Parmar 1 ; Ahmet S. Can 2. Body weight changes result from caloric excess or deficit. Weight gain results from a state of persistent energy excess.

Weight loss occurs when energy expenditure surpasses caloric intake for a significant period. Physiologic processes and external factors like culture, illness, and environmental exposures impact body weight. The human body has a high tolerance for gradual changes either way.

However, chronic energy imbalance produces systemic complications that, over time, can become fatal. This topic focuses on the mechanisms behind weight regulation and the role that appetite plays in it. Research has elucidated the central and peripheral mechanisms regulating weight and appetite.

These systems work synergistically to produce short- and long-term regulatory effects. Mechanisms that favor weight gain are survival-promoting evolutionary modifications.

However, such mechanisms are exaggerated in the modern world, where culture and technology contribute to a life of caloric excess and sedentariness.

Being underweight also remains a worldwide problem. Anorexia or loss of appetite is one cause of a persistently negative energy balance, and it may be due to food insufficiency, severe illness, and psychological causes.

Hypermetabolic states from medical conditions like hyperthyroidism, cancer, and severe burns may also lead to severe weight loss. The nervous and endocrine systems are the most important regulators of body weight. Their actions influence food-seeking behavior, physical activity, digestion, and nutrient metabolism.

Current research shows that the structures below are involved see Image. Central and Peripheral Control of Weight and Appetite. The cortico-limbic system houses the reward centers. This region is an important target in the pharmacologic treatment of obesity.

The frontal and prefrontal cortical regions regulate eating control and food choices. These areas modulate food-seeking behavior aided by the sensory, limbic, and autonomic nervous systems.

Evidence also links the right prefrontal cortex with spontaneous physical activity. Conversely, physical activity can increase the size of this area. The right prefrontal cortex is vital in long-term decision-making and judgment. Injuries in this region may explain poor food choices and non-adherence to weight control interventions.

Stress signals from this region also activate the hypothalamus-pituitary-adrenal axis, causing hypersecretion of cortisol that contributes to obesity. Rodent studies implicate the prefrontal cortex as the site of leptin's effect on appetite.

Frontal and prefrontal injuries cause appetite disturbances. Related conditions include the following:. The hypothalamus is critical to appetite and energy expenditure. This region coordinates with cortical, limbic, and autonomic centers and receives inputs from the gastrointestinal tract, pancreas, liver, adipocytes, leptin, and vagal branches.

The arcuate nucleus of the hypothalamus is located adjacent to the median eminence and 3rd ventricle. The area is highly vascularized. Thus, the arcuate nucleus is exposed to hormones passing through the blood-brain barrier.

Two antagonistic systems in the arcuate nucleus regulate appetite and maintain long-term and short-term energy balance. The first produces the prohormone pro-opiomelanocortin POMC , which suppresses appetite.

The second secretes neuropeptide Y NPY and Agouti-related protein AgRP , which stimulate appetite. POMC produces adrenocorticotropic hormone ACTH in the pituitary gland and is likewise metabolized into alpha-melanocyte stimulating hormone α-MSH and β-endorphins. Activation of the melanocortin 3 MC3R and melanocortin 4 MC4R receptors in the brain by POMC or α-MSH leads to satiety.

The NPY-AgRP neurons antagonize the POMC pathway and are activated by starvation. POMC gene mutation produces obesity, ACTH insufficiency, and hair depigmentation. MC4R mutations present with obesity, increased linear growth, hyperphagia, and hyperinsulinemia. An MC4R agonist, setmelanotide, is under development for POMC deficiency.

CART is a neuropeptide that suppresses appetite. The hypothalamus secretes this molecule in response to nutrient absorption information carried by gut vagal afferents. CART interacts with leptin, ghrelin, and the POMC pathway. Central 5HT-receptor activation suppresses appetite.

Orexins are hypothalamic peptide hormones that regulate energy balance and the sleep-wake cycle. Disordered orexin signaling has been linked to obesity, narcolepsy, and Klein—Levine syndrome.

