Obesity

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Template:TOC-right Obesity is the medical condition associated with excessive stores of body fat, to the extent that it causes serious health concerns.

Causes/etiology

Obesity is caused by a mix of environmental and genetic factors.[1][2] In only very few cases can obesity in humans be attributed to a single gene defect, but many genes have been found that have variants associated with an increased risk of obesity. One of the few genes that variants in the human population associated with increased risk of obesity is the gene for the melanocortin 4 receptor (MC4R). This receptor is expressed in the hypothalamus, and mediates the actions of alpha melanocyte stimulating hormone, a peptide released by a subpopulation of neurons in the arcuate nucleus in response to leptin. [3] (see Hunger for more information).

The secular increase in overweight and obesity (the increase that has taken place during the XXth century and is continuing today) is most obviously due to environmental changes (in the widest sense), the most commonly discussed obesogenic factors being diet and exercise ("The Big Two").

This is not to say that no relevant obesogenic changes in the Human genetic pool happened during this period, and this does not exclude epigenetic modifications of the genome. In a multi-center review of the literature on the possible causes of this secular trend, 10 other factors, including epigenetic changes and modifications in mating behaviours modulating the gene pool, were found to be equally plausible etiologic factors contributing to the epidemic, as Keith et al. argue.[4] This analysis, published in the International Journal of Obesity, found "evidence (in favor of the following factors was) in many cases (...) as compelling as the evidence for more commonly discussed putative explanations (diet and physical activity)":

  1. Sleep debt:  (Vgontzas et al. report primary causes of short sleep duration in obesity as chronic emotional disturbance and various difficulties sleeping.)[5]
  2. Endocrine disruptors (man made chemicals interfering with any possible step of hormone signalling. Exposure to low levels of estrogen mimics in the womb can cause "grotesque obesity"[6]. Bisphenol(A), and perhaps other polycyclic aromatic hydrocarbons appears to inhibit the burning of fat by interfering with catecholamines.[7] Exposure to organochlorines decrease thyroid hormone concentrations, resting metabolic rate, and fat oxidation in skeletal muscles[8].)
  3. Decreased smoking
  4. Pharmaceutical iatrogenesis (drug-induced weight gain: many modern drugs widely used today cause weight gain)
  5. Changes in distribution of ethnicity and age (some age and ethnic groups where obesity is more common have grown in number)
  6. Increasing gravida age (giving birth at an older age, which is a worlwide trend, is a risk factor for obesity in the offspring)
  7. Intrauterine and intergenerational effects (trends in obesity incidence may reflect (probably epigenetic) changes that occurred a generation or more before)
  8. High BMI leads to reproductive fitness (reproducing at a higher rate)
  9. Assortative mating and floor effects (a tendency to search for mates with comparable phenotypes (physical appearance), coupled to a floor effect (a loss of reproductive fitness with increasing leanness), leading, over time, in a snowball effect to epidemic proportions of overweight)

These explanations neither compete with each other, nor with the "Big Two", but demand more depth to the explanations coming out of interventions and researches that are focusing solely on caloric intake and expenditure (diet and exercise).

Nevertheless, any consideration of the role of increased caloric intake and decreased physical energy expenditure must also take into consideration the factors causing them. Some if not many of the above ten 'additional' contributions to the obesity epidemic, plausibly operate proximately to increase caloric intake and/or reduce physical energy expenditure. Sleep debt, for example, produces endocrine/metabolic changes in the body that increase appetite, as Keith et al. point out.[4] One might not find it surprising that people suffering from sleep deprivation reduce their physical energy energy expenditure because of tiredness. No need to expend much physical energy to keep warm or cool in a thermoneutral environment. Smoking cessation has a well known effect to increase caloric intake. The role of endocrine disruptors and pharmaceuticals requires further investigation as to the mechanisms of interruption of body weight regulation. Noting greater proportions of ethnic groups that have a propensity to obesity may help explain the rising obesity prevalence but in itself does provide causal mechanisms or exclude the proximate role of the Big Two. Keith et al. make an important contribution with their study in that their findings indicate that treatment aimed at reversing the "Big Two" will require consideration of the role of a number of factors potentially underpinning them.

