WHAT CAUSES OBESITY?

The pathogenesis of obesity involves the regulation of energy utilization, appetite, physical activity, and complex interactions with underlying hereditary and environmental factors.

Basically, obesity results from a chronic positive energy balance regulated by a complex interaction between endocrine tissues and the central nervous system. Obesity is characterized by the accumulation of excessive body fat (adipose tissue) and a mild state of chronic inflammation of this tissue that leads to a defective hormonal and immune system.

Depending on location, types of adipose tissue are parietal or visceral. Parietal is located under the skin, and visceral surrounds the internal organs. Compared to subcutaneous fat, visceral fat is more likely to raise the risk for serious medical issues. Visceral fat manufactures more of the proteins that cause inflammation in tissues and organs and narrowing of blood vessels.

Adipose tissue has always been considered a passive fuel reservoir and protection for internal organs, but it is recognized now as an endocrine organ that secretes multiple bioactive substances, including adipocytokines and hormones. It represents the largest endocrine gland in the human body. Adipocytokines are mediators that exert pro-inflammatory or anti-inflammatory actions. They regulate energy balance, food intake and satiety, and metabolism of steroid hormones; are involved in insulin sensitivity and appetite; and play a role in blood coagulation. Ongoing investigations into the complexities of adipocyte metabolism has improved the understanding of the pathogenesis of obesity.

The most important adipose tissue hormone secreted is leptin, a negative feedback signal that acts on the hypothalamus to alter the expression of several neuroendocrine peptides that regulate energy intake and expenditure. Leptin controls appetite intensity by signaling the brain to stop eating and helps the brain regulate how much energy the body burns throughout the day. Central resistance to leptin results in a feeling of hunger all the time and is a prominent factor leading to obesity. The discovery of immunological abnormalities in obesity related to leptin has given a new perspective to the understanding of obesity (Vaskovic, 2021; Khana & Rehman, 2022; Saber, 2021a; Hamdy, 2022).

The factors that contribute to the pathogenesis of obesity are complicated and involve much more than simply eating more food than the body requires. This has been the prevailing belief in the past, but today researchers recognize the influence of many factors that are unique to each individual. Currently, these causative factors for obesity have been identified:

• Genetics
• Epigenetics and obesogens
• Endocrine diseases
• Inflammation and infection
• Stress
• Gut microbiota
• Prenatal factors
• Postnatal factors
• Ultraprocessed foods
• Medications
• Obesogenic environment
• Food availability and access
• Culture and ethnicity
• Parenting style
• Work environment and occupation
• Food marketing
• Sleep deprivation
• Circadian misalignment

Genetics

Twin and adoptee studies have demonstrated the heritability of obesity to be as high as 75%. These studies show that obese individuals who were raised separately followed the same weight pattern as that of their biological parents or their identical twin. A person’s metabolic rate, spontaneous physical activity, and thermic response to food appear to be heritable to some extent. A strong genetic component underlying the large variations in body weight also determines a person’s response to the environment.

Obesity is classified as monogenetic, polygenetic, or syndromic.

MONOGETIC OBESITY

Monogenetic obesity is caused by rare mutations of one gene, typically causing severe early-onset obesity with abnormal feeding behavior and endocrine disorders. Studies about common or polygenic obesity have found over 900 genetic variants associated with obesity. Some genes associated with monogenetic severe obesity are described below:

• Leptin (LEP) mutations cause rapid weight gain after normal birth weight as a result of intense hyperphagia (intense hunger and excessive eating).
• Leptin receptor (LEPR) can cause a phenotype similar to that of leptin deficiency.
• Proopiomelanocortin (POMC) is involved in appetite regulation.
• Melanocortin-4 receptor (MC4R) deficiency in children results in early-onset obesity with hyperphagia and food-seeking behavior in early childhood.
• PR proconvertase 1 (PCSK1) is involved in the regulation of food ingestion, glucose, and energy homeostasis.
• Single-minded 1 (SIM1) deletions or mutations are associated with hyperphagia and food impulsivity.
• Brain-derived neurotrophic factor (BDNF) is implicated in the regulation of food intake and body weight.

POLYGENETIC OBESITY

Polygenetic obesity (also referred to as common obesity) is associated with several variants of different genes. Many of these genes are involved in neurogenesis, in the development of the central nervous system, and in pathways such as appetite and food intake regulation. Some of them are related to synaptic function, neurotransmitter signaling, and energy homeostasis. Genes associated with polygenetic obesity include:

• Melanocortin-4 receptor (MC4R)
• Proopiomelanocortin (POMC)
• Fat mass and obesity associated gene (FTO) (the first gene found to be associated with obesity)
• Neurexin III (NRXN3)
• Niemann-Pick disease, type C1 (NPC1)
• Neuronal growth regulator 1 (NEGRI)
• Glucosamine-6-phosphate deaminase 2 (GNPDA2)
• Mitochondrial carrier 2 (MTCH2)
• ETS Translocation variant 5 (ETV5)

SYNDROMIC DISORDERS OF OBESITY

Syndromic disorders of obesity are different from common obesity. They are characterized by early-onset, severe obesity and often are associated with hyperphagia.

• Alström syndrome is a disorder caused by mutations in the ALMS1 gene. In addition to severe obesity beginning in early life, the disorder results in short stature in adulthood, progressive visual and auditory impairment, insulin resistance, type 2 diabetes, hyperlipidemia, and progressive kidney dysfunction.
• Bardet-Biedl syndrome results from mutations in multiple BBS genes in children ages 1–2 years, causing central obesity, intellectual disability, hypotonia, retinitis, polydactyly, glucose intolerance, deafness, and renal disease.
• Beckwith-Wiedemann syndrome (also known as Laurence-Moon-Biedl syndrome) is caused by multiple genetic mutations, resulting in hyperinsulinemia, hypoglycemia, hemihypertrophy, and intolerance of fasting.
• Carpenter syndrome results from a mutation in the RAB23 gene, causing central obesity, intellectual disability, short stature, brachycephaly, polydactyly, syndactyly of feet, cryptorchism, and hypogonadism in males.
• Cohen syndrome is caused by a mutation in the COH1 gene, resulting in mid-childhood central obesity, intellectual disability, microcephaly, small hands and feet, cryptorchidism, hypotonia, and long, thin fingers and toes.
• Prader-Willi syndrome is caused by a mutation in the NDN gene, resulting in generalized obesity in children age 1–3 years. It is characterized by faltering early growth followed by hyperphagia and increased weight gain by age 2–3 years. It also results in mild to moderate cognitive deficit, microcephaly, short stature, and delayed puberty.
• Down syndrome is caused by an extra chromosome and results in distinctive physical features, developmental challenges, and increased leptin levels, which correlates with obesity.
  (Flores-Dorantes et al., 2020; Perrault & Rosenbaum, 2021; Schwarz, 2020)

