Version May 2024
INTRODUCTION — Obesity is a complex disease reflecting the interactions of environmental influences (eg, more calorically dense food and increasingly sedentary lifestyles) with multiple known obesity-risk genetic allelic variants of variable effect sizes [1-4]. These includes severe, usually early-onset obesity caused by single-gene mutations with distinctive phenotypes, the more common gene mutations associated with increased risks of weight gain but an overall smaller effect size, and obesity caused by various diseases in subjects in whom obesity would otherwise not occur [1]. The physiology and pathophysiology of obesity reflect the interactions of genes predisposing to or opposing weight gain and its comorbidities with an increasingly obesogenic environment (figure 1).
This topic will review the types of obesity caused by specific allelic variants, the genetic susceptibility to obesity, and their contributions to the pathogenetic mechanisms that regulate total body fat content and regional fat distribution.
An additional discussion of causes of and contributors to obesity in adults can be found elsewhere. (See "Obesity in adults: Etiologies and risk factors".)
HERITABLE FACTORS — Studies of adiposity between twins, adoptees, and their parents (biological versus adoptive), and within families, all suggest the existence of genetic factors in humans with obesity [5,6]. The heritability of adiposity estimated from twin studies is high, ranging from 40 to 75 percent [7], with only slightly lower values in twins raised apart compared with those raised together. Similarly, in adoptees, the body mass index (BMI) correlates better with that of their biologic parents than their adoptive parents. Over 500 adiposity- or adiposity-related trait genetic loci have been identified. In addition to BMI, responses to overfeeding and underfeeding, energy expenditure, food choices, hunger, and satiation have all been shown to be significantly heritable [7-12].
Common (multifactorial) obesity — Common (multifactorial) obesity is polygenic and reflects the cumulative interactions of multiple genetic loci favoring body adiposity with the environment. Body adiposity is heritable, but the genes that contribute to the more common forms of obesity have been a challenge to identify. However, genomic analyses have yielded information on allelic variants associated with obesity.
●In a combined meta-analysis including 82 genome-wide association studies (GWAS) and 43 metabochip studies in nearly 340,000 individuals, 97 loci associated with BMI were identified [13]. These loci account for approximately 2.7 percent of the variation in BMI; the authors estimate that as much as 21 percent of BMI variation can be accounted for by the most common allelic variants.
●Over 50 genetic loci have been associated with waist-to-hip ratios (adjusted for BMI) and demonstrate sexual dimorphism, which is often expressed in adipose tissue [14-22]. The relationship of BMI with a number of genes is shown in the figure (figure 2). In general, BMI-associated loci tend to be related to energy homeostatic pathways in the brain, while body fat-distribution associated loci tend to involve pathways regulating adipocyte biology [7].
Environmental factors appear to modify the genetic associations with BMI. In an observational study of almost 9000 adults aged ≥50 years, the magnitude of association between BMI and a polygenic risk score (a weighted sum of 29 single nucleotide polymorphisms [SNPs]) was higher in more recent birth cohorts compared with the earlier birth cohorts [23]. The difference is believed to be related to the duration of exposure to an increasingly "obesogenic" environment: the lifestyle transformation that began in the late 1970s, such as dietary changes with an increased food and sugar-sweetened beverage intake and reduction in regular physical activity. Younger cohorts were exposed to this environment at an earlier age, while older cohorts were not exposed until later in life.
Fat mass and obesity (FTO) gene variants — Among the genes identified by GWAS, the FTO (fat mass- and obesity-associated) gene on chromosome 16 has the strongest genetic association with obesity [15,24]. For example, SNP variants in the first intron of FTO on 16q12.2 are noteworthy among common obesity-risk alleles for their frequency (approximately 70 percent of all people are heterozygous or homozygous for an obesity-risk FTO SNP) and potency (1.3 to 1.7 times increased obesity risk in adults) [15]. A specific variant predisposes to type 2 diabetes through an effect on BMI [15], while others may independently increase diabetes risk via effects in other tissues [25]. In one study, among 13 European cohorts, 16 percent of adults were homozygous for the risk allele and weighed, on average, 3 kg more than those without the risk allele [15]. Both studies found an approximate 1.5-fold increase in the risk of obesity with the inherited risk genotype, which was seen in both children and adults. Several reports suggest that the at-risk FTO haplotype may account for up to 15 to 20 percent of common obesity [15,24,26].
