Obesity may be viewed as the direct consequence of traits evolved to avoid starvation.

These traits affect appetite and energy expenditure ensuring adequate intake during periods of abundance and diminished expenditure of energy during famine.

The Energy Balance Equation

Any consideration of obesity should begin with the simple tautologic expression known as the energy balance equation, given below.

Energy intake = Energy output + storage

Although superficially simple, each of the components of the equation is more complicated than it seems. Energy intake is food consumed but it is now recognized that gut bacteria, the microbiome, are involved in nutrient processing in ways that favor or antagonize weight gain. Compounds produced by the microbiome may also influence metabolism by pathways that are currently unrecognized. Both the micro- and the macronutrient content of the diet also play a role. Although energy intake is, thus, more than just calories ingested, appetite obviously plays a crucial role by regulating food intake.

The regulation of appetite involves a complex series of signals from the periphery and within the CNS; these stimulatory and inhibitory factors interact at the level of the hypothalamus to regulate energy intake.

The orexigenic pathways in the arcuate nucleus of the hypothalamus involve the Agouti-related peptide (AgRP) and the neurotransmitter neuropeptide y (NPY) while the anorexigenic ones involve pro-opiomelanocortin (POMC) which includes melanocyte-stimulating hormone (MSH), the endogenous ligand for the melanocortin-4 receptor (MC4R) and serotonin (5HT). Leptin, the polypeptide product of the ob/ob gene, is secreted by adipocytes and suppresses appetite by inhibiting the orexigenic pathways and stimulating the anorexigenic ones.

The components of this system represent potential druggable targets for the treatment of obesity if the obstacle of off-target effects, particularly those in the CNS, can be overcome.

Energy output, once equated with physical activity alone, is now recognized to include important inter-individual differences in basal metabolic rate (BMR) and in the efficiency with which ingested calories are utilized and stored.

BMR accounts for between 60% and 80% of total energy output depending on the level of physical activity. BMR is the heat generated from tissue metabolism throughout the body. About 10% of daily energy expenditure represents “adaptive” thermogenesis, generated by SNS stimulation of brown adipose tissue (BAT).

Fat storage depots, once considered inert energy repositories, are now recognized to produce a large variety of biologically active compounds that influence metabolism and the propensity for weight gain.

Leptin is a good example: synthesized in adipose tissue and reflective of an individual’s fat mass, leptin feeds back to the hypothalamus to suppress appetite and stimulate the sympathetic nervous system (SNS) which increases energy expenditure. Leptin, therefore, is involved in the maintenance of energy balance by affecting both the intake and the output sides of the energy balance equation.

Overfeeding studies have demonstrated conclusively that individuals differ in metabolic efficiency (the relationship between ingested calories and storage of fat).

When overfed a measured increase in caloric intake for significant periods of time individuals vary in the amount of weight gained. Some gain incrementally, close to the calculated caloric excess, while others dissipate more than half of the calories taken in excess. Overfeeding studies with pairs of twins show greater variation between twin pairs than within twin pairs, consistent with a genetic contribution to metabolic efficiency.

Studies indicate that genetic factors contribute between 40% and 50% to the development of obesity.

Thus, both the environment and genetics contribute to the pathogenesis of obesity.

Thrifty Metabolic Traits

Metabolic efficiency is one of several “thrifty” metabolic traits, evolved to resist death from starvation. These thrifty traits include lower metabolic rate, increased metabolic efficiency, and insulin resistance.

Lower BMR and more efficient metabolism resist death from starvation by decreasing the overall need for metabolizeable substrates. Insulin resistance diminishes the need for gluconeogenesis by diverting glucose from muscle which can utilize fat derived substrates, to the brain which requires glucose.

The cause of death in starvation is pneumonia, a consequence of muscle protein depletion which impairs the ability to cough and thus clear secretions from the upper airway.

The result is aspiration and death from pneumonia, as pointed out decades ago by Harvard Professor George Cahill.

In starvation gluconeogenesis is the only means of providing the brain with glucose, for practical purposes the only energy source the CNS is able to utilize.