Epigenetics and Obesogens

Environmental epigenetics looks at how chemicals or other environmental exposures can interfere with gene expression and thereby disrupt development. Epigenetics affects how genes are “read” by cells and subsequently how they produce proteins. Epigenetics is the study of gene expression, the switching on and off of gene action without causing a mutation (a change in the genetic code, or DNA). Gene expression signals the cells in the body on how and when to differentiate, a process through which a cell changes to become a more specialized type of cell.

When gene expression is altered—for example, by exposure to certain chemicals, radiation, or dietary nutrients—abnormal development of cells, organs, and systems can occur. Scientists recognize that these substances, referred to as obesogens, are endocrine disruptors that interfere with hormones that play a role in metabolism. Of particular importance, the critical window of exposure to obesogens is either during the prenatal or neonatal period, when the body’s weight-control mechanisms are being developed and can induce effects that manifest later in life.

Obesogens alter how fat cells develop, increasing the body’s fat cells. In some instances, these new cells become unusually large, allowing for fat to build up in the body, which leads to weight gain. These substances also may block fat-burning so that cells are unable to release stored fat. Obesogens can likewise alter appetite by affecting the hypothalamus, leading to a tendency to compulsively eat and not stop even if the person may no longer be hungry. Obesogens can also act indirectly to promote obesity by altering basal metabolic rate and gut microbiota to promote food storage (Brennan, 2021a; NIEHS, 2021a).

Chemicals that are classified as obesogens include:

• Cigarette smoke (nicotine, polycyclic aromatic hydrocarbons [PAHs], acrylamide). Acrylamide is also found in foods and can be formed as an unintentional byproduct of frying, baking, or roasting.
• Outdoor pollution:
  • Byproducts of fossil fuel burning, including diesel exhaust
  • Noxious gases (sulfur dioxide, nitrogen oxides, carbon monoxide, chemical vapors, etc.)
  • Ground-level ozone (a highly reactive form of oxygen and a primary component of urban smog)
• Tributyltin (TBT), which is a chemical widely used as a fungicide and heat stabilizer in polyvinyl chloride (PVC) piping. Exposure can occur via diet (such as seafood contaminated by TBT used in marine shipping), surface disinfectants, laundering sanitizers, and rodent repellents. Placental TBT has been found to be associated with a trend toward higher weight gain, but only in the first three months of life. Prenatal exposure to TBT results in increased lipid accumulation, increased adipose tissue mass, and reduced muscle mass (Egusquiza & Blumberg, 2020).
• Flame retardants. There are hundreds of different flame retardants, which are grouped based on whether they contain bromine, chlorine, phosphorus, nitrogen, metals, or boron. These chemicals can get in the air, water, and soil during manufacture; can leak from products into dust and air and then get on hands and food; and can be found in some electronic waste. Children are particularly vulnerable to their effects and have been found to have higher concentrations of them in their bodies than adults. These chemicals do not break down easily and can remain persistent in the environment for years; they can also bioaccumulate (build up in people and animals over time) (NIEHS, 2021b).
• Phthalates are a broad class of chemicals that are added to many consumer products to make them softer and promote flexibility, such as in tubing and vinyl flooring. They can be present in cosmetics, wood finishes, blood bags, building products, food packaging, and children’s toys (NIEHS, 2021c).
• Bisphenol A (BPA), produced in large quantities and used primarily in the production of polycarbonate plastics and epoxy resins, is linked to childhood obesity. BPA is an ingredient in some food and drink packaging, such as water and infant bottles and coated metal products (food cans, bottle tops, and water supply pipes); medical devices; compact discs; and as a developer in cash register receipts. BPA is also used in some dental sealants and composites (Amato et al., 2021).
• Pesticides, including herbicides, insecticides, fungicides, disinfectants, and compounds used to control mice and rats. Less well known are attractants, plant defoliants, swimming pool treatment, and plant growth regulators (EPA, 2021a).
• Polychlorinated biphenyls (PCBs) are industrial chemicals used widely in the past in products such as paints, cements, fluorescent light ballasts, sealants, and adhesives. They were banned in 1970 but are still present in air, water, soil, homes, communities, and bodies, since they do not break down easily. Although it is illegal to manufacture PCBs, some continue to be produced in the process of making pigments (e.g., for paints, inks, cosmetics, etc.). Because PCBs build up in the fat of animals, a major exposure for many people comes from food, particularly meat, dairy, and fish. PCBs are also present in older buildings such as schools (Fox-Rawlings, 2022; EPA, 2021b).

Endocrine Diseases

Along with the hormones released from adipocytes, other hormones secreted by the endocrine system can be involved in conditions that result in obesity. These endocrine conditions can include:

• Hypothyroidism
• Polycystic ovarian syndrome
• Hyperandrogenism in females
• Cushing’s syndrome
• Hypothalamic disorders
• Hypogonadism in males
• Growth hormone deficiency
• Pseudohypoparathyroidism

The mechanisms for the development of obesity vary in accordance with the endocrine condition. Hypothyroidism, for example, involves an accumulation of fluid-retaining hyaluronic acid, resulting in excess retention of salt and water, which is associated with changes in body weight and composition. It also affects body temperature, energy expenditure, food intake, and glucose and lipid metabolism (ATA, 2022).

Polycystic ovarian syndrome interferes with the body’s ability to use insulin. High insulin levels increase the production of male hormones and obesity. Because it is triggered by male hormones, the weight gain is typically in the abdomen (Watson, 2020).

