio compared with nonobese subjects. One of the hypotheses about associating microbiota with obesity could be that the gut microbiome in obese subjects may be contributing to weight gain by increased energy harvesting from nutrients.[24]
Sympathetic Nervous System
The sympathetic nervous system regulates energy expenditure by activating thermogenesis in response to food intake (especially carbohydrates), hyperinsulinemia, and cold exposure. Acutely sympathetic nervous system output manifests as part of 'flight or fight response.' It has variable responses depending on fasting state versus after food intake. Acutely it can stimulate glycogenolysis and lipolysis, whereas, in the fasting state, it stimulates gluconeogenesis. Leptin suppresses appetite and stimulates sympathetic outflow to increase energy expenditure.
High leptin levels in obese subjects do not lead to weight loss because of presumed leptin resistance. Still, these high levels of leptin lead to chronic overstimulation of the sympathetic nervous system. Obesity-related adverse cardiovascular effects, including hypertension, could be contributed by chronic sympathetic overflow.[25]
Stress and Obesity
There is enough epidemiological data to link chronic psychosocial stress to obesity. This obesogenic effect is secondary to chronic overactivity of the sympathetic nervous system and chronic activation of the hypothalamus-pituitary-adrenal axis. Acute activation of these systems usually is part of 'flight and fight response.' Acute activation of the sympathetic nervous system leads to increased energy disposal; on the contrary, chronic activation leads to insulin resistance, likely from receptor down-regulation in the fat cells. Chronic hypothalamus-pituitary-adrenal axis activation leads to hypercortisolism, promoting insulin resistance, central adiposity, visceral adiposity, and preference for energy-dense foods.[26]
Function
Regulation of Energy Expenditure
The body maintains a set point for weight and fat mass, known as adiposity, by regulating food intake and energy expenditure.
Three major components of energy expenditure (TEE–total energy expenditure) as illustrated above in a schematic diagram.[27]
REE–resting energy expenditure or basal metabolic rate (BMR). It includes sleeping energy expenditure and arousal-related energy expenditure. BMR is the biggest component of total energy expenditure, alluding to the largest energy expenditure required to maintain the human body. Basal metabolic rate is determined by age, sex, body composition, and genetic traits. Fat-free mass is the strongest predictor of resting metabolic rate. Roughly 5% of BMR is utilized to maintain arousal. Environmental and internal body temperature also affect BMR. The thyroid hormone is one of the essential hormones regulating BMR, among others. The sympathetic nervous system also modulates basal metabolic rate.
Harris and Benedict equation for calculating BMR[28]:
Men: 88.362 + (13.397 x weight in kg) + (4.799 x height in cm) - (5.677 x age in years )
Women: 447.593 + (9.247 x weight in kg) + (3.098 x height in cm) - (4.33 x age in years )
The thermogenic effect of food–on average, 8 to 10% of total energy consumed is used to process food. It also varies based on the food composition(carbohydrate 5 to 10%, fat 0-3%,protein 20 to 30%.)[29]
Physical activity-induced energy expenditure–this is the most variable component of energy expenditure. It combines energy expenditure from voluntary exercise and spontaneous activity, including non-exercise activity thermogenesis (NEAT) (e.g., walking to work). The energy expenditure from physical activity varies from 15% in a very sedentary person to 50% in a highly active subject. NEAT is proportionate to spontaneous activity (e.g., fidgeting). It is likely regulated by orexin via its action in the hypothalamus. Therefore, individuals with higher NEAT may be at a lesser risk of weight gain.
Clinical Significance
The first line of therapy for weight management is a lifestyle change and behavior modification which may also involve cognitive behavioral therapy. It is important to identify adverse risk factors contributing to a change in weight or appetite. It is important to consider patients' food preferences, cultural influences, resources for healthy food procuring, and whether a food reward mechanism is involved. Interrogating a person's daily routine and dietary habits gives clues to weight gain risk factors, including food choices, physical activity, psychosocial stressors, work environment, and sleep pattern. Risk factors can be addressed, or risk mitigation can be planned once risk factors are identified. Patients can benefit from a referral to a dietitian for nutritional counseling and/or a psychologist for cognitive behavioral therapy for behavioral change.[30]
Pharmacotherapy for weight management is based on our understanding of the physiology of energy balance. The field of obesity medicine is evolving as we get more insights into the pathophysiology of obesity. Medications that target separate pathways help in weight management. For example, phentermine works through the sympathetic nervous system by increasing energy expenditure; topiramate, on the other hand, suppresses appetite by working in the hypothalamus. GLP-1 agonists (e.g., liraglutide and semaglutide) achieve weight loss by suppressing appetite and decreasing food intake; they are particularly promising in patients with coexisting diabetes mellitus. Orlistat decreases absorption of fat by inhibiting gastric and pancreatic lipase. Leptin is central to the pathophysiology of obesity.[31] Its use for the treatment of obesity has not shown promising weight loss results, owing to leptin resistance in obese individuals. There is considerable interest in the development of future therapies for weight management.[32]
Surgical options are available when lifestyle modification and pharmacotherapy don't achieve desired weight loss. Metabolic surgeries for weight loss include a vertical gastric sleeve, Roux-en-Y gastric bypass, and adjustable gastric banding. The weight loss mechanism from the vertical gastric sleeve includes decreased food intake because of smaller stomach size and decreased ghrelin secretion, leading to appetite suppression. Roux-en-Y gastric bypass procedure achieves the highest weight benefit because of multiple mechanisms, including decreased nutrient absorption and nutrient bypassing of the upper small intestine, leading to increased GLP-1 secretion. Patients also achieve immediate improvement in glycemic control after the Roux-en-Y gastric bypass procedure. Finally, the adjustable gastric band helps in weight management by decreasing the size of the stomach.[33][32]
Appetite and maintenance of body mass are essential to the survival of every organism throughout evolution. We have realized that the 'calorie in and calorie out ' theory of weight maintenance is a mere oversimplification. Complex central and peripheral neuronal networks, hormones, and interactions among multiple organ systems like nervous, endocrine, and gastrointestinal systems maintain a setpoint for adiposity and body weight.
This homeostatic control is challenged by the obesogenic environment in the modern world, with an abundant supply of energy-dense food,pleasure-seeking food intake, sedentary lifestyle, and chronic psychosocial stress. Therefore, the fight against obesity needs to be multifaceted, including lifestyle modification, dietary interventions, pharmacotherapeutics, and, when all options are exhausted, metabolic surgery. The development of targeted pharmacotherapy and metabolic surgery for weight loss is thanks to the discovery and understanding of neuronal pathways and hormones regulating appetite and weight.
Physiology, Appetite And Weight Regulation