Gluconeogenic precursors come from the breakdown of protein, of which skeletal muscle is the largest reservoir.

Insulin resistance, defined as a decrease in insulin-mediated glucose uptake in skeletal muscle, directs glucose away from muscle toward the brain, thus sparing muscle protein breakdown.

Thrifty metabolic traits, evolved to prolong survival during famine, promote the development of obesity and type 2 diabetes mellitus when the food supply is abundant.

Those individuals well supplied with thrifty traits would survive famine better but are heir to obesity and type 2 DM in developed countries today. These thrifty traits have persisted since the adverse effects of obesity develop over decades, well past reproductive age in most subjects. This is in distinction to starvation which has its effects in the short term.

Examples of the impact of thrifty traits on the development of obesity may be found in indigenous populations worldwide. The aboriginal people of Australia, the Maoris of New Zealand, and the Pima Indians of the southwest US, all of which faced bare subsistence conditions for centuries, were known to be thin 100 years ago, and now are plagued by obesity and its complications.

Successful treatments for obesity should address both sides of the energy balance equation: appetite and energy expenditure.

CARDIOVASCULAR AND METABOLIC CONSEQUENCES OF OBESITY

Most organ systems are adversely affected by obesity. In some, obesity plays a major role in disease risk; in others, a contributory factor. Obesity has a dominant role in the development of cardiovascular disease, both directly and as a consequence of its role in the causation of type 2 DM and hypertension.

Body fat distribution plays an important role in the metabolic and cardiovascular complications of obesity.

Body mass index (BMI) and percent body fat are important indices of obesity but do not tell the whole story. The distribution of fat between upper body (central, abdominal) and lower body (gluteal) has been referred to as android (apple shaped) and gynoid (pear shaped) respectively, although the fat distribution is not specific for gender. Both men and women may have either type of distribution. Jan Vague, a French clinician practicing in the middle of the last century, coined the terms android and gynoid and noted that the metabolic (diabetes) and the cardiovascular complications of obesity (hypertension, myocardial infarction) tracked with the android form of obesity.

Using surrogate measures such as waist circumference or waist to hip ratio it has been firmly established that the upper body (android) form of obesity is associated with greater insulin resistance and hyperinsulinemia than the lower body form (gynoid). Insulin resistance, thus, tracks with the metabolic and cardiovascular complications of obesity. Fat within the abdomen, and in the liver seem to play and important role in the genesis of complications associated with obesity.

It is not clear what determines the distribution of body fat. Since intra-abdominal adipocytes are more sensitive to hormonal stimulation than adipocytes from peripheral sites, insulin-stimulated lipogenesis may be involved.

The activation of a glucocorticoid effect in intra-abdominal adipocytes by the action of 5-hydroxysteroid dehydrogenase is another possible mechanism; favoring the formation of active cortisol relative to inactive cortisone in abdominal adipocytes might be associated with expansion of the abdominal fat mass as seen in Cushing’s syndrome.

Abdominal (central, android) obesity is the major cause of insulin resistance.

Although insulin has many actions in the regulation of metabolism insulin resistance refers specifically to its effect on skeletal muscle uptake of glucose, since more than 80% of total body glucose uptake mediated by insulin goes into skeletal muscle. The insulin resistance is caused by lipid accumulation in muscle which blocks the translocation of the glucose transporter (GLUT 4) to the cell membrane, a necessary prerequisite for transport of glucose into the cell.

Hyperinsulinemia is a consequence of insulin resistance.

The impediment to glucose uptake raises the blood glucose level stimulating more insulin release from the pancreatic beta cells and establishing a new steady state with a normal to slightly elevated glucose level and an elevated level of insulin. When the beta cells can no longer keep up with the demand imposed by insulin resistance plasma glucose rises and impaired glucose tolerance followed by type 2 DM ensues.

Another theory postulates that hyperinsulinemia is primary, since it has been known for a long time that elevated insulin levels induce insulin resistance.

Many of the adverse effects of obesity are rooted in insulin resistance.