In Cushing’s syndrome, an interaction with thyroid and growth hormone increases the levels of cortisol in the body and plays an important role in increased adipocyte differentiation and adipogenesis. Increased levels of cortisol lead to a build-up of fat in characteristic sites such as the face, upper back, and abdomen (Mayo Clinic, 2021a).

Hypothalamic Obesity

Hypothalamic obesity is a rare syndrome caused by damage to the ventromedial or paraventricular region of the hypothalamus or the amygdala as a result of trauma, tumor, inflammatory disease, surgery in the posterior fossa, or increased intracranial pressure. These regions of the brain are responsible for the integration of metabolic information concerning nutrient stores with afferent sensory information about food availability. When this area is damaged, hyperphagia develops and obesity follows (Perreault & Bessesen, 2021).

Inflammation and Infection

Systemic inflammation makes the body more prone to insulin resistance, type 2 diabetes, and cardiovascular disease, which can lead to weight gain. The adipose tissue is known to be a storage place for various cytokines, especially interleukin 6 (IL6) and tumor necrosis factor (TNF). Chronic exposure to elevated IL6 is associated with the development of insulin resistance, metabolic syndrome, and type 2 diabetes.

A high-normal level of procalcitonin (PCT) reflects a state of inflammation and has been shown to be associated with central obesity but not with insulin resistance in obese patients.

There is also data suggesting that an infective cause may exist for obesity. Adenovirus-36 infection is associated with obesity in animal studies and in humans. The prevalence of this infection is 20% to 30% in people who are obese vs. 5% in people who are not. The role of infection in the pathogenesis of obesity, however, remains unclear (Hamdy, 2022; Lutz, 2020).

Stress

Research has shown that stress response may play a major role in the development and maintenance of obesity due to increased glucocorticoid exposure. There are many pathways that connect stress and obesity:

• Stress interferes with cognitive processes such as self-regulation abilities to control food intake.
• Stress can affect behavior by:
  • Inducing overeating and consumption of foods that are high in calories, fat, or sugar
  • Decreasing physical activity
  • Shortening sleep
• Stress triggers physiological changes in the hypothalamic-pituitary-adrenal axis, reward processing in the brain, and possibly the gut microbiota.
• Stress can stimulate production of biochemical hormones and peptides such as leptin, ghrelin, and neuropeptide Y, all of which are involved in regulating food intake.
• Obesity itself can increase stress due to the high prevalence of stigmatization.
  (Tomiyama, 2019)

Gut Microbiota

The human gastrointestinal tract is populated densely with bacteria, fungi, archaea, and viruses, collectively referred to as gut microbiota (GM). These microorganisms are important for body homeostasis. Because acids in the stomach and bile acids and pancreatic juice in the duodenum and jejunum can inhibit the growth of microorganisms, most inhabit the large intestine. Each person acquires their own unique microbiota, which begins to develop in infancy and is affected by the mother’s health, the type of delivery, breastfeeding history, age, use of antibiotics, geography, and diet—dietary habits being the main contributors to the diversity of the human gut microbiota.

GM influences how food is digested and absorbed and how dietary fats are stored. The microbiota may also impact the production of hunger hormones such as ghrelin. An unhealthy GM can increase inflammatory markers, which may result in weight gain and metabolic disease.

Endogenous microbiota can impact body immune response and metabolic homeostasis. Certain gut microbial strains have been shown to inhibit or attenuate immune responses related to chronic inflammation in experimental models, suggesting that specific species may play either a protective or pathogenic role in the progression of obesity. Obese patients have been found to have less diversity and richness in the bacterial component of their gut microbiota than normal-weight subjects and also show an increased ratio of Firmicutes to Bacteroidetes (the most common organisms in the fecal microbiota) regardless of dietary intake (Palmer, 2021).

Clinical trials are currently being conducted to verify findings obtain in studies using mice where fecal samples are transplanted from human twins, one obese and one lean into germ-free mice. The studies so far indicate that stool from the obese twin leads to increased mass in the mice, but does not when transplanting from the lean twin (NIH, 2021a).

Prenatal Factors

Intrauterine environment can shape the trajectory of weight gain and body fatness throughout the course of life. Three prenatal factors are the mother’s smoking habits, weight gain, and blood sugar levels during pregnancy.

MATERNAL PRENATAL SMOKING

Studies have shown a consistent connection between maternal smoking in pregnancy as well as exposure to secondhand smoke and an increased risk of children being overweight and obese by 3 years of age. In a meta-analysis of 14 studies, maternal smoking during pregnancy was associated with a 50% higher risk of childhood obesity. The mechanisms to explain the effect of smoking are not as yet understood but may result from fetal exposure to nicotine, which has a long-term effect on the control of food consumption and other appetitive behaviors, and carbon monoxide, which increases the risk of intrauterine growth retardation and low birth weight (Hollis & Robinson, 2022; Harvard T.H. Chan, 2022a).

MATERNAL WEIGHT

Increasing evidence implicates maternal obesity as a major determinant of health in offspring during childhood and later adult life. Children of pregnant women with obesity are at increased risk of developing obesity in childhood and as adults. Both prepregnancy obesity and maternal weight gain during pregnancy play important roles in determining birth weight with increased risk for a newborn who is large for gestational age.

Maternal obesity may affect long-term offspring outcomes as a result of epigenetic changes induced by fetal exposure to increased levels of glucose, insulin, lipids, and inflammatory cytokines during development. These in utero effects may cause permanent or transient changes in metabolic programming, leading to adverse health outcomes in adult life (Ramsey & Schenken, 2021).

MATERNAL BLOOD SUGAR LEVELS

One mechanism to explain the link between maternal obesity and excess fetal weight gain may be that the fetus is overnourished due to exposure to high maternal plasma concentrations of glucose, free fatty acids, and amino acids. In postnatal life there may be permanent consequences of prenatal overnutrition, which may include effects on control of appetite, neuroendocrine function, and energy metabolism, resulting in lifelong consequences for the child’s ability to regulate energy balance and body weight (Hollis & Robinson, 2022).

