Regulation of Body Weight

At any given time, up to 40 million Americans are on a diet, and probably as many more think they should be on a diet. Interestingly, weight itself often has nothing to do with people’s feelings about dieting — many people just think they are too fat, when in reality their weight is perfectly acceptable and well within health parameters.

 

While the quest for thinness is a national preoccupation, at the same time, obesity is the No. 1 nutritional disease in the U.S. More than two-thirds of adults are overweight; the prevalence of overweight Americans (body mass index [BMI] of 25 kg/m² or more) is 69% in adults older than 20. The percentage of overweight people increased from 47% in 1980, to 56% in 1994, to 68.5% in 2012.¹ The obesity rate for adults jumped from 15% in 1970, to 32% in 2004, and to 35% in 2012 (this indicates there was no significant change among obesity rates for adults and children from 2003–2004 to 2011–2012, according to the National Health and Nutrition Examination Survey [NHANES] data, which is good news).^{1,2 (Level B)} Although obesity crosses ethnic and socioeconomic boundaries, it is more prevalent in African Americans and Hispanics than in Caucasians or Asian-Americans.³

 

Weight Loss and Weight Control

 

From the 1970s, when the obesity epidemic was beginning, to today, the estimated caloric change is approximately 400 kcal/day. What is debated is if the change is from increased calories, decreased physical activity, or a combination of the two.⁴ Clearly, overweight, obesity, and associated diseases and conditions are major problems that most people try to solve by dieting.

 

Unfortunately, 80% of all diets fail. Of the 20% of dieters who do manage to lose weight, an estimated 95% regain what they took off, and many gain back even more weight than they originally lost. Only 5% of dieters who lose weight maintain the weight loss.

 

The quest for thinness can have lifelong health risks. Many diets are not nutritionally balanced. They have too few calories and nutrients, which puts stress on the body. Because improper nutrient intake is a risk factor for many diseases, some diets may put the dieter at increased risk for disease. Accordingly, health professionals across disciplines are examining many long-held beliefs about weight control in light of revolutionary findings concerning regulation of energy metabolism and which types of diets are effective. Hormone-like proteins, produced by genes in fat cells, are involved in the regulation of energy metabolism, energy expenditure and, ultimately, a person’s weight. Many diet strategies (such as low carbohydrate) appear to be an effective way to lose weight, although the long-term consequences are unknown.

 

These findings have sparked a re-examination of basic assumptions concerning weight and weight control, such as:

• What weight is healthy?
• What weight contributes to disease?
• How do adipose tissue, proteins, hormones and gut microbes regulate weight?

 

To answer the first question, it is important to understand how a healthy weight is determined, and the role of body composition in energy balance.

 

BMI

 

BMI is the recommended method to determine weight status and health risk. In metric measurements, BMI equals kg/m², or weight (in kilograms) divided by height (in meters squared). Using imperial measurements, BMI equals weight (in pounds) divided by height (in inches squared), and then multiplied by 703.

 

BMI = kg/m² OR lbs/in² x 703

 

According to the National Institutes of Health, this is an easy and useful guide for determining normal weight, overweight and obesity. BMI correlates to direct measures of body fat. The BMI ranges below are based on the relationship between body weight and disease and death.^5,6 Software and apps to calculate BMI are readily available.

 

BMI Classification of Overweight and Obesity7 (Level ML)
	BMI (kg/m2)	Obesity Class
Underweight	<18.5	—
Normal	18.5 to 24.9	—
Overweight	25 to 29.9	—
Obese	30 to 34.9	I
	35 to 39.9	II
Extreme Obesity	40+	III

 

A person with a BMI of 25 or greater is at increased risk for developing a number of health conditions, including diabetes, heart disease, stroke, hypertension, gallbladder disease and some cancers.

 

Body Composition

 

While useful, BMI does not take body composition into consideration. The body is made up of lean body mass (muscle), fat and bone. Fat-free mass is used to define “everything in the body except fat.” In some circumstances, a person may be classified as overweight based on BMI despite having a very low percentage of body fat and high percentage of lean body mass. Highly muscular athletes often fit into this category.

