Obesity

Obesity is the medical condition associated with excessive stores of body fat, to the extent that it causes serious health concerns. Obesity is a major problem in today’s society, with over 1 billion people being classed as obese worldwide.

Obesity is an increase in adipose tissue, so much so that it can cause a variety of adverse health consequences. These include many emotional and physical problems. For example, emotional problems include feelings of inferiority, low self esteem, and often in children, and bullying from classmates. Physical problems include high blood pressure, heart disease, some cancers and Diabetes mellitus type 2 which is where the body no longer responds to insulin and so cannot control its blood sugar levels. By 2025 300 million people are expected to suffer from obesity-related diabetes.

There are many methods of measuring body fat but the most popular method is using the body mass index (BMI) which measures the relationship between your weight and height. A measure of 30 or more puts you in the category of obese. This method is simple, but is inevitably imprecise; people carrying a lot of muscle will not receive an accurate BMI measure due to muscle being heavier than fat.

Causes/etiology
Obesity is caused by a mix of environmental and genetic factors.

Genetics
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. (see Hunger for more information).

Behavioural and environmental factors
The secular increase in overweight and obesity (the increase that has taken place during the 20th 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. These factors will be discussed after a critical appraisal of the role of the Big Two.

The Big Two
Diet

Sedendarity

Also see exercise

While it is clear that a sedendary lifestyle is involved in the development of a wide range of physical and mental ills, and that overweight and obesity are associated with a more sedendary lifestyle, it is far from obvious that lack of exercise is a major etiological factor in the present obesity epidemic. In a 5.6 years follow-up study of 393 middle-aged healthy subjects (whites), Cambridge epidemiologists demonstrated that carrying excess weight predicted a sedentary lifestyle, but that sedendary time did not predict weight gain.

Other behavioural and environmental factors
In Putative contributors to the secular increase in obesity: exploring the roads less traveled, an analysis published in the International Journal of Obesity, reviewers 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)":

Eating quickly and eating until full may be associated with obesity.
 * Eating habits

Sleep debt Vgontzas et al. report primary causes of short sleep duration in obesity as chronic emotional disturbance and various difficulties sleeping.

Endocrine disruptors

Endocrine disruptors are 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". Bisphenol(A), and perhaps other polycyclic aromatic hydrocarbons appears to inhibit the burning of fat by interfering with catecholamines. Exposure to organochlorines decrease thyroid hormone concentrations, resting metabolic rate, and fat oxidation in skeletal muscles .)

Decreased smoking

Cultural changes in perceptions of overweight

Pharmaceutical iatrogenesis

Many modern drugs widely used today cause weight gain.

Changes in distribution of ethnicity and age

Some age and ethnic groups where obesity is more common have grown in number)

Increasing gravida age

Giving birth at an older age, which is a worlwide trend, is a risk factor for obesity in the offspring.

Intrauterine and intergenerational effects

Trends in obesity incidence may reflect (probably epigenetic) changes that occurred a generation or more before)

Reproductive fitness

High BMI leads to reproductive fitness (reproducing at a higher rate)

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), would lead, 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. 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, 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.

Pathophysiology
Appetite: a cause and an effect

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. 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. ).

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."

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. It is now known that blocking type 1 cannabinoid receptors triggers the birth of new mitochondria (the fat-burning power plants of the cells) in fat cells, obviously a beneficial effect for weight loss (also see below, end of section).

The response to a meal in obesity: the insulin paradox

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. 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. 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

Magnesium is involved early in the development of obesity. Obese subjects, like type II diabetics, are magnesium deficient. 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, but how the heightened responsivity of cells to insulin, that is characteristic of the pre-obese state, relates to magnesium deficiency is not known.

Oxidative stress and reductant stress

At the scale of the fat cells, we are facing a paradox similar to the one involving insulin. 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.

Omega-6 vs. omega-3 unsaturated fatty acids

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.

New insights

As research advances, it will be possible to evaluate the relative contributions of various factors and identify the most crucial steps leading to obesity. Until recently, it was exceedingly difficult to differenciate between changes that resulted from obesity and those that led to this pathological change: the failure of leptin therapy is a good illustration of the problem (see adipocyte for details). New methodologies are developped to track and identify the most crucial obesogenic changes.