Gestational diabetes mellitus (GDM) subjects the fetus to periods of high blood glucose and elevated insulin, which can lead to increased body fat. Boys exposed to GDM have a more unfavorable fat distribution than those not exposed; however, no difference has been found in girls. Exposure to gestational diabetes, in particular prior to 26 weeks’ gestation, has been found to be associated with increased energy intake, increased reaction to food cues, increased waist-to-hip ratio, and as adults, metabolic syndrome (Lou et al., 2021).

Postnatal Factors

There are three postnatal factors during infancy that influence weight in later life. These include how rapidly an infant gains weight, how long an infant is breastfed, and how much an infant sleeps.

INFANT RAPID WEIGHT GAIN

Children who experience rapid weight gain postnatally have been found to have a significantly higher risk of being overweight or obese at preschool and school age, regardless of its occurrence at any time interval before the age of 2 years (Li et al., 2020).

BREASTFEEDING

Breastfeeding initiation and duration may influence obesity in later life. In two meta-analyses of breastfeeding vs. bottle feeding, breastfeeding was associated with a 13% and a 22% reduced risk of obesity in later life. Another analysis of 17 studies of breastfeeding duration found that each additional month that infants were breastfed was associated with a 4% lower risk of obesity later in life. However, it is not clear that breastfeeding itself actually prevents obesity, as both breastfeeding and obesity may be influenced by similar socioeconomic and cultural factors (Harvard T.H. Chan, 2022a).

INFANT SLEEP DURATION

It has been found that infants who slept fewer than 12 hours a day had double the odds of being overweight by the age of 3 years, compared with infants who slept more than 12 hours a day. Factors that were associated with shorter sleep duration included maternal depression during pregnancy, early introduction of solid foods (before four months), and television viewing (Harvard T.H. Chan, 2022b).

Ultraprocessed Foods

The increase in obesity around the world appears to be linked to changes in the global food system, leading to replacement of traditional meals with those that are made up of ultraprocessed foods. Scientific studies published between 2010 and 2020 and carried out in the United States, Canada, United Kingdom, France, Spain, Australia, Japan, Taiwan, Chile, Colombia, Argentina, Mexico, Brazil, and other countries consistently show that higher consumption of ultraprocessed food is associated with a reduction in diet quality and with an increased incidence of obesity and other chronic noncommunicable conditions and diseases such as diabetes, hypertension, heart disease, some cancers, and earlier mortality (Monteiro & Jamie, 2020).

Unprocessed or minimally processed foods represent a small proportion of, or are even absent from, the list of ingredients of ultraprocessed foods. Ultraprocessed foods are those that include formulations of ingredients typically created by a series of industrial techniques and processes. Ultraprocessed foods are made possible by the use of many types of additives, including those that imitate or enhance palatability. They typically contain little or no intact foods and are ready to drink, eat, or heat up. These foods have a poor nutrient profile, including high salt content or added sugar; unhealthy fats; and low dietary fiber, micronutrients, and phytochemicals. The processing itself makes these foods nutritionally unbalanced.

By design, these products are highly palatable, cheap, ubiquitous, and contain preservatives that offer a long shelf life. The convenience and attractiveness of these foods and their aggressive marketing are two reasons why they now amount to more than half of the total dietary energy consumed in high-income countries. In the United States, 67% of calories consumed by children and adolescents in 2018 came from ultraprocessed foods. At the same time, the consumption of unprocessed or minimally processed foods had decreased to 28% (Wang et al., 2021).

The NOVA classification system developed by researchers at the University of Sao Paulo, Brazil, places all foods into four groups:

• Group 1: Unprocessed or minimally processed foods (e.g., fresh or frozen fruits and vegetables)
• Group 2: Processed culinary ingredients (e.g., salt, sugar, molasses, syrup, honey, starch)
• Group 3: Processed foods (e.g., breakfast cereals, cheese, bread, meat products)
• Group 4: Ultraprocessed food and drink products:
  • Sodas and sweetened drinks, including energy drinks
  • Sweet or savory packaged snacks
  • Confectionery and industrialized desserts
  • Mass-produced packaged breads and buns
  • Cookies, pastries, cakes, and cake mixes
  • Margarine and other spreads
  • Sweetened breakfast cereal
  • Fruit yogurt
  • Preprepared meat, cheese, pasta, and pizza dishes
  • Packaged meatballs
  • Poultry and fish nuggets and other reconstituted meat products
  • Meat products that contain preservatives other than salt
  • Frozen or shelf-stable instant meals
  • Instant noodles and instant or canned soups
  • Baby formula and other baby food products
  • Weight-loss products such as meal replacement shakes and powders

Additionally, there are many other ready-to-consume formulations of several different ingredients. Besides large amounts of salt, sugar, oils, and fats, these foods include substances not commonly used in food preparation, such as modified starches, hydrogenated oils, protein isolates, and classes of additives whose purpose is to imitate sensorial qualities of unprocessed or minimally processed foods and their cooking preparations or to disguise undesirable qualities of the final product (Wang et al., 2021; Monteiro et al., 2019).

The effects of ultraprocessed foods on health are likely due to the synergistic effects of many compounds and components in these types of foods.

The ultraprocessed foods in the Western diet have presented a major challenge to gut microbiota, negatively impacting human digestive physiology, which may result in pathogenic effects on the immune system, which is mediated by gut microbiota. Common food additives such as salt, emulsifiers, stabilizers, bulking agents, sweeteners, and food coloring may disrupt gut bacteria. Metal and compounds found in the food packaging may trigger intestinal permeability and increase inflammatory markers (Olmo et al., 2021).

Addictive Potential of Processed Foods

One contributing factor to overweight and obesity is that certain foods have been shown to be capable of triggering an addictive response in some individuals. Human bodies are biologically “wired” to seek out high-fat, high-salt, and high-sugar foods. Sugar, salt, and fat have been so important in human evolution that the brain responds to these nutrients much like it does to other additive substances by “rewarding” individuals with the release of “feel-good” chemical messengers such as dopamine and an increased desire for more. In combination, these nutrients act synergistically and are far more addictive than any one alone.

For those people who are more predisposed to addiction, these foods can overpower other signals from the brain that tell them they are satiated, resulting in a cycle of overeating. And just as with other addictive substances, over time a tolerance to these foods may develop and more must be eaten to provide the same level of pleasure.