Obesity, particularly the abdominal form, is the major risk factor for the development of both type 2 DM and hypertension.

Insulin resistance with pancreatic failure leads to type 2 DM. Hypertension results from SNS stimulation driven by hyperinsulinemia and leptin, coupled with a direct effect of insulin on the renal tubular reabsorption of sodium.

High triglycerides and low HDL cholesterol constitute the characteristic dyslipidemia of obesity.

Population-based studies demonstrate that insulin plays a major role in the genesis of the obesity-related dyslipidemia.

Acanthosis nigricans is a dermatologic marker of hyperinsulinemia.

A velvety, verrucous pigmented lesion located behind the neck, in the axillae, and on the knuckles may occur in insulin-resistant states, perhaps because hyperinsulinemia stimulates epidermal growth factor receptors.

Insulin resistance, abdominal obesity, hypertension, and high triglycerides – low HDL, form a cluster known as “the metabolic syndrome.”

A better name for this constellation would have been the “insulin resistance syndrome” since insulin is the thread that ties these diverse manifestations together. The following may also be associated: small dense (atherogenic) LDL; microalbuminuria; type 2 DM; hyperuricemia; coagulation abnormalities (increased plasminogen activator inhibitor-1, PAI-1); nonalcoholic fatty liver disease (NAFLD); and increased inflammatory markers.

Although arguments abound as to whether this is a distinct syndrome, the clinical significance of this cluster is the enhanced cardiovascular risk that the various components confer.

The obesity paradox: longevity, including longevity in a variety of chronic disease, is greater in the overweight (BMI 25 to 30) and the modestly obese (BMI 30 to 33). There is a “J” curve relationship between obesity and mortality.

The reasons for this counterintuitive finding are not entirely clear. In part it may be that obesity itself without the confounding effects of diabetes or hypertension has a mild protective effect. The presence of hypertension and/or diabetes, of course, has a detrimental effect on longevity.

Since this direct relationship between BMI and mortality is stronger in the elderly, what the epidemiologists refer to “survivor bias” or “depletion of susceptibles” (those at risk die earlier) may be involved.

OBESITY AND OTHER DISEASES

Obesity exerts adverse effects on virtually all organ systems. In addition to the cardiovascular system and impaired carbohydrate tolerance outlined above, the most important organ systems or diseases impacted by obesity include the liver, the joints, the gut, respiration, and malignancies.

NAFLD, “fatty liver,” is increasingly recognized as an important complication of obesity since it may progress to NASH (nonalcoholic steatohepatitis) and thence to cirrhosis.

Accumulation of fat in the liver is a critical component of the abdominal (central) obesity phenotype, and occurs frequently in patients with the metabolic syndrome. As such it is associated with, and predictive of, increased cardiovascular morbidity and mortality.

The increased levels of free fatty acids in obesity, coupled with hyperinsulinemia, leads to increased triglyceride synthesis in hepatocytes. In and of itself NAFLD is not serious and is rapidly reversible; the danger lies in the progression to NASH and cirrhosis.

NASH evolves when fat in the liver stimulates inflammatory cell infiltration.

For reasons that are not entirely clear fat may trigger the release of proinflammatory cytokines from hepatocytes with resultant infiltration by inflammatory cells. The result is steatohepatitis which may be accompanied, in a minority of such patients, by fibrosis, loss of normal hepatic microarchitecture, and cirrhosis. The complications of cirrhosis that develops in patients with NASH are the same as those that complicate cirrhosis of other etiologies: portal hypertension, variceal hemorrhage, and hepatocellular carcinoma.

Osteoarthritis of the hips and knees, gastroesophageal reflux, sleep apnea, and polycystic ovarian syndrome complicate obesity.

Certain malignancies are more common in the obese including all portions of the GI tract, pancreas, liver, gall bladder, breast, ovarian and endometrial carcinomas, prostate cancer, and lymphomas.

The mechanisms are unclear but higher levels of insulin and insulin-like growth factors along with proinflammatory cytokines are potential factors.

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