The mechanisms of the association between FTO variants and obesity are unclear. Most studies indicate that the primary effects of obesity-risk FTO SNPs are to increase energy intake [27]. However, a noncoding causal variant in FTO has been identified that changes the function of adipocytes from energy utilization (beige fat) to energy storage (white fat) and decreases mitochondrial thermogenesis fivefold [28]. In studies using genetically engineered mice, when the effect of this variant was blocked, thermogenesis increased and no weight occurred despite consumption of a high-fat diet. In human adipocytes, blocking the gene's effect also increased energy utilization. This observation has important implications for potential new anti-obesity drugs. FTO is also an example of genetic and environmental interactions; SNPs’ effects on adiposity is influenced by physical activity as well as dietary macronutrient composition [29].
MONOGENIC FORMS OF OBESITY — Early-onset severe obesity is more likely be predominantly genetic in origin (table 1). In particular, the monogenic forms of obesity should be considered in the evaluation of adults or children with a lifetime history of obesity (table 2). In such patients, the identification of certain genetic mutations may be significant, as targeted therapies may be appropriate as a part of treatment. As an example, setmelanotide, a melanocortin 4 receptor agonist is available for the treatment of obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), leptin receptor gene (LEPR) deficiency, or Bardet-Biedl syndrome confirmed by genetic testing [30]. (See 'Leptin' below and 'Prohormone convertase (1/3)' below and 'Proopiomelanocortin' below and 'Bardet-Biedl syndrome' below.)
Prader-Willi syndrome — The Prader-Willi syndrome is a neurodegenerative disorder that is caused by genetic abnormalities of the long arm of chromosome 15 (q11-13). The majority of patients have a deletion of paternal DNA in this region; most of the remainder have two copies of maternal chromosome 15 (uniparental disomy) [31,32]. The key genetic material usually lacking is the SNRPN gene, which codes for a small nuclear ribonucleoprotein thought to be involved in imprinting genes from both parents. (See "Prader-Willi syndrome: Clinical features and diagnosis" and "Genomic disorders: An overview", section on 'Disease mechanisms' and "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Parent-of-origin effects (imprinting)'.)
Affected infants have poor muscle tone and feed poorly at birth. As they grow, their appetite becomes voracious and they go on to develop obesity, behavior problems (eg, irritability, tantrums), delayed development, short stature, and, later, hypogonadotropic hypogonadism. The clinical presentation, diagnosis, and management of patients with Prader-Willi syndrome is reviewed in detail elsewhere. (See "Prader-Willi syndrome: Management".)
Bardet-Biedl syndrome — The Bardet-Biedl syndrome is an autosomal recessive disorder characterized by obesity and several other abnormalities, including microorchidism in men, intellectual disability, retinal dystrophy, polydactyly, renal malformations (particularly calyceal abnormalities), and polyuria and polydipsia [33].
Mutations in at least 15 genes have been described in patients with this syndrome [34]. Disordered function of the primary cilia may be a fundamental defect in this syndrome [35]. Setmelanotide, a melanocortin receptor agonist, is available for the management of obesity in individuals ≥6 years of age with Bardet-Biedl syndrome [30].
Leptin — Leptin is a peptide hormone that reflects both energy stores (predominantly fat) and energy balance (weight loss or maintenance). It is produced in fat cells, the placenta, and, to a lesser degree, the gut [36]. Leptin binds to leptin receptors on the surface of neurons in the hypothalamus to modulate food intake and energy balance. Sensitivity to leptin is modulated by changes in energy balance (exogenous leptin is less effective during weight loss than maintenance of reduced weight) and energy stores (exogenous leptin is less effective at usual weight than during maintenance of reduced weight).
The LEP gene codes for leptin [37]. Mutations of the LEP gene or its receptor are rare causes of severe, early onset obesity [2,38,39]. These congenital disorders of leptin deficiency and dysfunction are autosomal recessive conditions characterized by severe, early onset obesity, hyperphagia, hypometabolism, delayed puberty, and glucose intolerance [39].
Pathogenic variants of the LEP gene can cause obesity disorders in humans via several mechanisms.
●Autosomal recessive loss-of-function mutations in the LEP gene can cause a lack of leptin synthesis or secretion. In these disorders, circulating leptin levels are low to undetectable. Over 20 distinct variants have been identified [40].