 

Another person may not be statistically overweight, but if his or her percentage of body fat is high, he or she may be at increased risk of developing one of the conditions associated with obesity. The average body fat percentage for an American woman is about 25% to 31%, while the average American man has approximately 18% to 24% body fat. The recommended amount of body fat for women is between 21% and 24% and between 14% and 17% for men. A man with more than 25% body fat is considered obese; a women with more than 32% body fat is considered obese.⁸

 

Distribution of body fat. Both the amount and the location of fat are important health considerations. Upper-body obesity (also known as android or central obesity) is associated with greater metabolic disturbances, such as glucose intolerance, elevated blood pressure and serum lipids, than lower-body obesity (also known as gynoid obesity). Those with more fat around the waist are at greater risk for increased morbidity and mortality, compared with those with more fat around the hips.

 

Upper-body obesity includes both visceral and subcutaneous abdominal fat deposits. Visceral fat refers to fat storage within the abdominal cavity, surrounding the organs. It is comprised of mesenteric and omental fat cells. Visceral fat is approximately 20% of total fat storage of adult males, and approximately 6% of total fat storage in adult females. Subcutaneous abdominal fat deposits are just below the skin in the abdominal area. Visceral fat is related to increased disease risk, not subcutaneous abdominal fat. In gynoid obesity, all fat storage sites are subcutaneous.^{9 (Level B)}

 

Unfortunately for many, genetics plays a more significant role in determining body fat distribution than any other factor. Environmental factors, such as diet and exercise, are more important in determining total body fat.¹⁰

 

Waist circumference. Both BMI and waist circumference should be considered in diagnosis and evaluation of obesity. Measuring waist circumference is a tool to help determine if a person carries excess fat around the abdomen. Experts recommend measuring waist circumference at least annually in the overweight and obese.⁷

 

To measure waist circumference, locate the upper hip bone and top of right iliac crest. Place a measuring tape in a horizontal plane around the abdomen at level of iliac crest. Before reading tape measure, ensure that tape is snug but does not compress skin, and is parallel to the floor. The measurement is made at the end of an exhalation. A waist circumference greater than 40 inches (102 cm) in men and greater than 35 inches (88 cm) in women is associated with increased disease risk, especially if the person falls into the overweight or obese category.⁶

 

What Is a “Healthy” Weight?

 

Being overweight or obese has health risks, but at what level of “fatness” does a person increase his or her risk of chronic disease? This is an important question for the healthcare team because so many people are overweight, and so few successfully lose weight and keep it off.

 

Losing weight can help reduce blood pressure, serum lipids and elevated blood glucose levels, all of which are risk factors for cardiovascular disease. Many people with type 2 diabetes can stop taking oral medications or avoid having to take insulin shots when they lose weight. High blood pressure is treated more easily as weight decreases. Moderate weight loss in those with hypertension can eliminate the need for medication in up to 50% of cases. Clearly, being overweight or obese has health risks that can be minimized by losing weight.^{10 (Level B), 11}

 

Furthermore, adults who maintain a healthy BMI seem to have an improved quality of life as they age.¹² Only 24.3% of women and 36.5% of men with a BMI more than 30 reported being in good or excellent health, compared with 46.8% of women and 53.8% of men who were at a healthy weight.^{12 (Level B)}

 

Yet the question remains: What is a healthy weight? The answers are not easy to come by. Many studies have investigated the relationship of BMI to morbidity and mortality, and come to different conclusions. Some studies have found that being overweight does not increase mortality, but being underweight does.¹³ Others have found an increase in morbidity and mortality in being overweight or having class I obesity, while other studies have not.¹⁴ It may also be a question of fitness: Those who are fit and overweight may be healthier than those of normal weight who are physically inactive.¹⁵

 

The 2010 Dietary Guidelines for Americans recommend a BMI of 18.5 kg/m² to 24.9 kg/m² to maintain a healthy weight. Weight loss of 3% to 5% of body weight is associated with clinically significant health improvements, with larger losses leading to even greater health improvements.^{7 (Level ML)}