Others have proposed that people experience a “process addiction” rather than a true addiction to food. People become dependent on the process that happens—the good, soothing feelings and pleasure that occur with eating—rather than to the food itself.

The foods found to be most likely to lead to compulsive overeating have one thing in common: a strong combination of carbohydrates, salt, and fat. This combination is difficult to find in nature, but the processing of foods can mix ingredients and chemically exaggerate flavors to create tastes that are very agreeable and hard to resist (Cleveland Clinic, 2021).

SALT

Throughout evolutionary history, salt has been a vital necessity for survival, and it has been a very rare resource. As a consequence, humans have evolved neuronal pathways for a habitual salt craving, which cannot be controlled. The importance of salt to overall health may explain why salty foods are so tasty and “you can’t eat just one.” Sodium appetite is an important instinctive behavior with high survival value, as there are many physiologic and cellular functions that depend on salt.

Neuronal mechanisms help drive the lust for salt. Neurons in the central amygdala become highly active when salt is being consumed. This area of the brain controls many innate and conditioned behaviors, including appetite-related and feeding behaviors. When salt is ingested, the central amygdala is activated, and the endogenous mu-opioid receptor signaling within this region promotes sodium intake. The reward results in craving more salt, resulting in the response of overeating (Research Features, 2021).

Monosodium glutamate (MSG) is a form of concentrated salt added to foods to enhance flavor; it contains about one third the sodium of table salt. This salt product may interfere with appetite suppression and cause hunger even after eating a large amount of food (Cardiff, 2021).

INDUSTRIAL SEED OILS

Traditional fats are olive oil, coconut oil, butter, ghee, and lard. Industrial seed oils are highly processed oils extracted from soybeans, corn, rapeseed (source of canola oil), cottonseed, and safflower seed. Industrial seed oils were originally used in the soapmaking process. It was discovered that these oils could be chemically altered by hydrogenation to turn into a solid cooking fat that resembled lard; this product was named shortening.

These industrial seed oils are used extensively in the making of processed foods; and foods rich in fat are hyperpalatable, which can lead to consumption in excess amounts.

The 11 criteria for substance use disorders as described in the DSM-5 can be applied to individuals with addiction to lipid-dense foods (especially trans and saturated fats). The interactions between fatty acids and specific receptors in taste bud cells elicit physiologic changes that are implicated in dietary fat preference through activation of the tongue-brain-gut axis (Sarkar et al., 2019).

The opioid and endocannabinoid systems play a crucial role in this process. The opioid system is connected to hedonic food properties and modulates the release of dopamine when food is consumed. The endocannabinoid system is more closely connected to homeostatic control of intake and positive feedback to the consumption of high-fat foods rather than carbohydrates or sugar (Blanco-Gandia et al., 2020).

SUCROSE AND HIGH-FRUCTOSE CORN SYRUP

Some 200 years ago, Americans ate about two pounds of sugar per year. Today, however, they consume on average more than 120 pounds per year. Some of this increase is thought to have occurred in the early 1990s when food makers began adding more sugar to improve their products’ flavor when simultaneously removing fat in order to label these products “fat free.” Since then, it has been found that added sugars in our food, mainly in the form of fructose, have contributed to high levels of obesity and chronic diseases such as diabetes and liver disease (Pfizer, 2022).

Sucrose, broadly known as granulated sugar, comes from cane or beets. It is made up of two molecules: glucose and fructose. The glucose molecule provides fuel and suppresses the hunger hormone ghrelin, which then stimulates leptin production. Leptin then tells the brain that we are full and decreases appetite. Fructose is a sugar found naturally in fruit, honey, and fruit juice. Unlike glucose, fructose does not trigger satiating hormones. While glucose is metabolized in every cell in the body, the fructose molecule is only metabolized by the liver.

Fructose corn syrup adds unnatural amounts of fructose to the diet, which the human body has not evolved to handle well. Fructose does not stimulate insulin secretion or enhance leptin production like glucose does. It also converts to fat more readily than any other sugars. Fructose has no effect on the hunger hormone ghrelin and can interfere with leptin levels, leading to overeating. High-fructose corn syrup (HFCS) is a highly processed syrup sweetener derived from cornstarch. The syrup is widely added to many kinds of processed foods, including soft drinks, breads and cereals, processed meats, dairy products, condiments and sauces, processed fruits and vegetables, crackers, candy, and jam and jellies.

HFCS increases appetite and contributes to diabetes, inflammation, and obesity. When sugar and HFCS are consumed to a specific threshold, the brain’s neurochemistry is altered. HFCS affects central appetite regulation by altering specific components of the endocannabinoid system. Sugar and HFCS have been implicated in food addiction because their intense sweetness elicits a dopamine rush in the brain that triggers cravings for more. Twenty minutes after drinking a soda containing HFCS, blood sugar spikes, causing an insulin burst. The liver responds by converting any sugar into fat. Forty-five minutes later, the body increases dopamine production, stimulating the pleasure centers of the brain. It has been demonstrated that the effects of sugar addiction, withdrawal, and relapse are similar to those of drugs of abuse (Mohiuddin, 2020).

CASEIN

Casein is a protein naturally found in milk and used in producing fast-food items, such as french fries, buns, milkshakes, creamy salad dressings, whipped toppings, and more. Over the last 30 years, casein has been used in foods to enhance physical properties such as whipping and thickening and to enhance nutritional value.

Casein in often called the “nicotine of fast food.” It naturally occurs in milk, but in fast food, it is transformed to a refined and concentrated form created by adding calcium hydrogen phosphate to concentrated milk solids. Casein is the addictive property in cheese.

Casein contains opiates, and as it is digested, it breaks apart to release tiny opiate molecules called casomorphins. One of these compounds has about one tenth the opiate strength of morphine. Casomorphins can attach to dopamine receptors, causing a dopamine “hit” of pleasure or reward. The addicting power of cheese, for example, may be caused by adding calcium hydrogen phosphate to remove water, lactose, and whey products, which then concentrates the casein. Because of the reward received from eating products containing casein, overconsumption is encouraged (Clark, 2021; Arakelyan, 2020).