●Another family of mutations in the LEP gene results in a leptin variant that either fails to bind to the leptin receptor (LEPR) or binds abnormally and acts as a competitive antagonist. In these conditions, circulating leptin levels are high. Case reports suggest that treating these patients with supraphysiologic doses of leptin can overcome this competitive antagonism and result in resumption of changes in eating behavior and weight loss [39,41].
●Mutations in the LEPR gene can produce leptin receptors that either do not bind leptin or do not signal normally. In these conditions, circulating leptin levels are high but physiologically appropriate for the patient's level of obesity [42,43]. Over 35 variants of the leptin receptor gene have been described.
Prohormone convertase (1/3) — Congenital deficiency of the PCSK1 gene, which encodes proprotein convertase 1/3, causes a severe multihormonal disorder marked by early-onset obesity. A systematic review from the Human Genome Epidemiology (HuGE) project demonstrated that three single nucleotide polymorphisms (SNPs rs6232, rs6234, and rs6235) in PCSK1 are associated with obesity in some populations [44].
Melanocortin-4 receptor — Congenital deficiency of melanocortin-4 receptor (MC4R) is associated with early-onset obesity and taller-than-average height. Evidence from one patient with a homozygous mutation in the receptor suggests that MC4R mediates most of the anorectic effects of leptin in early childhood but not the effect of leptin on linear growth and other endocrine axes [45,46]. In a genome-wide association study (GWAS) of 16,000 individuals (and confirmed in additional populations), common variants near the MC4R were associated with increasing body mass index (BMI) in both children and adults [16]. Heterozygous mutations in this gene are reported to be the most common monogenic cause of severe obesity in childhood in some [43,45] but not all [47] studies.
Proopiomelanocortin — Melanocyte-stimulating hormone (MSH) transmits the anorexic effect of leptin through the MC4R (see 'Melanocortin-4 receptor' above). Individuals with homozygous or compound heterozygous mutations in the gene encoding proopiomelanocortin (POMC) present with adrenal crisis in neonatal life due to corticotropin (ACTH) deficiency. ACTH is produced from POMC in the hypothalamus, as is alpha-MSH, an important factor for reducing food intake [48]. Therefore, patients with these POMC mutations also have early-onset obesity due to severe hyperphagia. Setmelanotide, a melanocortin receptor agonist, have been tested in patients with POMC deficiency with some success [49,50] and is available for treatment [51,52].
GNAS — Certain mutations in GNAS (guanine nucleotide binding protein [G-protein], alpha stimulating) are associated with Albright's hereditary osteodystrophy (ie, Type 1 pseudohypoparathyroidism), characterized by early-onset obesity, with or without developmental delay, short stature, brachydactyly, subcutaneous ossifications, pseudohypoparathyroidism (hypocalcemia, PTH resistance), and thyrotropin resistance (elevated thyroid-stimulating hormone [TSH] with normal or low free thyroxine [fT4]). Obesity is likely mediated by disrupted MC4R signaling (table 1) [53]. This is reviewed in detail elsewhere. (See "Etiology of hypocalcemia in infants and children", section on 'Type 1 PHP'.)
Other — Additional genes can also play a significant role in the development of obesity. Two of these are brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor tropomyosin-related kinase B (TrkB). Children with mutations have severe hyperphagia and obesity, impaired short-term memory, hyperactivity, and learning disability [54]. Patients with Wilms tumor-aniridia syndrome (WAGR) have a subset of deletions on chromosome 11p.12, encompassing the BDNF locus. These patients also have early-onset obesity [55] (see "Presentation, diagnosis, and staging of Wilms tumor", section on 'WAGR syndrome'). The second gene is single-minded 1 (SIM1) [56]; patients deficient in SIM1 are hyperphagic with evidence of autonomic dysfunction, which is also seen in MC4R deficiency, suggesting that some aspects of the clinical phenotype can be explained by altered melanocortin signaling. Carriers of the SIM1 mutation may have speech and language delay and exhibit neurobehavioral abnormalities including autistic types of behavior. These features can be seen in Prader-Willi syndrome but are not recognized features of MC4R deficiency.
PHYSIOLOGY AND PATHOPHYSIOLOGY OF OBESITY
Genetics and physiology — Almost every aspect of the behaviors and the metabolism affecting weight gain, and the responses to negative and positive energy balance, are heritable. Various assessments of eating behavior (food choice, caloric intake, etc) have estimated the genetic contribution to the variation in energy intake at between 20 and 50 percent [57].