 

Regulation of Food Intake

 

The body is able to regulate food intake and energy balance to maintain constant weight and fat stores through a complex network that includes many systems of the body: sensory perceptions, organs, nervous system, hormones, peptides, neurotransmitters, metabolism and metabolites.¹⁶

 

The brain monitors neural and chemical signals from the GI tract, liver, adipose (fat) tissue, nervous system and bloodstream. Once the signal is received and processed, the brain sends a message to turn eating cues on or off. The signaling travels two ways, as messages from the body are sent to the brain, and the brain sends signals back, via chemicals and the nervous system.

 

The process begins when the brain determines that blood glucose levels are too low. The vagus nerve and sympathetic nervous system send messages to begin to eat. Once food is ingested, chemical and neural feedback signals are sent continually to the brain so it can monitor levels of nutrients, and determine when to inhibit eating. Gastric distention occurs when the stomach is full, sending a message to stop eating; however, not everyone heeds this message.

 

Once food reaches the stomach and digestion begins, certain enzymes, hormones and peptides such as cholecystokinin, insulin, bombesin and somatostatin are produced and travel to the brain via the bloodstream. Based on the levels in the bloodstream, the brain turns eating cues on or off.

 

During and after a meal, serum insulin levels rise to clear glucose from the bloodstream. The insulin binds to receptors in the brain; when a certain level is reached, brain signals inhibit eating. Three to five hours after a meal, serum insulin levels fall, indicating low amounts of glucose in the bloodstream. This signals a need for more food, so the brain stimulates eating. As weight increases, the body becomes more resistant to insulin; more insulin is needed to get glucose into the cells. The resulting hyperinsulinemia very possibly increases hunger, so the person eats more food, contributing to obesity.

 

The vagus nerve provides feedback on the amount of nutrients ingested and when to alter food intake. It also stimulates the production of enzymes and hormones necessary for digestion and absorption. Neurotransmitters, produced in the peripheral or central nervous system, signal the brain about the need either to continue or to stop eating. Serotonin, a neurotransmitter, has a calming effect on the body and is understood to affect what some people call a “carbohydrate craving.” Serotonin is converted from tryptophan, which is an amino acid that crosses the blood-brain barrier. Tryptophan competes with five other large, neutral amino acids (tyrosine, leucine, phenylalanine, isoleucine and valine) for absorption. In protein foods, the ratio of tryptophan to other amino acids is low, so there is competition for access to the carrier molecule to cross the blood–brain barrier. Less tryptophan gets across, so less serotonin is produced. In carbohydrates, there is a higher ratio of tryptophan to the other amino acids, so more tryptophan can cross the blood–brain barrier, increasing serotonin production. Thus, carbohydrates can produce a biologically based calming effect.

 

In a classic study, when subjects were given a drug that increased serotonin production, their voluntary intake of carbohydrates decreased significantly, indicating that serotonin production has some effect on cravings for carbohydrates.¹⁷ Serotonin plays an important role in energy balance; not only is the amount of serotonin important, but having an adequate amount of serotonin transporter proteins is critical as well. It appears that epigenetic changes (hypermethylation) of the serotonin transporter gene could be associated with obesity by reducing the number of proteins and the amount of serotonin in the brain.¹⁸

 

Regulators are also responsible for increasing intake when needed. Hormones and neurotransmitters are sent from the blood and nervous system to indicate that energy is needed. These signals are translated into the motor actions necessary to obtain food and eat it.

 

Genes, Adipocyte Hormones and Proteins

 

The understanding of food intake and weight regulation has been revolutionized with the identification of the genes in adipocytes (fat cells) that are responsible for obesity. These genes have the ability to encode hormone-like proteins, and integrate feedback mechanisms from various parts of the body to control food intake, energy metabolism, body weight, and patterns of body fat distribution. These hormone-like proteins are known as adipokines.¹⁹

 

Leptin. The most-studied obesity gene, the human obese (ob) gene, encodes leptin, which is a protein. It is secreted from fat cells in proportion to body fat levels, and travels to the hypothalamus where it does its work.²⁰ The apparent role of leptin is to inhibit the production and release of neuropeptide Y (NPY), agouti-related protein (AgRP) and melanin-concentrating hormones (MCH). NPY stimulates food intake, reduces energy expenditure and promotes the activation of enzymes in fat cells, leading to weight gain.²⁰ The more NPY present, the greater the amount of food consumed, which results in increased body weight. Increased levels of leptin decrease NPY and prevent overconsumption of food and increased body weight.