The role of fetal programming,[9] [10] [11] perhaps operative in the higher risk of obesity in offspring of older and/or very lean women, emerges as an intriguing result of the analysis by Keith et al.[4]

Pathophysiology

Obesity is associated with a state of leptin resistance, analogous to the insulin resistance seen in type 2 diabetes. Leptin (from the greek leptos, "thin"), being secreted by fat tissues, is high in obese individuals. Nevertheless, the hypothalamus does not respond proportionately to these concentrations. Leptin is traditionally viewed as a major satiety signal. Indeed, leptin administration suppresses appetite. However, animals who are fed amounts of food comparable to those eaten by animals submitted to the anorexigenic (appetite-suppressing) effects of leptin do not lose weight as fast as their leptin-treated counterparts. [12] Going a step further, Rafael and colleagues observed that the satiety effect caused by leptin itself could be a consequence of the "dramatic" increase in fat combustion (lipolysis) elicited by leptin. In other words, leptin would cut appetite because it causes weight loss (by causing fat combustion) rather than, or in addition to, the opposite (for an exploration of the range of possible appetite-independent functions of leptin, see "Perspectives", in the Discussion section of Rafael & al.[12]).

A similar change occured in our understanding of ghrelin, away from hunger signalling, and towards metabolic fine-tuning of energy utilization. Ghrelin is a hormone secreted by the stomach which is often viewed as the appetite stimulant that counteracts leptin's anorexigenic effect. Again, it appears that this hormone does not act directly as an appetite stimulant, but rather modifies the way in which the body uses fat (versus carbohydrates): it increases fat storage. Concluding their study of mutants unable to secrete ghrelin (and, as a result, less "able" to gain weight when fed a high fat diet), Wortley & al. hypothesise:

The ability to efficiently build fat reserves in times of nutritional abundance appears to have resulted from evolutionary pressure to protect against subsequent periods of food scarcity. The tendency to efficiently store fat in times of caloric excess appears to have become paradoxically maladaptive in settings of continuous food availability, as indicated by the present epidemic of obesity in Western societies.[13]

Rimonabant, a recently developped antagonist of endocannabinoid receptors (receptors of endogenous cannabis-like signalling), is also often thought to induce weight loss (see Treatment, below) by decreasing appetite, as it is called an anorectic drug. The weight loss, however, extends well beyond the transient decrease in appetite. Studying candy-fed animals, researchers found that rimonabant actually increased the amount of fat available for combustion after a meal, and that this increase in availability was not an indirect, compensatory, consequence of food deprivation, but a direct neuroendocrine effect in its own right.[14]

Indeed, all consumers of refined starches, soft drings, high-fructose corn syrups and other energy-replete products are not born equal. Obese persons, after a meal, appear to burn less efficiently carbohydrates and even more poorly fat.[15] A contribution of leptin resistance was suggested, since leptin was higher in the obese men that were the least efficient metabolisers of fat. However, the arrow of causality may actually be oriented in the other direction. In persons with a stronger family history of obesity, the earliest obesogenic changes are not related to leptin, but to metabolic efficiency and to insulin status and responsiveness: subjects who are at increased risk of obesity oxidize carbohydrates more quickly, oxidize fat more slowly, and have lower insulin, consistent with a greater than usual insulin sensitivity.[16] These findings are in sharp contrast with those implicating obesity with the development, over the long term, of the opposite of insulin sensitivity, i.e. insulin resistance.

Magnesium is involved early in the development of obesity. Obese subjects, like type II diabetics, are magnesium deficient.[17] Magnesium is required in more than 300 enzymatic reactions, including several that are rate-limiting in carbohydrate utilization. Insulin action is closely dependent on magnesium availability in cells and, conversely, high glucose exposure leads to magnesium depletion and insulin resistance. In obese children, magnesium deficiency precedes insulin resistance[17], but the relationship between magnesium and the heightened responsivity of cells to insulin a heightened response to insulin is characteristic of the pre-obese state.[16] The exact role of magnesium in the progression to obesity is not fullly understood.

