The Ob(Lep) Gene and Weight Loss
Structure of the obese protein leptin-E100
The Ob(Lep) gene (Ob for obese, Lep for leptin) is located on chromosome 7 in humans. Human leptin is a 16 kDa protein of 167 amino acids. Leptin should not to be confused with Lectin or Lecithin.
Leptin (from Greek meaning thin), the satiety hormone, is a hormone made by fat cells which regulates the amount of fat stored in the body. It does this by adjusting both the sensation of hunger, and adjusting energy expenditures. Hunger is inhibited (satiety) when the amount of fat stored reaches a certain level. Leptin is then secreted and circulates through the body, eventually activating leptin receptors in the arcuate nucleus of the hypothalamus. Energy expenditure is increased both by the signal to the brain, and directly via leptin receptors on peripheral targets. The effect of leptin is opposite to that of ghrelin, the hunger hormone. Ghrelin receptors are on the same brain cells as leptin receptors, so these cells receive competing satiety and hunger signals. Leptin and ghrelin, along with many other hormones, participate in the complex process of energy homeostasis. Although regulation of fat stores is deemed to be the primary function of leptin, it also plays a role in other physiological processes, as evidenced by its multiple sites of synthesis other than fat cells, and the multiple cell types beside hypothalamic cells which have leptin receptors. Many of these additional functions are yet to be defined.
Leptin was approved in the United States in 2014 for use in congenital leptin deficiency and generalized lipodystrophy.
An analog of human leptin metreleptin (trade name Myalept) was first approved in Japan in 2013, and in the United States (US) in February 2014. In the US it is indicated as a treatment for complications of leptin deficiency, and for the diabetes and hypertriglyceridemia associated with congenital or acquired generalized lipodystrophy. Leptin is known to interact with amylin, a hormone involved in gastric emptying and creating a feeling of fullness. When both leptin and amylin were given to obese, leptin-resistant rats, sustained weight loss was seen. Due to its apparent ability to reverse leptin resistance, amylin has been suggested as possible therapy for obesity.
Historically, the existence of a hormone regulating hunger and energy expenditure was hypothesized based on studies of mutant obese mice that arose at random within a mouse colony at the Jackson Laboratory in 1950. Mice homozygous for the ob mutation (ob/ob) ate voraciously and were massively obese. In the 1960s, a second mutation causing obesity and a similar phenotype was identified by Douglas Coleman, also at the Jackson Laboratory, and was named diabetes (db), as both ob/ob and db/db were obese. Rudolph Leibel and Jeffrey M. Friedman reported the mapping of the ob gene in 1990. Consistent with Coleman’s and Leibel’s hypothesis, several subsequent studies from Leibel’s and Friedman’s labs and other groups confirmed that the ob gene encoded a novel hormone that circulated in blood and that could suppress food intake and body weight in ob and wild type mice, but not in db mice.
In 1994, with the ob gene isolated, Friedman reported the discovery of the gene. In 1995, Caro’s laboratory provided evidence that the mutations present in the mouse ob gene did not occur in humans. Furthermore the ob gene expression was increased in human obesity, which led to postulate the concept of leptin resistance. At the suggestion of Roger Guillemin, Friedman named this new hormone leptin from the Greek lepto meaning thin. Leptin was the first fat cell-derived hormone to be discovered. Subsequent studies confirmed that the db gene encodes the leptin receptor and that it is expressed in the hypothalamus, a region of the brain known to regulate the sensation of hunger and body weight.
Coleman and Friedman have been awarded numerous prizes acknowledging their roles in discovery of leptin, including the Gairdner Foundation International Award(2005), the Shaw Prize (2009), the Lasker Award, the BBVA Prize and the King Faisal International Prize. The discovery of leptin has been documented in a series of books including Fat: Fighting the Obesity Epidemic by Robert Pool, The Hungry Gene by Ellen Ruppel Shell, and Rethinking Thin: The New Science of Weight Loss and the Myths and Realities of Dieting by Gina Kolata.Fat: Fighting the Obesity Epidemic and Rethinking Thin: The New Science of Weight Loss and the Myths and Realities of Dieting review the work in the Friedman laboratory that led to the cloning of the ob gene.
A mutant leptin was first described in 1997, and subsequently six additional mutations were described. All of those affected were from Eastern countries; and all had variants of leptin not detected by the standard immunoreactive technique. The most recently described eighth mutant reported in January2015 is unique in that it is detected by the standard immunoreactive technique, indicating that leptin levels are elevated but the leptin is nonfunctional. These eight mutations all cause extreme obesity in infancy, with hyperphagia. Leptin is produced primarily in the adipocytes of white adipose tissue. It is also produced by brown adipose tissue, placenta (syncytiotrophoblasts), ovaries, skeletal muscle, stomach (the lower part of the fundic glands), mammary epithelial cells, bone marrow, pituitary, liver, gastric chief cells and P/D1 cells. Leptin circulates in blood in free form, bound to proteins and leptin levels vary exponentially, not linearly, with fat mass. Leptin levels in blood are higher between midnight and early morning, perhaps suppressing appetite during the night. The diurnal rhythm of blood leptin levels can be modified by meal-timing. In humans, many instances are seen where Leptin dissociates from the strict role of communicating nutritional status between body and brain and no longer correlates with body fat levels:
1. Leptin level is decreased after short-term fasting (24-72 hours), even when changes in fat mass are not observed.
2. Leptin plays a critical role in the adaptive response to starvation.
3. In obese patients with obstructive sleep apnea, leptin level is increased, but decreased after the administration of continuous positive airway pressure. In non-obese individuals, however, restful sleep (i.e., 8-12 hours of unbroken sleep) can increase leptin to normal levels.
4. Serum level of leptin is reduced by sleep deprivation.
5. Leptin level is increased by perceived emotional stress.
6. Leptin level is decreased by increases in testosterone levels and increased by increases in estrogen levels.
7. Leptin level is chronically reduced by physical exercise training.
8. Leptin level is increased by dexamethasone.
9. Leptin level is increased by insulin.
10. Leptin levels are paradoxically increased in obesity.