 

Leptin is released in proportion to body fat levels, as shown by studies demonstrating a correlation of leptin levels with BMI. Most obese and severely obese humans produce high levels of leptin in direct proportion to their BMI.²¹ “Leptin resistance,” which is the inability to respond to high levels of leptin, appears to contribute to obesity and is caused by a number of pathophysiological factors.²¹

 

The size of fat cells makes a difference in leptin production. Large fat cells produce more leptin than normal or small ones. To prevent too much weight gain, the body will increase leptin levels in tandem with increasing fat mass and food intake. As leptin increases, NPY decreases, signaling the body to turn off appetite to prevent weight gain.

 

 

Leptin and Weight Regulation20
Food intake increases	Food intake decreases
↓	↓
Leptin increases	Leptin decreases
↓	↓
NPY, AgRP and MCH decreases	NPY, AgRP and MCH increases
↓	↓
Food intake decreases	Food intake increases
↓	↓
Weight decreases	Weight increases

 

 

The opposite would occur with a decrease in food intake. When a person goes on a diet, the fat cells shrink and less leptin is produced, allowing an increase in the production of NPY. The increased NPY stimulates the appetite to make up for the energy deficit. This may explain why diets fail, and why so many people gain back the weight they lose. Once weight is lost, the body, due to the decrease in leptin, tries to gain that fat mass back. In essence, human genetic makeup is biased in favor of weight gain as a means of survival. However, if there is leptin resistance, the body would not get the signal that intake had increased, and would not decrease production of NPY or other signals to decrease intake.

 

Ghrelin. This peptide was discovered in 1999. It is involved in meal initiation in the gut. Produced in the small intestine, stomach, pituitary and ghrelin neurons in the hypothalamus, it works by altering levels of peptides in the hypothalamus that control eating.^16,22 Data indicate that ghrelin is a potent stimulator of food intake; however, increases in ghrelin after weight loss have not been associated with regaining weight.²³

 

Adiponectin and resistin. Secreted by fat cells, these proteins affect storage and breakdown of fat, and the regulation of appetite via communication with the central nervous system and GI tract.¹⁹

 

Cholecystokinin (CCK). This peptide stimulates bile production in the liver and the release of enzymes from the pancreas, and decreases the rate of gastric emptying. CCK also stimulates the vagus nerve, affecting neurotransmitters in the brain that provide a message of satiety. CCK may also stimulate short-term satiety by influencing the release of leptin.²⁴

 

Peptide YY (PYY). Similarly to CCK, PYY increases the release of neurotransmitters in the brain to increase satiety. PYY also delays gastric emptying and inhibits gastric acid secretion.²⁵

 

Glucagon-like peptide-1 (GLP-1). GLP-1 is a peptide hormone that stimulates the release of insulin from the pancreatic beta cells in response to a meal. GLP-1 also suppresses glucagon secretion from alpha cells of the pancreas, delaying gastric emptying and suppressing appetite.^{26 (Level B), 27}

 