The regulation of body weight — Energy intake and expenditure are remarkably coupled to regulate body weight in the face of wide daily fluctuations in diet and physical activity. This “coupling,” which opposes ongoing weight perturbation, is evident in the surprisingly small, average yearly weight gain by adults in the United States (0.5 to 1.5 kg/year, or about 4000 kcal of stored energy). Since adults in the United States consume, on average, approximately 900,000 kcal/year, this small weight gain represents a (largely involuntary) positive energy balance of approximately 0.4 percent. What many consider “normal” age-related weight gain actually reflects a well-coordinated system to prevent major changes in energy stores. If energy intake and output were not coupled, then increasing or decreasing energy expenditure by as little as 50 kcal/day (roughly equivalent to the energy expended in walking 0.5 to 0.75 km) without changing energy intake would result in a net energy imbalance of 25,000 kcal (about 4.5 kg of body weight) over one year.
Resistance to weight loss and maintenance of reduced weight — Among individuals with overweight or obesity, the likelihood of losing and sustaining greater than 10 percent of body weight (without bariatric surgery) has remained at about 15 percent over the past several decades [58]. The metabolic, neuroendocrine, autonomic, and behavioral responses to active weight loss and to maintenance of weight loss are distinct.
In most studies, lifestyle, pharmacologic, or surgical treatments of obesity result in weight loss of varying slope for about six to nine months, followed by a plateau period, with a subsequent period of weight regain [59-64]. This observation that weight loss generally occurs over a limited period of time, whereas maintenance of reduced weight will require, in most cases, a lifetime of diligent attention, suggests that efforts to lose more weight should be concentrated on the relatively brief weight loss period. As described below, the “normal” coupling of energy expenditure and intake at the usual weight (eg, increased energy expenditure leads to increased energy intake) is lost after weight loss; such individuals become both hypometabolic and hyperphagic. Therefore, efforts to sustain weight loss should be designed to reverse or counterbalance the disproportionately decreased energy expenditure and increased appetite that occurs. These differences also suggest different therapeutic approaches may be necessary for weight loss and maintenance of reduced weight [65].
With weight loss and a reduction in fat mass, there is an accompanying reduction in circulating leptin levels which alters efferent signals from adipocytes, the gut, and endocrine organs. These physiologic responses to the maintenance of reduced weight can be mitigated or reversed by the administration of exogenous leptin and may account for the physiologic basis for the high recidivism after successful weight loss [66]. For individuals who successfully lose weight, a lifetime of committed effort to decreased energy intake and increased expenditure is required to sustain the reduced weight; the energy balance required to maintain their weight is in excess of the levels required in those who are “naturally” at the same weight. There is a strong underlying genetic basis for many of these responses as evidenced by studies of identical twin pairs to over- and underfeeding [11,12]. The net result of these homeostatic changes are changes in skeletal muscle (increased work efficiency), neuronal signaling related to energy intake (increased food reward and impulsivity, delayed satiation), and neuroendocrine function (decreased circulating concentrations of bioactive thyroid hormones and leptin). In large, longitudinal weight loss studies, different phenotypes and genotypes are correlated with weight loss or weight regain [67,68]. However, most of these genotypes are not common predictors of both weight loss and weight regain. The effects of weight loss and maintenance of reduced weight on energy homeostatic systems that favor weight regain and the greater responsiveness to leptin repletion are different (table 3). Taken together, the distinct genotypes, phenotypes, and therapeutic responses to leptin indicate that different mechanisms are relevant to losing weight versus keeping it off.
Physiological processes affecting energy balance — The control of energy stores is achieved through coordinated regulation of energy intake and expenditure in response to signals from adipose, gastrointestinal, and other endocrine tissues and is integrated by the liver and elements of the central nervous system, including regulatory (hypothalamus, brain stem), hedonic/emotional (amygdala, ventral striatum, orbitofrontal cortex) and executive/restraint (cingulate, middle frontal, supramarginal, precentral, and fusiform gyri) centers. The brain processes efferent information and initiates metabolic and cognitive responses according to whether food is needed and, if so, when and where to obtain it. The brain also initiates signals that alter the metabolism of nutrients as well as the cognitive processes involved in food seeking.