At the scale of the fat cells, we are facing a similar paradox. Obesity may present associated with a range of anormalities: insulin resistance, chronic inflammation, oxidative stress and a range of ills aggregating in what has been called the metabolic syndrome. It thus appears reasonable to assume that fat cells, in obesity, are in a state of oxidative stress. However, studying obesity in isolation, it became apparent that obesity at the fat cell level required the opposite of oxidative stress, e.g. a balance between oxidants and reductants tilted in favour of the latter.[18]

The amount of fat to which fat cells are exposed condition their development. The type of fat also is a determinant of fat cell growth (hypertrophy) and multiplication (hyperplasia), a factor that has been largely disregarded until recently. The amount of omega-6 fatty acids in the diet, in absolute terms as well as relative to the amounts of omega-3 fatty acids, have risen sharply since 1945 due to the invention of novel techniques to extract fat from vegetable sources. Omega-6 fatty acids, as a prostacyclin precursors, enhance cyclic AMP-dependent signaling pathways in preadipocytes and promote the development of mature adipocytes. Only by modulating the proportion of omega-6 fatty acids in the diet (without increasing total caloric intake), it is possible to cause in animals a 50% increase in body mass.[19]

As

Treatment

The mainstay of treatment for obesity is an energy-limited diet and increased exercise. In studies, diet and exercise programs have consistently produced an average weight loss of approximately 8% of total body mass (excluding study drop-outs). While not all dieters will be satisfied with this outcome, studies have shown that a loss of as little as 5% of body mass can create large health benefits. A more intractable therapeutic problem appears to be weight loss maintenance. Of dieters who manage to lose 10% or more of their body mass in studies, 80-95% will regain that weight within two to five years, supporting the finding that the body has various mechanisms that maintain weight at a certain set point.

In a clinical practice guideline by the American College of Physicians, the following five recommendations are made:[20]

  1. People with a BMI of over 30 should be counseled on diet, exercise and other relevant behavioral interventions, and set a realistic goal for weight loss.
  2. If these goals are not achieved, pharmacotherapy can be offered. The patient needs to be informed of the possibility of side-effects and the unavailability of long-term safety and efficacy data.
  3. Drug therapy may consist of sibutramine, orlistat, phentermine, diethylpropion, fluoxetine, and bupropion. For more severe cases of obesity, stronger drugs such as amphetamine and methamphetamine may be used on a selective basis. Evidence is not sufficient to recommend sertraline, topiramate, or zonisamide.
  4. In patients with BMI > 40 who fail to achieve their weight loss goals (with or without medication) and who develop obesity-related complications, referral for bariatric surgery may be indicated. The patient needs to be aware of the potential complications.
  5. Those requiring bariatric surgery should be referred to high-volume referral centers, as the evidence suggests that surgeons who frequently perform these procedures have fewer complications.

A clinical practice guideline by the US Preventive Services Task Force (USPSTF) concluded that the evidence is insufficient to recommend for or against routine behavioral counseling to promote a healthy diet in unselected patients in primary care settings, but that intensive behavioral dietary counseling is recommended in those with hyperlipidemia and other known risk factors for cardiovascular and diet-related chronic disease. Intensive counseling can be delivered by primary care clinicians or by referral to other specialists, such as nutritionists or dietitians.[21][22]

Counseling

A meta-analysis of randomized controlled trials concluded that "compared with usual care, dietary counseling interventions produce modest weight losses that diminish over time."[23]

The role of genetic counseling is unclear[24]; however, based on a study done of hypercholesterolemia, it is possible that genetic counseling might lead to patients preferring medication over diet therapy.[25]

Portion control plate

A randomized controlled trial found that patients using portion control plates and log books had more weight loss and less use of hypoglycemic drugs.[26]

Internet-based counseling

The Internet offer a method to increase patient participation in their health care. A randomized controlled trial showed some benefit in a weight loss program that used the Internet.[27]

Diets

Descriptions of common diets
heading heading
Dr Atkins' diet low-carbohydrate
initially < 20 g of carbohydrate daily, subseequently 50 g/day
Ornish diet vegetarian
Rosemary Conley low-fat and social support
Slim-Fast plan meal replacement
Weight Watchers balanced diet with social support
Zone diet low-carbohydrate diet
carbohydrates, proteins, and fats in 40:30:30 ratio