Select Genes, Adipocyte Hormones and Proteins and Their Role in Obesity19,20,23-27
	Origin	Role in Obesity
Leptin	Protein secreted from fat cells	Inhibits production and release of NPY in hypothalamus to prevent overeating/weight gain May correlate with BMI and adipose tissue
Neuropeptide Y (NPY)	Peptide released from the hypothalamus	Stimulates food intake, reduces energy expenditure Promotes activation of enzymes in fat cells, leading to weight gain
Ghrelin	Gut peptide produced in small intestine, stomach, pituitary and hypothalamus	Alters levels of peptides in hypothalamus that control eating Stimulates food intake
Adiponectin and Resistin	Proteins secreted by fat cells	Role in storage and breakdown of fat and regulation of appetite via communication with central nervous system and GI tract Adiponectin may lower glucose by increasing sensitivity to insulin Healthy eating may improve adiponectin levels
Cholecystokinin (CCK)	GI tract, produced in the duodenum of small intestine by cells on the mucosal epithelium	Stimulates bile production in the liver Stimulates release of enzymes from the pancreas Decreases the rate of gastric emptying Stimulates the vagus nerve, affecting neurotransmitters in the brain that provide a message of satiety
Peptide Y (PYY)	GI tract, mainly by cells in the ileum and colon	Increases release of neurotransmitters in the brain to increase satiety Delays gastric emptying Inhibits gastric secretion
Glucagon-like Peptide-1 (GLP-1)	GI tract, mainly by cells in the ileum and colon	Stimulates release of insulin from the pancreatic beta cells in response to a meal Suppresses glucagon secretion from alpha cells of the pancreas Delays gastric emptying and suppresses appetite

 

 

Genetics and Weight Regulation

 

Considerable research confirms that genetics play a major role in the human response to food and in energy balance; estimates are that 35% to 60% of obesity is attributed to hereditary factors. Some factors include the basic neurophysiological systems of the brain that regulate food intake, body composition, metabolic rates that affect ability to lose and regain weight, and eating behavior traits.¹⁰

 

Research has identified hundreds of genes associated with body weight, energy balance and food intake regulation. Mutations in one particular gene, melanocortin-4 receptor (MC4R), have been related to uncontrolled overeating, binge-eating behaviors, hyperinsulinemia, leptin resistance, increased fat mass and body size.^{28 (Level B)} Researchers found strong evidence that mutations in the MC4R gene contributed to obesity in Hispanic children by altering the regulation of physical activity, energy expenditure and fasting serum ghrelin.²⁸

 

A study of 12 pairs of identical twins supports the theory that some have a genetic tendency to gain more weight than others, even when energy intakes are comparable. When identical twins ate an extra 1,000 kcal/day for 100 days, some of the pairs gained 9 pounds each; while others gained up to 29 pounds each. Although the weight gained varied from twin set to twin set, it was found that each pair of twins gained similar amounts of weight; percentage and distribution of body fat was also similar.²⁹

 

Although research suggests that a significant percentage of obesity is linked genetically, the contribution of genetic factors to obesity is highly variable. It is possible that one person’s weight may be 90% genetically influenced, while another’s is only 10% influenced by genetics.³⁰

 

A recent large-scale review looking at 12 studies including 8,179 monozygotic and 9,977 dizygotic twin pairs in addition to individual participant data for 629 monozygotic and 594 dizygotic pairs suggests that the heritability of BMI over all age categories from preadolescence through late adulthood ranges from 61% to 80% for men and women combined.³¹ Much work remains to be done to determine the interaction of obesity genes, their mutations and the predisposition to gain weight.

 

Adipose Tissue and Energy Balance

 

The discovery that adipose tissue secretes many peptides and hormones has altered our understanding radically of its role in weight regulation, metabolism and chronic disease. Now considered an endocrine organ, adipose tissue regulates the storage and breakdown of fat, communicates with the central nervous system and GI tract, and constitutes an important factor in energy balance, inflammation, glucose regulation, insulin sensitivity and chronic diseases.¹⁹

 

Researchers have found that as the amount of adipose tissue changes, so does the quantity of the peptides and proteins secreted. For instance, adiponectin is a protein involved in lowering serum glucose by increasing sensitivity to insulin. It is also anti-atherogenic, anti-inflammatory and antihypertensive, and having low concentrations of adiponectin has been linked to occurrences of some types of malignancies.³² As fat cell mass increases, adiponectin levels decrease, and the pro-inflammatory cytokines tumor necrosis factor-alpha and interleukin-6 increase. This causes a corresponding decrease in the sensitivity of muscles to insulin and increases inflammation in the tissues.^{33 (Level B)} Adiponectin levels are influenced by genetics, nutrition, exercise, and abdominal adiposity, and are probably inversely associated with visceral fat. The obese who have metabolic syndrome, diabetes and heart disease have lower adiponectin levels than healthy or non-obese people with type 2 diabetes. When someone goes on a diet and loses weight, adiponectin levels increase, as does insulin sensitivity.³²