Energy intake — The regulation of energy intake is essential in active weight loss and maintenance of weight loss, and there are physiologic alterations that affect this process. In studies of the National Weight Control Registry, successful maintenance of reduced body weight is associated with extremely high levels of dietary restraint [69]. Similarly, in the Look AHEAD and Diabetes Prevention Trials (DPT), dietary restraint has also been positively associated with the degree of weight loss and negatively associated with the rate of weight regain during a lifestyle intervention program among adults with type 2 diabetes or pre-diabetes [70-74].
Among weight-reduced individuals, functional magnetic resonance imaging (fMRI) demonstrates increased signalling in areas related to reward (mainly the orbitofrontal cortex) and decreased signalling in the hypothalamus and brain areas related to restraint (mainly the prefrontal cortex) in response to visual food cues [75]. These changes indicate increased hunger, delayed satiation, and decreased perception of fullness. In another study, individuals were put on a very low-calorie diet for 10 weeks and then followed throughout the remainder of the year, during which time a variety of measures were taken [76]. Hunger ratings initially fell but rebounded after the very low-calorie diet. The gastrointestinal peptide ghrelin, which stimulates appetite, increased after diet-induced weight loss; there was a decrease in other circulating mediators that inhibit intake (eg, leptin, peptide YY, cholecystokinin [CCK], pancreatic polypeptide). Further, in other studies, the changes promoting increased energy intake during and after weight loss can be partially reversed by repletion with the adipocyte-derived hormone leptin [77,78].
Energy expenditure — Twenty-four-hour total energy expenditure (TEE) consists of three basic components [79]:
●Resting energy expenditure – The largest component is resting energy expenditure (REE), which accounts for about 60 percent of TEE and reflects cardiorespiratory work and the work of maintaining transmembrane ion gradients at rest.
●Non-resting energy expenditure – Approximately 30 percent of TEE is due to energy expended in physical activity and is known as non-resting energy expenditure (NREE) or activity energy expenditure (AEE).
●Thermic effect of feeding – The thermic effect of feeding (TEF), otherwise known as diet-induced thermogenesis (DIT), constitutes about 10 percent of TEE.
Maintenance of a 10 percent or greater reduction in body weight (by any individual, lean or obese) is accompanied by a highly variable (+5 to -35 percent) decline in total energy expenditure that is approximately 300 to 400 kcal/day below that predicted by the new body weight and composition; this “hypometabolism” persists in individuals successfully maintaining reduced weight for a long period of time [80,81]. A reduction in NREE accounts for the majority (approximately 150 to 250 kcal/day) of the decline in energy expenditure; the remainder is accounted for by declines in REE. Additional weight loss (>10 percent) results in further declines in NREE but not REE [82]. The decline in NREE is due mainly to an approximately 20 percent increase in skeletal muscle chemomechanical contractile efficiency during low levels of energy expenditure [83]; this may have implications for the type of exercise that might be most beneficial in weight loss and/or sustaining weight loss. (See "Obesity in adults: Behavioral therapy", section on 'Maintenance of weight loss' and "Obesity in adults: Role of physical activity and exercise".)
Of note, the hypometabolism following weight loss can be partially reversed by leptin repletion, whereas energy expenditure during weight loss appears to be unaffected [66,78].
Gut microbiome — The gut microbiome consists of approximately 100 trillion microbes that can affect the absorption and digestibility of ingested calories. Based predominantly on rodent studies demonstrating the effects of gut microbial transplant on adiposity, the composition of the gut microbiota has been hypothesized to affect both adiposity as well as the response to dietary intervention in humans. As an example, individuals with a higher versus lower gut Prevotella to Bacteroides ratio lost significantly more weight on a calorie-restricted, high-fiber diet [84]. However, there is little evidence at present to support a causal versus associative relationship between the microbiome and obesity. For example, individuals with obesity develop a microbiome similar to that of lean individuals after losing weight (with a higher Firmicutes to Bacteroidetes ratio), which is reversed with weight regain [85]. While there is some evidence that the gut microbiome may affect the risk of adiposity-related comorbidities such as type 2 diabetes and inflammation, there is no evidence that manipulation of the gut microbiome will be an effective obesity treatment [86].