Starving in a sea of plenty

In March 2008, the Public Library of Sciences journal published a twin study that carefully selected, out of a pool of 2,453 young healthy twin pairs, 14 pairs of twins that were discordant for obesity (one twin being obese, and the other not). This study design allowed to rule out all genetic factors, as well as intrauterine influences and several environmental factors commonly shared amongst siblings of similar ages. The most significant changes that were found in adipocytes were a sharp decrease in the number of mitochondria, the power plants of the cells that are involved in fat burning, and a specific decrease in their ability to oxidize (burn) three amino acids called branched-chain amino acids, that are the first amino acids to be used as fuel when other sources are unavailable. These amino acids, being poorly catabolized, were higher in the circulation; this signalled the release of higher amounts of more insulin, possibly leading to a vicious cycle. Considering metabolic pathways that were, on the contrary, up-regulated, the Finnish researchers found that numerous known and lesser-known inflammatory cascades were overactive. The sharp decline in the number of mitochondria remains the most important finding, which will help to design therapies adressing the fact that, in the disease of affluent civilisations par excellence, fat cells and their energy-producing organelles, the mitochondria, are "starving in a sea of plenty".

The gut flora of the obese: the enemy within

The gut flora, which fulfills an essential symbiotic role in animal metabolism, is probably the first victim of a high-fat diet. Before one becomes obese due to dietary excesses, the trillions of micro-organisms which inhabit our intestines have already transformed into a pro-inflammatory, obesogenic organ.

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:
 * 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.

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."

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

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.

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.

Diets
The United States Department of Health and Human Services and Department of Agriculture jointly recommend:
 * "Keep total fat intake between 20 to 35 percent of calories."
 * "Consume less than 10 percent of calories from saturated fatty acids"
 * "Less than 300 mg/day of cholesterol"
 * "Keep trans fatty acid consumption as low as possible"
 * "The Average Macronutrient Distribution Range (AMDR) for carbohydrates is 45 to 65 percent of total calories."
 * "The recommended dietary fiber intake is 14 grams per 1,000 calories consumed."

MyPyramid.gov offer online dietary support at http://www.mypyramidtracker.gov/.

Various alternative dietary approaches have been proposed, some of which have been compared by randomized controlled trials:
 * A comparison of Dr Atkins' diet, Slim-Fast plan, Weight Watchers "pure points programme", and Rosemary Conley's found no significant differences.
 * A comparison of Atkins, Zone diet, Ornish diet, and LEARN diet in premenopausal women found the greatest benefit from the Atkins diet.
 * A comparison of Atkins diet, Zone diet, Weight Watchers, and Ornish diet noted:
 * "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"


 * A comparison of three diets: 1) low-fat, restricted-calorie; 2) Mediterranean, restricted-calorie; or 3) low-carbohydrate, non-restricted-calorie found:
 * Least weight loss occurred in the low-fat, restricted-calorie group
 * More favorable effects on lipids with the low-carbohydrate diet
 * More favorable effects on glycemic control with the Mediterranean diet

Carbohydrate-restricted (low carbohydrate) versus fat-restricted (low fat) diets
Many studies have focused on diets that reduce calories via a low-carbohydrate (Atkins diet, South Beach diet, Zone diet) diet (< 20-30 grams/day of carbohydrate) 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.


 * A comparison of three diets: 1) low-fat, restricted-calorie; 2) Mediterranean, restricted-calorie; or 3) low-carbohydrate, non-restricted-calorie found:
 * Least weight loss occurred in the low-fat, restricted-calorie group
 * More favorable effects on lipids with the low-carbohydrate diet
 * More favorable effects on glycemic control with the Mediterranean diet

A meta-analysis that included older randomized controlled trials (but not the two more recent studies above) found:
 * "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."

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

The Women's Health Initiative Randomized Controlled Dietary Modification Trial 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
 * an insignificant reduction in invasive breast cancer
 * no reductions in colorectal cancer

Additional recent randomized controlled trials have found that:
 * A comparison of Atkins, Zone diet, Ornish diet, and LEARN diet in premenopausal women found the greatest benefit from the Atkins diet.


 * 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." This is consistent with prior studies of diabetic patients in which low carbohydrate diets were more beneficial.

Low glycemic index and low glycemic load diets
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.

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

High versus standard protein
There was no difference from amount of protein according to a randomized controlled trial.

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".

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

Drugs
A systematic review found that the average weight loss after at least one year was:
 * 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.

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.

Investigational drugs
Tesofensine increases the transmission of the biogenic amines noradrenaline, dopamine, and serotonin, by inhibiting presynaptic reuptake.

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.

In the United States, Medicare will only only pay for procedures performed at approved facilities.

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 restrictive procedures. The most common approaches are reducing the volume of the stomach, producing an earlier sense of satiation (e.g. by adjustable gastric banding and vertical banded gastroplasty).


 * 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. The reduction in intestinal absorptive capacity may cause, for instance, persistent anemia only reversible though the intravenous route.

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:
 * 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. 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). 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.

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). 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.

Eating breakfast may reduce weight gain by adolescents