Various dietary approaches have been proposed, some of which have been compared by randomized controlled trials:

"all 4 diets resulted in modest statistically significant weight loss at 1 year, with no statistically significant differences between diets"
"The higher discontinuation rates for the Atkins and Ornish diet groups suggest many individuals found these diets to be too extreme"

Low carbohydrate versus low fat diets

Many studies have focused on diets that reduce calories via a low-carbohydrate (Atkins diet, Zone diet) diet versus a low-fat diet (LEARN diet, Ornish diet). The Nurses' Health Study, an observational cohort study, found that low carbohydrate diets based on vegetable sources of fat and protein are associated with less coronary heart disease.[30]

A meta-analysis of randomized controlled trials by the Cochrane Collaboration in 2002 concluded[31] that fat-restricted diets are no better than calorie restricted diets in achieving long term weight loss in overweight or obese people.

A more recent meta-analysis that included randomized controlled trials published after the Cochrane review[32][33][29] found that "low-carbohydrate, non-energy-restricted diets appear to be at least as effective as low-fat, energy-restricted diets in inducing weight loss for up to 1 year. However, potential favorable changes in triglyceride and high-density lipoprotein cholesterol values should be weighed against potential unfavorable changes in low-density lipoprotein cholesterol values when low-carbohydrate diets to induce weight loss are considered."[34]

The Women's Health Initiative Randomized Controlled Dietary Modification Trial[35] found that a diet of total fat to 20% of energy and increasing consumption of vegetables and fruit to at least 5 servings daily and grains to at least 6 servings daily:

  • no reduction in cardiovascular disease[36]
  • an insignificant reduction in invasive breast cancer[37]
  • no reductions in colorectal cancer[38]

Additional recent randomized controlled trials have found that:

  • The choice of diet for a specific person may be influenced by measuring the invididual's insulin secretion:
In young adults "Reducing glycemic [carbohydrate] load may be especially important to achieve weight loss among individuals with high insulin secretion."[40] This is consistent with prior studies of diabetic patients in which low carbohydrate diets were more beneficial.[41][42]

Low glycemic index

"The glycaemic index factor is a ranking of foods based on their overall effect on blood sugar levels. Low glycaemic index foods, such as lentils, provide a slower more consistent source of glucose to the bloodstream, thereby stimulating less insulin release than high glycaemic index foods, such as white bread."[43][44]

The glycemic load is "the mathematical product of the glycemic index and the carbohydrate amount".[45]

In a randomized controlled trial that compared four diets that varied in carbohydrate amount and glycemic index found complicated results[46]:

  • Diet 1 and 2 were high carbohydrate (55% of total energy intake)
    • Diet 1 was high-glycemic index
    • Diet 2 was low-glycemic index
  • Diet 3 and 4 were high protein (25% of total energy intake)
    • Diet 3 was high-glycemic index
    • Diet 4 was low-glycemic index

Diets 2 and 3 lost the most weight and fat mass; however, low density lipoprotein fell in Diet 2 and rose in Diet 3. Thus the authors concluded that the high-carbohydrate, low-glycemic index diet was the most favorable.

A meta-analysis by the Cochrane Collaboration concluded that low glycemic index or low glycemic load diets led to more weight loss and better lipid profiles. However, the Cochrane Collaboration grouped low glycemic index and low glycemic load diets together and did not try to separate the effects of the load versus the index.[43]

Exercise

A meta-analysis of randomized controlled trials by the international Cochrane Collaboration found that "exercise combined with diet resulted in a greater weight reduction than diet alone".[47]

Use of a pedometer may assist in exercising for weight loss.[48]

Drugs

A systematic review found that the average weight loss after at least one year was:[49]

  • Orlistat: 2.9 kg, but produced gastrointestinal side effects.
  • Sibutramine: 4.2 kg, but raised blood pressure and pulse.
  • Rimonabant: 4.7-kg, but associated with increased psychiatric disorders. About a third of patients discontinued treatment.[50][49]

For patients with diabetes mellitus type 2, metformin (Glucophage) can assist in weight loss—rather than sulfonylurea derivatives and insulin, which often lead to further weight gain. The thiazolidinediones (rosiglitazone or pioglitazone) can cause slight weight gain, but decrease the "pathologic" form of abdominal fat, and so may help obese diabetics.