 

The obese produce less adiponectin, and more resistin and pro-inflammatory cytokines, leading to a systemic inflammatory state. Obesity is now seen as a low-grade inflammatory state, characterized by increased C-reactive protein (CRP) levels and other inflammatory mediators.³² Chronic inflammation may be at the root of metabolic syndrome.¹⁹

 

As weight is lost and fat mass decreases, there is improvement in glucose regulation, insulin sensitivity, immune function, blood pressure regulation and atherosclerosis as adiponectin increases and pro-inflammatory cytokines decrease. This may explain how obesity causes metabolic syndrome, diabetes, heart disease and other chronic diseases.³⁴

 

Healthy eating may also improve adiponectin levels. The Nurses Health Study found that the nurses with the healthiest diet had a 24% higher median total adiponectin, 32% greater high molecular weight adiponectin, 41% lower CRP, and 16% lower resistin.³⁵

 

Energy balance is complex.

 

What’s Involved in Energy Balance?
Organs	Chemicals	Genetics	Diet	Behaviors
Brain	Peptides	DNA	Hunger	Physical activity
Nervous system	Neurotransmitters	Epigenetics	Nutrient composition	Psychological eating
GI tract/ gut microbes	Hormones	Body composition	Total intake	Food habits
Stomach	Cytokines	—	Metabolism	Environment
Pancreas	Adipokines	—	Gut microbes	—
Fat cells	—	—	—	—
Liver	—	—	—	—

 

 

Intestinal Microbiota

 

Variations in the types and amounts of bacteria naturally occurring in the human GI tract have also been linked to obesity. The human GI tract is host to trillions of bacteria that have metabolic interactions with each other and the human host, influencing human nutrition and metabolism.³⁶ Gut microbiota synthesize essential B vitamins and vitamin K, and harvest energy from the diet that is used to produce short-chain fatty acids. These fatty acids provide an energy source for cells in the colon and liver. Through their interactions with receptors on the epithelial cells, they release various cellular factors that influence human metabolism that may play a role in the development of metabolic syndrome, diabetes and nonalcoholic fatty liver disease.³⁶

 

The role of gut microbiota on body-weight regulation originated from studies using mice models in which transplantation of intestinal microbiota from obese mice to lean mice led to 60% increase in body fat content and development of insulin resistance despite reduced food intake.³⁷ Additional studies using animal models have indicated that obesity is associated with characteristic changes in the composition of gut microbiota.

 

Bacteria within the intestine play an important role in energy absorption (particularly of complex carbohydrates), and in sugar and short-chain fatty acid metabolism. Studies in obese mice lacking the leptin gene suggest that these mice absorb more energy (calories) from dietary carbohydrate than conventional (non-obese) mice, which may be contributing to obesity. While there is less data in humans, association studies indicate there are alterations in the gut microbiota in the obese compared with lean people, with the obese having reduced microbial diversity and alterations in the genes involved in metabolic pathways.³⁸

 

Roux-en-Y gastric bypass (RYGB) surgery in obese humans has been shown to result in changes in the gut microbiota, suggesting that weight reduction may influence gut microbiota composition.³⁸ While there are several possible mechanisms that may explain the link between weight and gut microbiota in humans, increased efficiency of energy absorption from food in obese compared with lean people is one possible factor.³⁶

 

Conclusion

 

While new discoveries point to a genetic and molecular basis for obesity, they are not the entire story. Genetics and environment combine to play a role in people who are overweight or obese — and who can successfully lose weight and keep it off. Other factors such as metabolism, thermic effect of food, body composition, hormones, activity of the sympathetic nervous system, gut microbiota, epigenetics and nutrient composition of the diet all interact to determine how weight is regulated.