Obesity pathophysiology
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2013 AHA/ACC/TOS Guidelines on Management of Overweight and Obesity |
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Risk calculators and risk factors for Obesity pathophysiology |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor-in-Chief: Salman J. Khan, M.D.
Pathophysiology
Lifestyle
Most researchers have concluded that the combination of an excessive nutrient intake and a sedentary lifestyle are the main cause for the rapid acceleration of obesity in Western society in the last quarter of the 20th century. [1]
Despite the widespread availability of nutritional information in schools, doctors' offices, on the internet and on groceries,[2] it is evident that overeating remains a substantial problem. For instance, reliance on energy-dense fast-food meals tripled between 1977 and 1995, and calorie intake quadrupled over the same period.[3]
However, dietary intake in itself is insufficient to explain the phenomenal rise in levels of obesity in much of the industrialized world during recent years. An increasingly sedentary lifestyle also has a significant role to play. More and more research into child obesity, for example, links such things as the school run, with the current high levels of this disease. [4]
Less well established life style issues which may influence obesity include a stressful mentality and insufficient sleep.
Genetics
As with many medical conditions, the calorific imbalance that results in obesity often develops from a combination of genetic and environmental factors. Polymorphisms in various genes controlling appetite, metabolism, and adipokine release predispose to obesity, but the condition requires availability of sufficient calories, and possibly other factors, to develop fully. Various genetic conditions that feature obesity have been identified (such as Prader-Willi syndrome, Bardet-Biedl syndrome, MOMO syndrome, leptin receptor mutations and melanocortin receptor mutations), but known single-locus mutations have been found in only about 5% of obese individuals. While it is thought that a large proportion of the causative genes are still to be identified, much obesity is likely the result of interactions between multiple genes, and non-genetic factors are likely also important.
A 2007 study identified fairly common mutations in the FTO gene; heterozygotes had a 30% increased risk of obesity, while homozygotes faced a 70% increased risk.[5]
On a population level, the thrifty gene hypothesis postulates that certain ethnic groups may be more prone to obesity than others, and the ability to take advantage of rare periods of abundance and use such abundance by storing energy efficiently may have been an evolutionary advantage in times when food was scarce. Individuals with greater adipose reserves were more likely to survive famine. This tendency to store fat is likely maladaptive in a society with stable food supplies.[6]
Medical Illness
Certain physical and mental illnesses and particular pharmaceutical substances may predispose to obesity. Apart from the fact that correcting these situations may improve the obesity, the presence of increased body weight may complicate the management of others.
Medical illnesses that increase obesity risk include several rare congenital syndromes (listed above), hypothyroidism, Cushing's syndrome, growth hormone deficiency.[7] Smoking cessation is a known cause for moderate weight gain, as nicotine suppresses appetite. Certain medications (e.g. steroids, atypical antipsychotics, some fertility medication) may cause weight gain.
Mental illnesses may also increase obesity risk, specifically some eating disorders such as bulimia nervosa, binge eating disorder, and compulsive overeating (also known as food addiction).
Neurobiological Mechanisms
Flier[8] summarizes the many possible pathophysiological mechanisms involved in the development and maintenance of obesity. This field of research had been almost unapproached until leptin was discovered in 1994. Since this discovery, many other hormonal mechanisms have been elucidated that participate in the regulation of appetite and food intake, storage patterns of adipose tissue, and development of insulin resistance. Since leptin's discovery, ghrelin, orexin, PYY 3-36, cholecystokinin, adiponectin, and many other mediators have been studied. The adipokines are mediators produced by adipose tissue; their action is thought to modify many obesity-related diseases.
Leptin and ghrelin are considered to be complementary in their influence on appetite, with ghrelin produced by the stomach modulating short-term appetitive control (i.e. to eat when the stomach is empty and to stop when the stomach is stretched). Leptin is produced by adipose tissue to signal fat storage reserves in the body, and mediates long-term appetitive controls (i.e. to eat more when fat storages are low and less when fat storages are high). Although administration of leptin may be effective in a small subset of obese individuals who are leptin deficient, many more obese individuals are thought to be leptin resistant. This resistance is thought to explain in part why administration of leptin has not been shown to be effective in suppressing appetite in most obese subjects.