Bariatric surgery

Bariatric surgery (or "weight loss surgery") is the use of surgical interventions in the treatment of obesity. As every surgical intervention may lead to complications, it is regarded as a last resort when dietary modification and pharmacological treatment have proven to be unsuccessful.

Types of surgery

Weight loss surgery relies on various principles. Band surgery is reversible, while bowel shortening operations are not. Some procedures can be performed laparoscopically.

  • Predominantly malabsorptive procedures Others procedures also reduce the length of bowel that food will be in contact with, directly reducing absorption (gastric bypass surgery).

Complications

Complications from weight loss surgery are frequent.[51] The reduction in intestinal absorptive capacity may cause, for instance, persistent anemia only reversible though the intravenous route.[52]

Effectiveness of surgery

Weight loss

In general, the malabsorptive procedures lead to more weight loss than the restrictive procedures. A meta-analysis by the American College of Physicians reports the following weight loss at 36 months:[53]

  • Biliopancreatic diversion - 53 kg
  • Roux-en-Y gastric bypass (RYGB) - 41 kg
    • Open - 42 kg
    • Laparoscopic - 38 kg
  • Adjustable gastric banding - 35 kg
  • Vertical banded gastroplasty - 32 kg
Mortality

Two studies report decrease in mortality from bariatric surgery.[54][55] In the Swedish randomized controlled trial, patients with a body mass index of 34 or more for men and 38 or more for women underwent various types of bariatric surgery and were followed for a mean of 11 years. Surgery patients had 5.0% mortality while control patients had 6.3% mortality. This means 75 patients must be treated to avoid one death after 11 years (number needed to treat is 77).[54] In a Utah retrospective cohort study that followed patients for a mean of 7 years after various types of gastric bypass, surgery patients had 0.4% mortality while control patients had 0.6% mortality.[55]

Remission of diabetes

Bariatric surgery remits diabetes mellitus type 2 in more than 1 of every two people after 2 years if they are similar to the patients in the randomized controlled trial / meta-analysis by Dixon et al. (Number needed to treat is 1.7).[56] In this trial 73% of the patients who remitted their diabetes versus 13% of the patients in the control group.

Prevention

Display of calorie information on the menus or menu boards of restaurants has been proposed by the city of New York.[57]

Eating breakfast may reduce weight gain by adolescents[58]