Autonomic nervous system — Weight loss and maintenance of reduced weight provoke declines in sympathetic nervous system activity and increases in parasympathetic nervous system activity. These changes combine to reduce both REE and NREE. Decreased catecholamine excretion also inhibits the release of bioactive thyroid hormones. This decline in sympathetic nervous system tone is at least partially reversed by leptin repletion during maintenance of reduced weight but not during weight loss (table 3) [66,78]. Autonomic nervous system tone may also modulate feeding behavior by effects on gut peptides such as CCK, glucagon-like peptide 1 (GLP-1), nesfatin 1, peptide YY (PYY), and pancreatic polypeptide [66,77,87,88].
Neuroendocrine systems — Weight loss and maintenance of reduced weight may both be associated with a “sick euthyroid” profile characterized by decreased circulating concentrations of bioactive thyroid hormones (triiodothyronine [T3] and thyroxine [T4]) and TSH, and increased circulating concentrations of the bioinactive reverse T3 (figure 3 and table 3) [89,90]. Additional studies suggest that thyroid hormone repletion after, but not during, weight loss may reverse the increased muscle efficiency that occurs as a result of weight loss [91]. Administration of leptin to weight-reduced individuals “reverses” the decline in T3 and T4 but not TSH.
Afferent signals from fat, the gastrointestinal tract, and endocrine organs — The afferent signals that carry messages about nutrient surpluses or deficits include neural circuits, circulating hormones, and nutrients themselves.
Adipose tissue — Leptin, produced primarily by adipocytes, is the most potent afferent signal regulating body energy stores. During a period of stable weight, circulating concentrations of leptin are proportional to fat mass, with only a small decrease in this ratio during maintenance of reduced weight. During weight loss (negative energy balance), circulating leptin concentrations are approximately 25 to 50 percent lower than during weight maintenance at the same weight. Leptin repletion following weight loss reverses many of the metabolic and behavioral changes that oppose the maintenance of a reduced weight, while leptin administration during weight loss has only a small effect on appetite [66]. Taken together these data suggest that both leptin secretion and action are sensitive to both energy stores (fat mass) and energy balance (weight loss).
Gut hormones — Several gut hormones may be involved in regulation of food intake, including ghrelin, GLP-1, CCK, enterostatin, and peptide YY 3-36. All of these, except ghrelin, inhibit food intake. (See "Overview of gastrointestinal peptides in health and disease".)
Stimulators of food intake
●Ghrelin - Ghrelin, a peptide produced in the stomach and duodenum, is an endogenous ligand for the growth hormone (GH) secretagogue receptor. This peptide has two major effects; it stimulates GH secretion and increases food intake [92-95]. Serum concentrations increase in anticipation of a meal and are suppressed by food ingestion and gastric distention. In one study, ghrelin increased GH secretion and food intake in healthy men [96].
Serum ghrelin concentrations increase after diet-induced weight loss, suggesting it plays a role in the compensatory changes in appetite and energy expenditure that make maintenance of diet-induced weight loss difficult [92]. A similar increase in serum ghrelin occurs after exercise-induced weight loss (with no change in caloric intake) [97]. By contrast, in one study, gastric bypass was associated with low serum ghrelin concentrations, raising the possibility that its absence plays a role in the prolonged weight loss that often occurs after bypass [92]. However, not all studies have reported low serum ghrelin concentrations after gastric bypass [98] or after laparoscopic gastric banding [99]. Ghrelin, and the effects of bariatric surgery on ghrelin levels are reviewed in detail elsewhere. (See "Bariatric procedures for the management of severe obesity: Descriptions" and "Ghrelin", section on 'Obesity' and "Ghrelin", section on 'Gastric bypass surgery'.)
●Neuropeptide Y - Neuropeptide Y is one of the most potent stimulators of food intake known. It appears to predominantly stimulate carbohydrate intake. The physiology of neuropeptide Y reviewed in detail elsewhere. (See "Pancreatic polypeptide, peptide YY, and neuropeptide Y".)
●Others - Melanin-concentrating hormone, GH-releasing hormone, norepinephrine, and orexin-A and orexin-B (also called hypocretin) stimulate centrally mediated drive for food intake. Like neuropeptide Y, norepinephrine appears to predominantly stimulate carbohydrate intake [100].
The importance of melanocyte-stimulating hormone (alpha-MSH) has been demonstrated by the observations that disruption of the melanocortin-4 receptor (MC4R) in the hypothalamus leads to massive obesity; the identification of an agouti-related peptide (AgRP), which may compete with the hormone; and the description of obesity caused by proopiomelanocortin (POMC) mutations [101]. (See 'Melanocortin-4 receptor' above and 'Proopiomelanocortin' above.)