Evidence shows that food and drug reward pathways converge within the limbic system. Stimulation of the reward centers by highly palatable foods is similar to the effects of psychoactive drugs. Dopamine is the neurotransmitter mediating these signals. Adipocytes have endocrine, immunologic, and energy balance regulatory functions.

Most importantly, adipocytes secrete leptin, which suppresses appetite and helps reduce weight. White adipose tissue in the subcutaneous and visceral regions is important in body insulation, mechanical support, and energy balance.

Excess glucose is stored as triglycerides in the adipocytes during times of food surplus or low energy expenditure. States of starvation or increased energy expenditure result in triglyceride breakdown into free fatty acids and glycerol.

Brown adipose tissue is important in energy expenditure as it is the main site of adaptive thermogenesis. Mitochondria in this tissue have the transmembrane protein, uncoupling protein-1 UCP -1 , which increases heat production thermogenesis in response to a stimulus.

Brown tissue stimulation also helps promote a negative energy balance by improving insulin sensitivity, cellular glucose consumption, and free fatty acid oxidation. Both food ingestion and cold exposure can induce adaptive thermogenesis.

In adults, brown adipose tissue is found in the supraclavicular region and upper trunk. In infants, it is abundant in the adrenal, kidney, mediastinal, and neck areas. The sympathetic nervous system promotes brown tissue-mediated thermogenesis. Research has shown that white adipose tissue can be induced to express 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. Physiologically, browning is mediated by adrenergic stimulation, thyroid hormone, stress, and exercise. This transformation is a potential target for obesity pharmacotherapeutics. The peptide hormone leptin is produced mainly by the adipocytes, gastric mucosa, and enterocytes.

This hormone is a marker of energy stores, as triglyceride levels in the fat cells determine the level of leptin secretion. Leptin receptors aka obesity receptors or OB-R are found in the central nervous system, including the arcuate nucleus of the hypothalamus. Leptin signals satiety.

Leptin level is decreased in starvation, which increases appetite. Long-term starvation and low leptin levels also lead to decreased sympathetic nervous system output and thyroid function.

Leptin must cross the blood-brain barrier to stimulate brain receptors, including those in the hypothalamus. The arcuate nucleus is an important site of leptin action. However, leptin administration is ineffective in obese patients. Adipocytes have immunoregulatory functions apart from their role in energy balance.

These cells also secrete inflammatory cytokines, such as TNF-α and interleukin Adiponectin is an adipokine that reduces insulin resistance and inflammation.

Resistin is an adipokine that increases insulin resistance and inflammatory responses. The cannabinoid receptors CB-1 and CB-2 are involved in the browning of white adipose tissue. CB-1 is mainly expressed in the central nervous system, and its inhibition leads to appetite suppression and weight loss.

CB-2 is expressed by the muscles, white adipose tissue, and white blood cells and is important in the inflammatory response. These receptors have gained considerable attention as potential targets for obesity treatment.

Post-menopausal hypoestrogenemia or estrogen level decline is associated with obesity and central fat accumulation. This condition leads to increased food intake and reduced energy expenditure. Estrogen receptor alpha ERα has been implicated in mediating estrogen's effect on weight regulation.

This receptor isoform is expressed in the arcuate nucleus, paraventricular nucleus, and ventromedial nucleus in the hypothalamus, and the brainstem's nucleus of the solitary tract.

Activation of ERα has been shown to mediate satiety and greater physical activity in animal models. Ghrelin's actions are both central and peripheral. This substance may be partly responsible for the hedonistic drive to eat, as it stimulates the food reward pathway. Ghrelin also increases insulin secretion and sensitivity, induces thermogenesis, and has a role in the sleep-wake cycle.

The mucosa of the empty stomach secretes ghrelin, and ingesting food suppresses its release. Ghrelin suppression varies with the type of food ingested and the circadian rhythm.

This molecule has also been called the "hunger hormone. Cholecystokinin CCK is released from the duodenum and the jejunum in response to protein and fat absorption.

This hormone slows down gastric emptying, stimulates gallbladder contraction, and suppresses food intake by signaling the hypothalamus. CCK acts through CCK—1 receptors in the gastrointestinal tract and CCK-2 receptors in the central nervous system.