References

  1. ↑ Stunkard AJ et al. (1990). "The body-mass index of twins who have been reared apart". N. Engl. J. Med. 322 (21): 1483–7. PMID 2336075. [e]
  2. ↑ Christakis NA, Fowler JH (2007). "The spread of obesity in a large social network over 32 years". N Engl J Med 357: 370–9. DOI:10.1056/NEJMsa066082. PMID 17652652. Research Blogging.
  3. ↑ Farooqi IS et al. (2003). "Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene". N Engl J Med 348 (12): 1085–95. DOI:10.1056/NEJMoa022050. PMID 12646665. Research Blogging.
  4. ↑ 4.0 4.1 4.2 Keith SW, Redden DT, Katzmarzyk PT, et al (November 2006). "Putative contributors to the secular increase in obesity: exploring the roads less traveled". Int J Obes (Lond) 30 (11): 1585–94. PMID 16801930.
  5. ↑ Vgontzas AN, Lin HM, Papaliaga M, Calhoun S, Vela-Bueno A, Chrousos GP, Bixler EO. (2008) Short sleep duration and obesity: the role of emotional stress and sleep disturbances. Int. J Obes. (Lond) 32:801-9. PMID 18253159.
    • Objective and Conclusion from Free Abstract:
    • OBJECTIVE: Many epidemiologic studies have reported that obesity is associated with short sleep duration. How the degree of obesity or other clinical characteristics of the obese individuals, such as sleep disturbances or emotional stress, define this relation is not known.
    • CONCLUSION: Self-reported short sleep duration in obese individuals may be a surrogate marker of emotional stress and subjective sleep disturbances, whose detection and management should be the focus of our preventive and therapeutic strategies for obesity.
  6. ↑ Newbold RR, Padilla-Banks E, Snyder RJ, Jefferson WN (July 2005). "Developmental exposure to estrogenic compounds and obesity". Birth Defects Res. Part A Clin. Mol. Teratol. 73 (7): 478–80. PMID 15959888. . Also see the overview from the Our Stolen Future online resource:
    • Excerpts:
    • This study with mice provides a striking example of how exposure in the womb to an estrogen mimic, diethylstilbestrol, (DES), can lead to grotesque obesity in adulthood. The level of DES required to cause the effect is extremely low... (...) Exposure to synthetic chemicals with estrogenic properties has increased dramatically over the 20th century. One of the most widespread current exposures is to bisphenol A, used to make polycarbonate plastic and other consumer products. Experiments with mice have shown that BPA exposure in the womb causes large increases in post-pubertal weight, and that exposures to very low levels during adulthood can induce insulin resistance. The CDC estimates that 95% of Americans are exposed to bisphenol A at levels within the range of concentrations used in these animal experiments.
  7. ↑ Irigaray P, Ogier V, Jacquenet S, et al (April 2006). "Benzo[a]pyrene impairs beta-adrenergic stimulation of adipose tissue lipolysis and causes weight gain in mice. A novel molecular mechanism of toxicity for a common food pollutant". FEBS J. 273 (7): 1362–72. PMID 16689925. .
    • Conclusions:
    • The weight gain occurred consistently without detectable changes in food intake. These results reveal a novel molecular mechanism of toxicity for the environmental pollutant B[a]P and introduce the notion that chronic exposure of human population to B[a]P and possibly other polycyclic aromatic hydrocarbons could have an impact on metabolic disorders, such as obesity.
  8. ↑ Pelletier C, Imbeault P, Tremblay A (February 2003). "Energy balance and pollution by organochlorines and polychlorinated biphenyls". Obes Rev 4 (1): 17–24. PMID 12608524.
  9. ↑ Breier BH, Vickers MH, Ikenasio BA, Chan KY, Wong WP. (2001) Fetal programming of appetite and obesity. Mol. Cell Endocrinol. 185:73-9. PMID 11738796.
    • Abstract: Obesity and related metabolic disorders are prevalent health issues in modern society and are commonly attributed to lifestyle and dietary factors. However, the mechanisms by which environmental factors modulate the physiological systems that control weight regulation and the aetiology of metabolic disorders, which manifest in adult life, may have their roots before birth. The 'fetal origins' or 'fetal programming' paradigm is based on the observation that environmental changes can reset the developmental path during intrauterine development leading to obesity and cardiovascular and metabolic disorders later in life. The pathogenesis is not based on genetic defects but on altered genetic expression as a consequence of an adaptation to environmental changes during fetal development. While many endocrine systems can be affected by fetal programming recent experimental studies suggest that leptin and insulin resistance are critical endocrine defects in the pathogenesis of programming-induced obesity and metabolic disorders. However, it remains to be determined whether postnatal obesity is a consequence of programming of appetite regulation and whether hyperphagia is the main underlying cause of the increased adiposity and the development of metabolic disorders.
  10. ↑ Vickers MH, Reddy S, Ikenasio BA, Breier BH. (2001) Dysregulation of the adipoinsular axis -- a mechanism for the pathogenesis of hyperleptinemia and adipogenic diabetes induced by fetal programming. J Endocrinol. 170:323-32. PMID 11479129.