While leptin and ghrelin are produced peripherally, they control appetite through their actions on the central nervous system. In particular, they and other appetite-related hormones act on the hypothalamus, a region of the brain central to the regulation of food intake and energy expenditure. There are several circuits within the hypothalamus that contribute to its role in integrating appetite, the melanocortin pathway being the most well understood.[8] The circuit begins with an area of the hypothalamus, the arcuate nucleus, that has outputs to the lateral hypothalamus (LH) and ventromedial hypothalamus (VMH), the brain's feeding and satiety centers, respectively.[9]
The arcuate nucleus contains two distinct groups of neurons.[8] The first group coexpresses neuropeptide Y (NPY) and agouti-related peptide (AgRP) and has stimulatory inputs to the LH and inhibitory inputs to the VMH. The second group coexpresses pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) and has stimulatory inputs to the VMH and inhibitory inputs to the LH. Consequently, NPY/AgRP neurons stimulate feeding and inhibit satiety, while POMC/CART neurons stimulate satiety and inhibit feeding. Both groups of arcuate nucleus neurons are regulated in part by leptin. Leptin inhibits the NPY/AgRP group while stimulating the POMC/CART group. Thus a deficiency in leptin signaling, either via leptin deficiency or leptin resistance, leads to overfeeding and may account for some genetic and acquired forms of obesity.
Impaired Brain Response to Nutrients in Obese Individuals: A Link to Compulsive Eating behavior
Brain is actively involved in shaping eating behavior. Whenever food is consumed, brain gives a response to the nutrient intake. According to the latest research, the brain has an impaired response to nutrients in obese individuals as compared to lean people.
Several neurotransmitters have been studied for rewarding effects of food intake. These include dopamine, cannabinoids, opioids, serotonin, and neuropeptides.[10][11] These neurotransmitters play a major role in homeostatic regulation of food intake.[12] In a normal human being food consumption is followed by the release of these neurotransmitters from the brain to provide the feeling of satisfaction and reward. Dopamine is the thoroughly investigated and considered to be the primary neurotransmitter involved.[13] Dopamine is a neurotransmitter that has an important role in motivation, processing of reward and behavior change through its projections from dorsal striatum, ventral tegmental area (VTA) and Nucleus accumbens (NAc). [14][15] Dopamine releases from dorsal striatum in response to the pleasure of food intake and activates many brain regions such as the midbrain, subcallosal cingulate and Prefrontal cortex.[16] Furthermore, dopamine increases in VTA and NAc areas. The quantity of dopamine determines the pleasure arising from food, greater the magnitude greater will be the feeling of reward and pleasure.[17] When dopamine activity reach a significant level and the feeling of reward is achieved, food intake is stopped.
In obesity, there is a decrease release of dopamine in response to food. This can be attributed to chronic food exposure and diminished dopamine activity.[18][19] It occurs due to decrease in D2 receptors in the dorsal striatum.[20] Consequently, this causes compensatory overeating to achieve the required feeling of reward.[21][22] As per the clinical trial by Volkow et al using PET and multiple tracers, both drug addicts and individuals with morbid obesity have a smaller number of dopamine (D2) receptors in the striatum as compared to the healthy population.[23] This shows the compulsive behavior in this population segment.
Wang and Haltia in their studies found out that lower D2 receptors are linked with higher Body Mass Index in individuals with obesity.[24][25] These discoveries shows that impaired Dopamine receptor activity increases feeding and the risk for obesity.[26] Guo et al. discovered that obesity and opportunistic eating were negatively associated with dopamine magnitude in ventromedial striatum, a region supporting reward and motivation.[27]
This mechanism shows that brain has centers where changes occur in response to nutrient intake. In obese individuals, there is impaired mechanism towards food intake. These findings are critical as they might be the reasons behind eating disorders and failed weight loss efforts.
Microbiological Aspects
The role of bacteria colonizing the digestive tract in the development of obesity has recently become the subject of investigation. Bacteria participate in digestion (especially of fatty acids and polysaccharides), and alterations in the proportion of particular strains of bacteria may explain why certain people are more prone to weight gain than others. Human digestive tract are generally either members of the phyla of bacteroidetes or of firmicutes. In obese people, there is a relative abundance of firmicutes (which cause relatively high energy absorption), which is restored by weight loss. From these results it cannot yet be concluded whether this imbalance is the cause of obesity or an effect.[28]
Social Determinants
Some obesity co-factors are resistant to the theory that the "epidemic" is a new phenomenon. In particular, a class co-factor consistently appears across many studies. Comparing net worth with BMI scores, a 2004 study[29] found obese American subjects approximately half as wealthy as thin ones. When income differentials were factored out, the inequity persisted—thin subjects were inheriting more wealth than fat ones. A higher rate of a lower level of education and tendencies to rely on cheaper fast foods is seen as a reason why these results are so dissimilar. Another study finds women who married into higher status are predictably thinner than women who married into lower status.
A 2007 study of more than 32,500 children of the original Framingham Heart Study cohort followed for 32 years indicated that BMI change in friends, siblings or spouse predicted BMI change in subjects irrespective of geographical distance. The association was strongest among mutual friends and lower among siblings and spouses (although these differences were not statistically significant). The authors concluded from the results that acceptance of body mass plays an important role in changes in body size.[30]
Environmental Factors
While it may often appear obvious why a certain individual gets fat, it is far more difficult to understand why the average weight of certain societies have recently been growing. While genetic causes are central to understanding obesity, they cannot fully explain why one culture grows fatter than another.