PROCESSED FOODS CONTAINING CAFFEINE

The combination of sugar and caffeine in beverages raises the risk of being overweight. Children who drink one or more 12-ounce sweetened soft drink daily have a 60% higher chance of becoming obese. Young people consume the largest quantities of caffeinated sugar-sweetened beverages and have experienced the greatest relative gains in obesity. Evidence of the addictive properties of both caffeine and sugar have been documented, and abruptly stopping caffeine may cause withdrawal symptoms in those who consume a lot of it. A single energy drink may contain as much as 500 mg of caffeine, which is the same amount as in about 14 cans of soda.

Caffeine is also found in chocolate, coffee ice cream or frozen yogurt, and iced tea, which can contain as much sugar and caffeine as soda (Falbe et al., 2019; Morin, 2022).

Medications

Certain medications can cause individuals to gain weight. Described below are some medications that can affect the body’s metabolism and slow calorie burning, stimulate appetite, cause water retention, or alter how the body stores and absorbs sugars and other nutrients.

• Drugs for diabetes (e.g., insulin, thiazolidinediones, sulfonylureas)
• Antipsychotic drugs (e.g., haloperidol, clozapine, risperidone, olanzapine, quetiapine, lithium)
• Antidepressant drugs (e.g., amitriptyline, imipramine, paroxetine, escitalopram, citalopram, mirtazapine, sertraline)
• Drugs for epilepsy (e.g., valproate, divalproex, carbamazepine, gabapentin)
• Steroid hormone drugs (e.g., prednisone, birth control pills)
• Blood pressure–reducing drugs (e.g., beta-blockers)

It is important to note that not all medicines of these types cause weight gain. For example, metformin for diabetes and topiramate for seizures and migraines may cause weight loss instead of weight gain (URMC, 2022).

Physical Activity

Physical activity refers to any body movement that burns calories, whether for play or for work. Exercise, a subcategory of physical activity, refers to planned, structured, and repetitive activities with the goal of improving physical fitness and health.

Regular physical activity is a vital necessity for good health. Physical activity helps to reduce blood pressure; reduce risks for type 2 diabetes, heart attack, and stroke; relieve symptoms of depression and anxiety; and maintain a healthy weight.

Research has indicated that physical activity prevents obesity in the following ways:

• By increasing total energy expenditure, decreasing fat around the waist as well as total body fat, and slowing abdominal obesity development
• By building body mass through muscle-strengthening activities and thus increasing the energy the body burns even at rest
• By reducing depression and anxiety, which may boost motivation to maintain an exercise regimen
  (Harvard T.H. Chan, 2022c)

The “energy out” side of the energy balance equation has tilted severely toward weight gain. The more active people are, the more likely they are to maintain a steady weight. The more sedentary, the more they are likely to gain weight over time (PCSFN, 2021).

Globally, people are less active than they were in the past due to economic growth, technological advancements, and social changes. In just a generation, the number of students who walk and bike to school each day has declined dramatically, while the childhood obesity rate and physical inactivity have climbed.

The good news is that the number of Americans who engaged in physical activity rose steadily from 2010 to 2019, and the number of fitness centers and health clubs also experienced a near continual increase between 2009 and 2019. Statistics also indicate an increase in outdoor activities since 2008, with the most popular being running, jogging, and trail running (Lange, 2021).

Despite this increase in physical activity, however, recent statistics show that:

• Only 1 in 3 children are physically active every day.
• Less than 5% of adults participate in 30 minutes of physical activity each day.
• Only 35%–44% of adults 75 years or older are physically active, and only 28%º–34% of adults ages 65–74 are physically active.
• More than 80% of adults do not meet the guidelines for both aerobic and muscle-strengthening activity.
• More than 80% of adolescents do not get enough aerobic physical activity to meet the guidelines for youth.
• Children now spend more than seven and a half hours a day in front of a screen (e.g., TV, video games, computer).
• The average amount of time spent on sports, exercise, and recreation in the United States is 20 minutes per day.
  (RXResource, 2022; Lange, 2021)

Obesogenic Environment

An obesogenic environment is the sum of influences that the surroundings, opportunities, or conditions of life have on promoting obesity in individuals and populations. This includes the physical surroundings as well as the conditions in which an individual lives or works. These factors influence the development of a person or a group of persons and how they feel or function (Kaczynski et al., 2020).

BUILT ENVIRONMENT

The built environment underwent changes beginning early in the 20th century when motor vehicles began to take over the streets. As a result, many aspects of today’s built environment—housing, roads, walkways, population density, transportation, shops, parks, and public spaces—do not encourage walking, biking, or other physical activities. Many communities are built in ways that make it difficult or unsafe to be physically active. It may be hard for families to get to parks and recreation centers, and public transportation may not be available.

Zoning laws have separated residential, commercial, and industrial uses and have increased the distances between homes, jobs, and shops. Many towns and cities have become spread out along roads, making it necessary for people to drive just about everywhere. It has been hypothesized that this “urban sprawl” and lack of mixed land use are associated with overweight or obesity more than any other physical environmental factor (Lam et al., 2021).

Recreational and transport physical activity are driven by the features of the built environment. Physical activity is promoted by the built environment through walkable neighborhoods, presence of sidewalks, walking paths and bike paths, and recreational and sports infrastructure, including parks, pools, playgrounds, and sport clubs.

“SCREEN TIME”

Screens are ubiquitous in today’s environment, and almost everyone’s daily routine includes them, including children. Children ages 8–10 spend an average of six hours per day in front of a screen, kids ages 11–14 spend an average of nine hours per day in front of a screen, and youth ages 15–18 spend an average of seven and a half hours per day in front of a screen (OSF HealthCare, 2020). It has been shown that screen time greater than two hours per day is associated with increased rates of obesity and that teens who spend five hours or more watching TV are five times more likely to become overweight. This increased risk for obesity occurs because:

• Screen time is a sedentary activity (i.e., time spent not being physically active).
• Screen time, particularly within 4 hours of bedtime, leads to poor sleep.
• TV commercials and other screen ads can lead to unhealthy food choices.
• Screen time is associated with “mindless” eating behaviors and intake of sugar-sweetened beverages.