    • Abstract: Obesity and its related disorders are the most prevalent health problems in the Western world. Using the paradigm of fetal programming we developed a rodent model which displays the phenotype of obesity and metabolic disorders commonly observed in human populations. We apply maternal undernutrition throughout gestation, generating a nutrient-deprived intrauterine environment to induce fetal programming. Maternal undernutrition results in fetal growth retardation and in significantly decreased body weight at birth. Programmed offspring develop hyperphagia, obesity, hypertension, hyperleptinemia and hyperinsulinism during adult life and postnatal hypercaloric nutrition amplifies the metabolic abnormalities induced by fetal programming. The adipoinsular axis has been proposed as a primary candidate for linking the status of body fat mass to the function of the pancreatic beta-cells….Our data suggest that reduced substrate supply during fetal development can trigger permanent dysregulation of the adipoinsular feedback system leading to hyperleptinemia, hyperinsulinism and compensatory leptin production by pancreatic delta-cells in a further attempt to reduce insulin hypersecretion in the progression to adipogenic diabetes.
  11. ↑ Vickers MH, Breier BH, Cutfield WS, Hofman PL, Gluckman PD. (2000) Fetal origins of hyperphagia, obesity, and hypertension and postnatal amplification by hypercaloric nutrition. Am J Physiol Endocrinol. Metab 279:E83-E87. PMID 10893326.
    • Abstract: Environmental factors and diet are generally believed to be accelerators of obesity and hypertension, but they are not the underlying cause. Our animal model of obesity and hypertension is based on the observation that impaired fetal growth has long-term clinical consequences that are induced by fetal programming. Using fetal undernutrition throughout pregnancy, we investigated whether the effects of fetal programming on adult obesity and hypertension are mediated by changes in insulin and leptin action and whether increased appetite may be a behavioral trigger of adult disease….This study is the first to demonstrate that profound adult hyperphagia is a consequence of fetal programming and a key contributing factor in adult pathophysiology. We hypothesize that hyperinsulinism and hyperleptinemia play a key role in the etiology of hyperphagia, obesity, and hypertension as a consequence of altered fetal development.
  12. ↑ 12.0 12.1 Rafael J, Herling AW (March 2000). "Leptin effect in ob/ob mice under thermoneutral conditions depends not necessarily on central satiation". Am. J. Physiol. Regul. Integr. Comp. Physiol. 278 (3): R790–5. PMID 10712302. "Reduction of body mass in leptin-treated ob/ob mice was faster than in pair-fed ob/ob controls" (Free full text)
  13. ↑ Wortley KE, Anderson KD, Garcia K, et al (May 2004). "Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel preference". Proc. Natl. Acad. Sci. U.S.A. 101 (21): 8227–32. DOI:10.1073/pnas.0402763101. PMID 15148384. Research Blogging. (Free full text)
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  18. ↑ Galinier A, Carrière A, Fernandez Y, et al (May 2006). "Adipose tissue proadipogenic redox changes in obesity". J. Biol. Chem. 281 (18): 12682–7. PMID 16377639. (Free full text)
  19. ↑ Massiera F, Saint-Marc P, Seydoux J, et al (February 2003). "Arachidonic acid and prostacyclin signaling promote adipose tissue development: a human health concern?". J. Lipid Res. 44 (2): 271–9. PMID 12576509. (Free full text)
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  21. ↑ Behavioral counseling in primary care to promote a healthy diet: recommendations and rationale.. Retrieved on 2007-05-22.
  22. ↑ Pignone MP, Ammerman A, Fernandez L, et al (2003). "Counseling to promote a healthy diet in adults: a summary of the evidence for the U.S. Preventive Services Task Force". American journal of preventive medicine 24 (1): 75-92. PMID 12554027. [e]
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  30. ↑ Halton TL et al. (2006). "Low-carbohydrate-diet score and the risk of coronary heart disease in women". N Engl J Med 355: 1991-2002. DOI:10.1056/NEJMoa055317. PMID 17093250. Research Blogging.
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  51. ↑ Encinosa WE et al. (2006). "Healthcare utilization and outcomes after bariatric surgery". Medical Care 44: 706-12. DOI:10.1097/01.mlr.0000220833.89050.ed. PMID 16862031. Research Blogging.
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  57. ↑ Rivera R. (2007) “New York City Reintroduces Calorie Rule,” The New York Times, October 25, 2007, http://www.nytimes.com/2007/10/25/nyregion/25calories.html (accessed October 26, 2007).
  58. ↑ Timlin MT, Pereira MA, Story M, Neumark-Sztainer D (2008). "Breakfast eating and weight change in a 5-year prospective analysis of adolescents: Project EAT (Eating Among Teens)". Pediatrics 121 (3): e638-45. DOI:10.1542/peds.2007-1035. PMID 18310183. Research Blogging.
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