This is most notable in the United States. In the years from just after the Second World War until 1960 the average person's weight increased, but few were obese. In the two and a half decades since 1980 the growth in the rate of obesity has accelerated markedly and is increasingly becoming a public health concern.
There are a number of theories as to the cause of this change since 1980. Most believe it is a combination of various factors.
- Lack of activity: obese people are less active in general than lean people, and not just because of their obesity. A controlled increase in calorie intake of lean people did not make them less active; correspondingly when obese people lost weight they did not become more active. Weight change does not affect activity levels, but the converse seems to be the case.[31]
- Lower relative cost of foodstuffs: massive changes in agricultural policy in the United States and Europe have led to food prices for consumers being lower than at any point in history. This can raise costs for consumers in some areas but greatly lower it in others. Current debates into trade policy highlight disagreements on the effects of subsidies. In the United States, production of corn, soy, wheat and rice is subsidized through the U.S. farm bill. Corn and soy, which are main sources of the sugars and fats in processed food, are thus cheap compared to fruits and vegetables.[32]
- Increased marketing has also played a role. In the early 1980s in America the Reagan administration lifted most regulations pertaining to sweets and fast food advertising to children. As a result, the number of advertisements seen by the average child increased greatly, and a large proportion of these were for fast food and sweets.[33]
- The changing workforce as each year a greater percent of the population spends their entire workday behind a desk or computer, seeing virtually no exercise. In the kitchen the microwave oven has seen sales of calorie-dense frozen convenience foods skyrocket and has encouraged more elaborate snacking.
- A social cause that is believed by many to play a role is the increasing number of two income households in which one parent no longer remains home to look after the house. This increases the number of restaurant and take-out meals.
- Urban sprawl may be a factor: obesity rates increase as urban sprawl increases, possibly due to less walking and less time for cooking.[34]
- Since 1980 fast food restaurants have seen dramatic growth in terms of the number of outlets and customers served. Low food costs, and intense competition for market share, led to increased portion sizes—for example, McDonalds french fries portions rose from 200 calories (840 kilojoules) in 1960 to over 600 calories (2,500 kJ) today.
References
- ↑ Sara Bleich, David Cutler, Christopher Murray, Alyce Adams. Why is the Developed World Obese? National Bureau of Economic Research Working Paper No. 12954. Issued in March 2007.
- ↑ Centers for Disease Control and Prevention. Nutrition For Everyone. National Control for Health Statistics. Accessed July 15, 2007.
- ↑ Lin BH, Guthrie J and Frazao E (1999). "Nutrient contribution of food away from home". In: Frazao E (Ed). America's Eating Habits: Changes and Consequences. Agriculture Information Bulletin No. 750, US Department of Agriculture, Economic Research Service, Washington, DC, pp. 213–239. Fulltext index.
- ↑ http://politics.guardian.co.uk/publicservices/story/0,,2147839,00.html
- ↑ Frayling TM, Timpson NJ, Weedon MN; et al. (2007). "A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity". Science. 316 (5826): 889–94. doi:10.1126/science.1141634. PMID 17434869.
- ↑ Chakravarthy MV, Booth FW (2004). "Eating, exercise, and "thrifty" genotypes: connecting the dots toward an evolutionary understanding of modern chronic diseases". J. Appl. Physiol. 96 (1): 3–10. doi:10.1152/japplphysiol.00757.2003. PMID 14660491.
- ↑ Rosén T, Bosaeus I, Tölli J, Lindstedt G, Bengtsson BA (1993). "Increased body fat mass and decreased extracellular fluid volume in adults with growth hormone deficiency". Clin. Endocrinol. (Oxf). 38 (1): 63–71. PMID 8435887.
- ↑ 8.0 8.1 8.2 Flier JS (2004). "Obesity wars: molecular progress confronts an expanding epidemic". Cell. 116 (2): 337–50. PMID 14744442.
- ↑ Boulpaep, Emile L.; Boron, Walter F. (2003). Medical physiology: a cellular and molecular approach. Philadelphia: Saunders. ISBN 0-7216-3256-4.
- ↑ Cota, D. et al. (2006) Cannabinoids, opioids and eating behavior: the molecular face of hedonism? Brain Res. Rev. 51, 85–107
- ↑ Atkinson, T. (2008) Central and peripheral neuroendocrine peptides and signalling in appetite regulation: considerations for obesity pharmacotherapy. Obes. Rev. 9, 108–120
- ↑ Cason, A.M. et al. (2010) Role of orexin/hypocretin in reward-seeking and addiction: implications for obesity. Physiol. Behav. 100, 419– 428
- ↑ Wise, R. (2006) Role of brain dopamine in food reward and reinforcement. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 361, 1149– 1158
- ↑ Wang, G.J.; Volkow, N.D.; Thanos, P.K.; Fowler, J.S. Imaging of brain dopamine pathways: Implications for understanding obesity. J. Addict. Med. 2009, 3, 8–18.