Inhibitors of food intake — A number of gut hormones inhibit food intake. However, it is often difficult to separate effects on decreasing food intake from other effects such as aversion to food [101].
●GLP-1 released from cells in the gastrointestinal tract has an important role in glucose homeostasis and decreases hunger, increases satiety, and slows gastric emptying (table 4). (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Gastrointestinal peptides' and "Obesity in adults: Drug therapy", section on 'GLP-1 receptor agonists' and "Obesity in adults: Drug therapy".)
●CCK decreases food intake by inducing satiety and delaying gastric emptying (table 5). (See "Physiology of cholecystokinin".)
●Pancreatic polypeptide, oxyntomodulin, and peptide YY 3-36 also suppress food intake in both lean and obese subjects. (See "Pancreatic polypeptide, peptide YY, and neuropeptide Y".)
Brain: Key modulator of body weight — Messages reach the brain from the periphery via the circulation (eg, leptin, glucose), particularly through the more permeable blood brain barrier around the median eminence, or via vagal afferents of the autonomic nervous system. Information from the gastrointestinal tract and oropharynx is neurally transmitted to the hindbrain and processed in the nucleus of the tractus solitarius. Certain physiological states, such as pregnancy or obesity, may decrease the transport of leptin into the cerebrospinal fluid and/or decrease transduction of the leptin signal, thereby diminishing the leptin response at any given circulating leptin concentration [102,103].
In addition, several other regions in the brain are important in processing information about food in relationship to body weight, including the arcuate nucleus at the base of the hypothalamus, the paraventricular nucleus, the ventromedial and lateral hypothalamus, and selected regions of the amygdala.
Body fat distribution — As with total body fat, the distribution of visceral and subcutaneous fat also has genetic determinants [4]. Gonadal steroids play a major role in determining the distribution of body fat. At the onset of puberty, males experience a decrease in fat mass and increase in lean body mass, whereas females increase their body fat relative to their muscle mass; these differences persist throughout life.
Both gonadal steroid and GH secretion decline with age. This may explain the increase in visceral fat in males with aging. Similarly, in postmenopausal females, the decline in estrogen and age-associated decrease in GH may account for the rapid increase in visceral fat.
In addition to the heritability of weight, the metabolic rate, thermic response to food, and spontaneous physical activity are, to a variable degree, heritable as well [6]. With respect to body weight, percentage of fat, fat mass, and estimated subcutaneous fat, there was approximately three times more variance among pairs than within pairs. Thus, both current weight status and the metabolic processes underlying weight gain have a strong inherited component. (See 'Heritable factors' above.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Obesity in adults".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Weight loss treatments (The Basics)")
●Beyond the Basics topics (see "Patient education: Losing weight (Beyond the Basics)")
SUMMARY
●Genetic contribution to obesity – Genetic factors interact with environmental influences to produce obesity. Studies suggest that heritable factors are responsible for 40 to 75 percent of the variation in adiposity. There are many genes with polymorphisms related to obesity that have been identified by genome-wide studies (figure 2). (See 'Heritable factors' above.)
There are a number of single-gene mutations associated with obesity, including clinical syndromes that include obesity as one of the features. (See 'Monogenic forms of obesity' above.)
●Regulation of body weight and energy balance – Body weight is regulated by a feedback mechanism in which signals from adipose tissue, the gut, and endocrine organs inform the brain regarding energy stores (fat mass) and energy balance (weight gain or loss). At the body’s usual weight, energy intake and expenditure are remarkably coupled in the face of wide daily fluctuations in diet and physical activity to oppose sustained alteration in adiposity. During and after weight loss, energy intake and expenditure are uncoupled to promote weight regain via hyperphagia and hypometabolism. (See 'The regulation of body weight' above and 'Resistance to weight loss and maintenance of reduced weight' above.)
Regulation of energy homeostasis and body weight is a complex process involving the central and autonomic nervous systems, neuroendocrine functions, gut hormones, and the leptin signaling pathway from adipocytes to the highest cortical centers of the brain. The net effect of these systems is that attempts to lose weight or sustain weight loss are met by variable changes in these systems leading to weight regain. (See 'Physiological processes affecting energy balance' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges George Bray, MD, who contributed to an earlier version of this topic review.
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