More than two hours of daily screen time is also associated with decreased executive function, decreased inhibition, increased impulsivity and inattention, cognitive changes associated with ADHD, binge eating, and loss of eating behavior control (Bleistein, 2022; NIH, 2021b).

FOOD AND NUTRITION ENVIRONMENT

What people choose to eat plays a large role in determining risk of overweight or obesity. People’s choices are shaped by the world in which they live. In the United States, physical and social surroundings influence what one eats and can make it difficult to choose healthy over unhealthy foods. The food and nutrition environment includes all the factors involved in the ability to access foods: the availability of foods, culture and ethnicity, parenting, marketing, and other significant factors.

Food Availability and Access

Availability and access to foods that support healthy eating patterns is a major issue in the domain of neighborhood/built environment, and studies show there is a relationship between access to food and rates of obesity. People living in neighborhoods with fewer fresh produce sources and plentiful fast-food restaurants and convenience stores are at a higher risk for obesity compared to at-risk rates found in areas with increased access and higher density of full-service restaurants and grocery stores.

In addition, the food environment surrounding schools has been found to impact children and adolescents. Students whose schools were within a half mile of a fast-food restaurant were more likely to be overweight or obese than students whose schools were farther away from such restaurants.

Transportation and distance impact low-income and rural communities. Individuals without a vehicle or access to convenient public transportation, or who do not have food venues with healthy choices within walking distance, have limited access to foods that support healthy eating patterns.

Studies have provided evidence that neighborhoods with a high proportion of low-income or minority residents have fewer supermarkets but more convenience stores relative to more advantaged areas. People in predominantly Black low-income neighborhoods live an average of 1.1 miles farther from the closest supermarket than people living in predominantly White low-income neighborhoods.

Another barrier to accessibility of healthy food choices is the “food desert,” where food sources are lacking or limited. These often occur in low-income areas that are more likely to have a high share of convenience stores and small food markets, which tend to carry foods of lower nutritional quality compared to large chain supermarkets.

Affordability also influences access to nutritious foods. Research has shown that low-income groups tend to rely on foods that are less expensive and convenient to access, but are low in nutrient density. In those areas without supermarkets, people face higher prices for many healthy foods because small stores typically charge more for foods such as fresh produce. Conversely, studies have shown that price reductions for healthier foods contribute to increased purchasing of these foods (ODPHP, 2022).

An estimated 1 in 8 Americans lack access to enough food. Children from food-insecure households have been found to have higher BMI and waist circumference and greater odds of being classified as overweight or obese. They consume more sugar from sugar-sweetened beverages and less frequently eat breakfast and dinner with family compared to children from food-secure households.

Those in food-insecure homes obtain a higher portion of their energy needs from fat and carbohydrates; eat less protein and fewer fruits and vegetables; and eat irregular meals or skip breakfast. Girls in food insecure homes have a greater risk for weight gain and overweight than boys. Evidence supports a link between food insecurity, stress, and compromised mental health among females in high-income countries (Au et al., 2019).

Culture and Ethnicity

Culture affects the circumstances in which we eat, the types of food we eat, whom we eat with, the times of the day that we eat, and the quantities we eat. Food is culture and presents an everyday actualization of one’s ethnic identity. Food contains childhood memories, religious meaning, and connections to one’s origins.

Ethnic minority groups living in developed countries have higher rates of obesity. In the United States, they initially have lower BMI than U.S.-born individuals. However, this advantage erodes over time as they become acculturated, adhering less to traditional diets and engaging in less physical activity.

Social isolation, depression, and stress related to immigration influence the development of obesity. Among some populations, eating is also a culturally sanctioned form of stress reduction, leading to overconsumption.

Obesity disproportionately affects ethnic minority children. Research has found acculturation to be linked with rapid weight gain in infancy due to more acculturated mothers formula-feeding their infants rather than breastfeeding them. And among many cultures, there is the cultural belief that a chubby baby is proof of good parenting.

Parental feeding practices that may contribute to obesity include urging children to eat until they are “stuffed” or pressuring children to “clean” their plates. Conversely, some parents closely monitor their children’s food intake, restrict unhealthy food and snacks, and require scheduled meal times, which are protective factors against obesity.

Another protective influence commonly found among some cultures and ethnic groups is the theme of family, specifically family meals. Having such meals as infrequently as one to two times a week has been found to be protective against overweight and obesity. Another protective influence is parents who express disappointment and frustration that their children prefer processed, fast food, and continue cooking traditional foods despite their children’s preferences.

According to some research, the most prominent belief about physical activity across ethnic groups is that it should simply be a part of daily life as it was in their country of origin. This research found that most ethnic minority families valued sedentary activities, especially watching television. Migrant farmworkers often believed that too much physical activity can be unhealthy. Every ethnic group studied mentioned weather as a barrier to physical activity; it was either too hot or too cold (Gale, 2019; Chatham & Mixer, 2019).

Parenting Style

Parental feeding style affects children’s eating behaviors. Three negative feeding styles have been found to be linked to overweight and obesity. These include:

• Authoritarian style makes high demands and shows low responsiveness to the child’s wishes. It involves low support for child autonomy in eating and shows little trust in a child’s hunger/satiety signs. Example: A child cleans her plate even though she is full in order to please her parents. Effect: Ignoring a child’s appetite may lead to loss of ability to regulate internal hunger and fullness cues.
• Permissive/indulgent style involves making few demands, having very few rules, catering to the child’s food preferences, and providing low control. This style is often linked with high intake of sweets and high-fat foods. Example: A child has eaten a cookie for dessert and demands more. The parent’s response is, “Okay, you can have as many as you want.” Rewarding is another example of an indulgent style. Example: A parent tells a child at the dinner table, “If you eat all your broccoli, I’ll take you out for ice cream.” Effect: The child tends to become out of touch with what and how much to eat.
• Uninvolved/neglectful style includes low demands and low responsiveness to the child, lack of support, and lack of structure and control. Parents show low sensitivity to their child’s needs and fail to plan and prepare food in a regular, reliable manner, considering food and feeding to be a low priority. Example: A child is hungry, but there is no response from the parent to provide a regular meal because they consider food and feeding to be a low priority, they have not gone shopping, and therefore no one prepares a meal. Effect: The child becomes preoccupied with food, worried, and anxious, causing over- or under-eating.