The sympathetic nervous system regulates energy expenditure by activating thermogenesis in response to food intake, hyperinsulinemia, and cold exposure. Sympathetic activation enhances glycogenolysis and lipolysis in the fed state but stimulates gluconeogenesis in starved states.

Leptin stimulates sympathetic outflow to increase energy expenditure. High leptin levels associated with leptin resistance lead to chronic sympathetic stimulation. Obesity-related adverse cardiovascular effects, including hypertension, may be attributed to chronic sympathetic overflow.

During a meal, the central nervous system gets signals from vagal afferents and various peripheral tissue hormones passing through the blood-brain barrier. Processes that can increase appetite also occur outside of the system described above.

For instance, the brain stem receives information from taste receptors when food enters the oral cavity. Different brain nuclei also receive olfactory information essential to the hedonic drive of eating. This component is not an inherent part of the human body, but the gut microbiome's impact on weight regulation is nonetheless significant.

Gut microflora metabolizes carbohydrates, proteins, and fatty acids. Research has shown an association between altered gut bacterial diversity and obesity. The body maintains a set point for weight and fat mass aka, adiposity by regulating food intake and energy expenditure. Total Energy and Expenditure Components.

REE or BMR includes sleeping-related and arousal-related energy expenditure. REE is the biggest component of total energy expenditure, as it represents the energy required to maintain the human body. Age, sex, body composition, and genetics determine REE value.

The thyroid hormone and sympathetic nervous system enhance REE. Fat-free mass is the strongest predictor of resting metabolic rate. Environmental and internal body temperature also affect REE. The Harris-and-Benedict BMR equation differs for men and women: [26].

The thermic energy of nutrition TEN is the increase in energy expenditure from metabolizing nutrients, which varies by food composition.

Activity-induced energy expenditure is the most variable TEE component. Major contributors include voluntary exercise and non-exercise activity thermogenesis NEAT. Sources of NEAT include walking to work and daily spontaneous movements like writing, fidgeting, and lifting loads.

NEAT is regulated by orexin via hypothalamic stimulation. Individuals with higher NEAT are less likely to gain weight. Weight regulation disorders manifest as extreme chronic weight changes with concomitant metabolic derangements.

On one extreme is obesity, a condition marked by chronic caloric excess and weight gain. On the other is malnutrition, characterized by severe weight loss or poor weight gain from a chronically negative energy balance.

Nutrient deficiencies commonly accompany malnutrition. Both obesity and malnutrition can result from the failure of central and peripheral body weight regulators. Obesity is an emerging epidemic in the modern world.

The worldwide adult obesity burden has increased by Appetite regulation plays a huge role in the development of obesity. The condition has various complications, such as type 2 diabetes mellitus, cardiovascular disorders, osteoarthritis, and obstructive sleep apnea.

Sleep disorders increase the risk of obesity and diabetes. Sleep deprivation and poor sleep quality increase appetite by reducing leptin and upregulating ghrelin and orexin.

Sleep-deprived individuals also have reduced thyroid-stimulating hormone. Chronic psychosocial stress positively correlates with weight gain. The sympathetic nervous system and hypothalamus-pituitary-adrenal axis are chronically hyperactive, leading to insulin resistance, hypercortisolism, central adiposity, visceral adiposity, and a preference for energy-dense foods.

The first line of therapy for weight management is lifestyle change and behavior modification, which may also involve cognitive behavioral therapy.

Obesogenic factors must be identified and addressed in a multidisciplinary approach. The second line of therapy is pharmacotherapy. Anti-obesity medications target various mechanisms promoting chronic caloric excess. For example, orlistat inhibits lipase action, blocking gastrointestinal fat absorption.

Incretin medications like tirzepatide and the GLP-1 analog semaglutide act centrally and peripherally. Surgery is an option when health goals are not achieved after several months of lifestyle modification and pharmacotherapy.

Techniques for weight loss include vertical gastric sleeve, Roux-en-Y gastric bypass, and adjustable gastric banding. The vertical gastric sleeve decreases food intake by reducing stomach size.