- ↑ Abizaid, A.; Liu, Z.W.; Andrews, Z.B.; Shanabrough, M.; Borok, E.; Elsworth, J.D.; Roth, R.H.; Sleeman, M.W.; Picciotto, M.R.; Tschop, M.H.; et al. Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite. J. Clin. Investig. 2006, 116, 3229–3239.
- ↑ Wise, R. (2006) Role of brain dopamine in food reward and reinforcement. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 361, 1149– 1158
- ↑ Rothemund, Y.; Preuschhof, C.; Bohner, G.; Bauknecht, H.C.; Klingebiel, R.; Flor, H.; Klapp, B.F. Differential activation of the dorsal striatum by high-calorie visual food stimuli in obese individuals. Neuroimage 2007, 37, 410–421.
- ↑ Tang-Christensen, M.; Vrang, N.; Larsen, P.J. Glucagon-like peptide containing pathways in the regulation of feeding behaviour. Int. J. Obes. Relat. Metab. Disord. 2001, 25, S42–S47.
- ↑ Steele, K.E.; Prokopowicz, G.P.; Schweitzer, M.A.; Magunsuon, T.H.; Lidor, A.O.; Kuwabawa, H.; Kumar, A.; Brasic, J.; Wong, D.F. Alterations of central dopamine receptors before and after gastric bypass surgery. Obes. Surg. 2010, 20, 369–374.
- ↑ Geiger, B.M. et al. (2009) Deficits of mesolimbic dopamine neurotransmission in rat dietary obesity. Neuroscience 159, 1193– 1199
- ↑ Lenard, N.R.; Berthoud, H.R. Central and peripheral regulation of food intake and physical activity: Pathways and genes. Obesity (Silver Spring) 2008, 16, S11–S22.
- ↑ Arora, S.; Anubhut. Role of neuropeptides in appetite regulation and obesity—A review. Neuropeptides 2006, 40, 375–401.
- ↑ Volkow, N.D.; Wang, G.J.; Fowler, J.S.; Telang, F. Overlapping neuronal circuits in addiction and obesity: Evidence of systems pathology. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2008, 363, 3191–3200.
- ↑ McFarland, K.; Ettenberg, A. Haloperidol does not affect motivational processes in an operant runway model of food-seeking behavior. Behav. Neurosci. 1998, 112, 630–635.
- ↑ Wang, G.J.; Volkow, N.D.; Logan, J.; Pappas, N.R.; Wong, C.T.; Zhu, W.; Netusil, N.; Fowler, J.S. Brain dopamine and obesity. Lancet 2001, 357, 354–357.
- ↑ Haltia, L.T.; Rinne, J.O.; Merisaari, H.; Maguire, R.P.; Savontaus, E.; Helin, S.; Nagren, K.; Kaasinen, V. Effects of intravenous glucose on dopaminergic function in the human brain in vivo. Synapse 2007, 61, 748–756.
- ↑ Restaino, L.; Frampton, E.W.; Turner, K.M.; Allison, D.R. A chromogenic plating medium for isolating Escherichia coli O157:H7 from beef. Lett. Appl. Microbiol. 1999, 29, 26–30.
- ↑ Ley RE, Turnbaugh PJ, Klein S, Gordon JI (2006). "Microbial ecology: human gut microbes associated with obesity". Nature. 444 (7122): 1022–3. doi:10.1038/4441022a. PMID 17183309.
- ↑ Zagorsky JL. Is Obesity as Dangerous to Your Wealth as to Your Health? Res Aging 2004;26:130-152. PDF fulltext.doi:10.1177/0164027503258519.
- ↑ Christakis NA, Fowler JH (2007). "The Spread of Obesity in a Large Social Network over 32 Years". 357 (4): 370–379. doi:10.1056/NEJMsa066082. PMID 17652652.
- ↑ Levine JA, Lanningham-Foster LM, McCrady SK, Krizan AC, Olson LR, Kane PH, Jensen MD, Clark MM (2005). "Interindividual variation in posture allocation: possible role in human obesity". Science. 307 (5709): 584–6. PMID 15681386 doi:10.1126/science.1106561.
- ↑ Pollan, Michael (April 22, 2007). "You Are What You Grow". New York Times. Retrieved 2007-07-30.
- ↑ Brian Wansink and Mike Huckabee (2005), “De-Marketing Obesity,” California Management Review, 47:4 (Summer), 6-18.
- ↑ Lopez R (2004). "Urban sprawl and risk for being overweight or obese". Am J Public Health. 94 (9): 1574–9. PMID 15333317.