A positive parental feeding style is authoritative, meaning that it makes high demands but is also highly responsive to the child. This style of feeding includes:

• Age-appropriate monitoring of eating and food purchasing behaviors
• Appropriate portion sizing
• Limiting snacking
• Allowing the child to contribute ideas for meals and snacks and showing respect for the child’s food choices
• Modeling healthy eating behaviors
• Establishing food routines, an appropriate feeding environment, and regular family meals
• Avoiding the purchase of unhealthy foods and dining at unhealthy restaurants
  (Chen, 2020; Alahmadi, 2019)

WORK ENVIRONMENT AND OCCUPATION

The type, hours, and place of work have been recognized as sources of adverse environmental exposures that can lead to overweight and obesity.

• Long working hours are associated with risk of a shift from a normal weight to overweight but not from overweight to obese. Mechanisms may include lack of exercise, unhealthy diet, and extended periods of sitting. People working long hours may not have the resources, time, or remaining energy to engage in a healthy lifestyle (Virtanen et al., 2020).
• Rotating shift work has been identified as a risk factor for overweight or obesity. Shift workers have 1.5 times higher odds of being overweight/obese. The more years of exposure increases the risk, with the strongest relationship among those working shifts for more than 20 years (Hulsegge et al., 2020).
• Night shift work influences BMI and the risk of obesity due to changes in metabolism, insulin sensitivity, and appetite, and a reduction in energy for physical activity secondary to disrupted or insufficient sleep. An unhealthy diet and irregular eating patterns are also linked to weight gain and risk of obesity (Myers et al., 2021).
• Blue-collar workers (which may include machine operators, construction workers, public safety workers, and sales/office workers) have a higher risk of obesity. This may be due to a variety of mechanisms, such as low access to and participation in wellness programs; exposure to environmental hazards; and adverse working conditions, such as a “fire station eating culture,” answering night calls and related sleep interruption, sedentary work, and stressful supervisor leadership (Myers et al., 2021).
• Stress among those with low control and low autonomy in their work can relate to anxiety in relation to job insecurity. This stress often leads to making “comfort food” choices and could affect behaviors such as alcohol consumption and sedentary leisure activities. It also may result in modification of endocrine factors related to weight gain (Elhussiney & Mahfouz, 2020).

FOOD MARKETING

Advertisements for unhealthy foods are everywhere, and marketing to young people to “hook” them on food manufacturers’ products presents a very profitable investment. Food marketing is highly effective at stimulating and reinforcing food consumption, particularly for energy-dense foods. To date, food advertising almost exclusively promotes ultraprocessed food and beverage products high in fats, sugars, and sodium.

Studies have found that one effect of unhealthy food marketing is increased saliva secretion and uptake of appetite-stimulating hormones such as ghrelin and insulin. This leads to increased appetite and increased food intake that then reinforces reactivity to food cues. This reaction to food cues is known as the incentive-sensitization process (Folkvord & Hermans, 2020).

Children are constantly exposed to advertisements (just as are adults), coming into contact with ads in many different ways every day through television and product placement in movies, websites, games, at supermarkets, and even in schools.

A study of the most popular YouTube videos for children and the advertisements shown before and during those videos found that 72% of ads were for food and beverages, with over half of those for foods eaten for fun rather than for nutritional value. Another study of children 4 to 6 years of age found that they believed a food product packaged with a cartoon character or collectible toy tasted better than the same food in a package without the character or toy.

Researchers have calculated that the average child ages 5 to 8, who watches about 80 minutes of television each day, is exposed to at least 827 advertisements on television each year. Only 16 countries have regulations on food marketing to children, and the United States is not one of them (Barber, 2020; OEH, 2021).

SLEEP DEPRIVATION

Sleep deprivation or deficiency is a state in which the person cannot make up lost hours of sleep, which increases the risk of obesity and other chronic health conditions. A nurses’ health study found an association between those who slept the least (5 hours or less a night) and those having the highest BMI and greatest weight gain. One reason may be a disruption in appetite and satiety hormones. With lack of sleep, ghrelin levels rise, while leptin levels drop. This can result in a higher calorie consumption and trigger the “reward” area in the brain to increase a preference for foods high in fat and carbohydrates.

Contrary to expectations, however, due to fatigue, sleep deprivation does not result in any increases in physical activity. Less physical activity combined with increased calorie intake increases obesity risk. Other effects include increased fat storage in the abdominal area, higher body mass index, poorer-quality diet, and decreased insulin sensitivity (Harvard T.H. Chan, 2022c).

Short sleep duration is a risk factor or marker of the development of obesity in infants, children, and adolescents. National Sleep Foundation guidelines are given in the table below.

RECOMMENDED SLEEP

Age	Duration (hours)
(NSF, 2020a)
Newborns (0–3 months)	14–17
Infants (4–11 months)	12–16 (including naps)
Toddlers (1–2 years)	11–14
Preschool-aged children (3–5 years)	10–13
School-aged children (6–13 years)	9–11
Teenagers (14–17 years)	8–10
Adults (18–64 years)	7–9
Older adults (65 and over)	7–8

CIRCADIAN MISALIGNMENT

The circadian rhythm is the natural cycle of physical, mental, and behavior changes a body goes through over a 24-hour period of time. These rhythms are mostly the result of exposure to light and darkness, and they affect sleep, body temperature, hormone production, appetite, and other body functions. The circadian cycle can be disrupted by such things as:

• Shift work
• Inconsistent sleep and wake times
• Lack of bedtime routine
• Insufficient light exposure during the day and bright light exposure at night (blue light having the strongest impact)
• Drinking caffeine or alcohol too close to bedtime
• Using smartphones/computers late at night
• Jet lag
• Some medications (e.g., corticosteroids, beta blockers)

Studies show that mistimed eating, such as eating at night when the body should be sleeping, can also alter the circadian rhythm of various tissues. Metabolically active, insulin-sensitive tissues, such as the liver and adipose tissue, are particularly affected. Eating out of sync with the internal clock increases the risk of obesity, metabolic syndrome, and type 2 diabetes (Tuvia et al., 2021; NIH, 2021c; NSF, 2020b).