Insulin. Insulin is a hormone that is critical in the conversion of blood sugar (glucose) into energy. The process of digestion breaks down carbohydrates from our diet into sugar molecules (of which glucose is one) and proteins from our diet into their smaller components, amino acids. Right after a meal, the amount of glucose in the blood rises and signals the release of insulin, which then pours into the bloodstream. Insulin enables the glucose and amino acids to enter cells in the body, importantly, those in the muscles. Here, insulin and other hormones direct whether these nutrients will be burned for energy or stored for future use. The inability to use insulin efficiently (insulin resistance) has been associated with both obesity and diabetes.

Leptin. Leptin is a hormone that is released by fat cells and also possibly by cells in the stomach. When researchers first observed that genetically fat mice were deficient in leptin and that injecting them with leptin caused them to become thin, they believed that leptin offered a solution for obesity. The specific role that leptin plays in obesity, if any, however, is still unclear and may be complex. People who are overweight but lack a genetic susceptibility to obesity tend to have normal or high levels of leptin. When such people diet, leptin levels drop in direct association with reductions in weight. The most likely scenario is that in people without genetic deficiencies, leptin levels rise as more fat is stored in the cells and signal the hypothalamus to suppress appetite. Falling levels then signal the brain to stimulate appetite. In overweight people who are genetically deficient in leptin, however, the brain is tricked into thinking that it is always starving because there is no leptin to suppress appetite. Some researchers hope that although leptin is not a weight-loss agent for non-genetically obese people it may help people maintain normal weight after losing it. Leptin may also affect the body’s resistance to the effects of insulin, a hormone that is critical for metabolizing blood sugar.

Agouti-Related Protein (AGRP). AGRP is a newly discovered protein that is controlled by leptin and regulates how many calories are consumed.

Wnt-10b. A protein called Wnt-10b apparently acts as a “fat switch” by turning off two molecules that regulate genes controlling fat cell formation.

Resistin. Resistin, a newly discovered hormone, is produced by fat cells and produces resistance to the activity of insulin. Some experts believe it may help explain the role of obesity in diabetes type 2. More research is warranted.

Other Chemicals. Certain hormones (particularly neuropeptide Y, pro-opiomelanocortin, and melanocyte stimulating hormone) and brain chemicals known as endorphins and enkephalins may play a critical role in appetite regulation. Cholecystokinin, a hormone released in the upper intestine that stimulates digestive juices, may work with leptin to stimulate or suppress appetite. A family of proteins known as uncoupling proteins (UCPs) may be critical in converting energy into heat rather than having it stored as fat.

Specific Genetic Factors
There are at least seven known genetic mutations that have been associated with specific and uncommon cases of severe obesity. A few are as follows:

A number of variants of the leptin gene, including those that cause leptin deficiencies and obesity, have been identified.

A gene called melanocortin-4 receptor that plays a key role in shutting off the urge to eat is defective in some families with a history of obesity.

Researchers have also identified a mutation in a gene for a protein called proopiomelanocortin, which results in a syndrome of obesity, red hair, and deficiencies in stress hormones.

About 5% of severely obese people have mutations that over-respond to agouti-related protein.

Genetics also determine the number of fat cells a person has, and some people are simply born with more.

The Thrifty Gene
Although genetic abnormalities may make it harder or easier to lose weight, the prevalence of obesity has dramatically increased over the past two decades, and genes cannot have changed within that short amount of time. The human metabolism evolved over centuries so that it could conserve energy and store fat during times of famine. Most cases of obesity occur now in people with normal physiology who live in industrialized nations where food is overly plentiful, and it is easy to avoid expending enough energy to burn the excess calories. One theory that combines genetic and environmental factors suggests that type 2 diabetes and the obesity that usually accompanies this disorder are derived from genetic actions that were once important for survival.

 
• Some experts postulate the existence of a so-called “thrifty” gene, which regulates hormonal fluctuations to accommodate seasonal changes. Theoretically, it works in the following manner:  
• In certain nomadic populations, hormones are released during seasons when food supplies have traditionally been low, which results in resistance to insulin and efficiently increased fat storage.  
• The process is reversed in seasons when food is readily available.  
• Because modern industrialization has made high-carbohydrate and fatty foods available all year long, the gene no longer serves a useful function and is now harmful because fat, originally stored for famine situations, is not used up.

Such a theory could explain the high incidence of type 2 diabetes and obesity found in Pima tribes and other Native American tribes with nomadic histories and Western dietary habits. The traditional low-fat high-fiber foods (corn, lima beans, white and yellow teparies, mesquite, and acorns) of the Pima people may have protected this genetically susceptible population in the past from the high incidence of obesity and Type 2 diabetes they are experiencing now.

Medical or Physical Causes of Obesity
A number of medical conditions may contribute to being overweight, although rarely are they a primary cause of obesity.

 
• Some overweight people may believe their weight problem is due to hypothyroidism; patients with an underactive thyroid, however, generally show only a moderate weight increase of five to 10 pounds, mainly due to accumulation of fluid.  
• Very rare genetic disorders, including Froehlich’s syndrome in boys, Laurence-Moon-Biedl, and the Prader-Willi syndromes, cause obesity.  
• Abnormalities or injury to the hypothalamus region in the brain can cause a condition called hypothalamic obesity.  
• Cushing’s disease is a rare condition caused by high levels of steroid hormones, which results in obesity, a moon-shaped face, and muscle wasting.  
• Obesity is also linked with polycystic ovarian syndrome, a common hormonal disorder in women.

Effects of Certain Medications
Some prescription medications contribute to weight gain, usually by increasing appetite. Such drugs include the following:

 
• Corticosteroids.  
• Some female hormone treatments, including some oral contraceptives (usually temporary) and certain progestins (such as Megestrol) used to treat cancer.  
• Antidepressants, and other psychoactive drugs, including certain antipsychotics, lithium, and antiseizure agents (such as valproate).  
• In a particularly unfortunate conflict of interest for obese individuals with type-2 diabetes, the use of insulin and insulin-stimulating drugs used to treat the condition often leads to weight gain.  
• Certain anti-seizure agents used in epilepsy and bipolar disorder can cause significant weight gain.  
• Certain antipsychotics.  
• Although drugs are not usually the primary cause of obesity or of being overweight, some people may be mistakenly tempted to stop taking their medications without their doctors’ knowledge.