Ghrelin secretion abates, leading to appetite suppression. Roux-en-Y gastric bypass procedure achieves the highest weight benefit.

Besides limiting nutrient absorption, post-surgical effects include increased GLP-1 secretion and improved glycemic control. Adjustable gastric bands also decrease stomach size. Severe weight loss may be unintentional or intentional. Unintentional causes result from food insufficiency and disease.

Eating disorders are the most common cause of intentional weight loss. Kwashiorkor and marasmus are conditions characterized by protein-energy malnutrition and associated with poor socioeconomic status.

Young children are the most vulnerable. Kwashiorkor presents with widespread edema owing to severe protein deficiency. Patients must be evaluated for emergent conditions like sepsis and heart failure and subsequently stabilized.

Management includes careful refeeding, vitamin supplementation, treatment of co-existing illnesses, physical therapy, and guardian and patient education.

Anorexia nervosa and bulimia nervosa are eating disorders affecting young women more than men. About 5 million Americans are diagnosed with an eating disorder every year.

Anorexia nervosa patients have a history of severe fasting, excessive physical activity, or both. Being underweight is common. Bulimia nervosa patients are more likely to binge before purging or engaging in excessive physical activity.

Body weight may be below normal, normal, or above normal. Management should address nutritional deficiencies and the underlying mental health condition. Total Energy Expenditure Components. Shown on this pie graph are resting energy expenditure, thermogenic effect of food, voluntary exercise, and NEAT or non-exercise activity thermogenesis.

Created and Contributed by Rasik Parmar, MD. Disclosure: Rasik Parmar declares no relevant financial relationships with ineligible companies. Disclosure: Ahmet Can declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4. You are not required to obtain permission to distribute this article, provided that you credit the author and journal. Turn recording back on. National Library of Medicine Rockville Pike Bethesda, MD Web Policies FOIA HHS Vulnerability Disclosure.

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Affiliations 1 B. Medical College, Ahmedabad India. Once in ketosis, you burn fat for energy instead of sugar. When in ketosis, many people report that they experience a drop in their appetite , especially for sugary foods and refined carbs.

The keto diet can be combined with intermittent fasting for even more help with weight control and managing food intake. Emphasize healthy fats in your diet, which are just as crucial for feeling full and staying satisfied as fiber and protein are.

At the same time, avoid sugar and most carbs other than non-starchy vegetables. To help regulate your appetite hormones and train your body when to expect to eat, try to have meals at the same times every day if you can.

Eat until satisfied, but not stuffed, to the point that you can skip snacks. Aim for balanced meals that will do the best job of turning off hunger.

Consider stopping eating at least two to three hours before going to sleep, which helps support general metabolic health. Try to eat about every three to five hours depending on your schedule and exact diet. Related: 7 Natural Fat Burners that Work.

Is there a pill that curbs your appetite? While some formulas can help dull hunger, most are unsafe and can cause side effects. Commercially sold diet pills usually contain a mix of stimulants, including caffeine, herbs, and sometimes digestive enzymes or acids.

Generally, they come with adverse reactions, such as anxiety and indigestion, making them a risky way to shed extra weight. Some of the main reasons that appetite-suppressing weight loss products are considered to be at least somewhat dangerous include:.

However, too much caffeine within a short time period can cause strong side effects, such as:. Due to interactions with medications or changes in blood pressure, other side effects of popular weight loss pills can include:.

Some commercially available thermogenic supplements especially those containing ephedrine, also called ephedra have even been found to induce acute liver failure and contribute to serious reactions like excessive bleeding, increased pressure in the brain, fatigue, malaise and jaundice.

This is one reason why ephedrine is now banned as a dietary supplement ingredient in the U. What else will suppress your appetite naturally? Here are some natural appetite suppressant tips:. Follow dosage directions carefully, as high doses can possibly cause dangerous reactions like poisoning, yellow appearance of the skin or mucous membranes, vomiting, dizziness, diarrhea, and heart problems.

If you have any of the below health conditions, talk to a professional before attempting to suppress your appetite for weight loss especially if you take medications daily :. Popular Posts All Time This Week {position} Detox Your Liver: A 6-Step Liver Cleanse.

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