Leptin and the Obesity Gene
September 1, 1997 5 minutes read
Leptin and the Obesity Gene
By Leon Speroff, MD
The race is on. since the cloning of the ob gene in 1994, pharmaceutical companies are vigorously pursuing leptin research, resulting in an outpouring of scientific leptin reports in the last two years. The incredible interest and volume of work are fueled by the potential for a money-making therapeutic agent for the treatment of obesity.
Leptin is a peptide secreted in adipose tissue that circulates into blood that is bound to a family of proteins and acts on the central nervous system neurons that regulate eating behavior and energy balance.1 The rodent models used to study leptin were described more than 30 years ago. The ob/ob mouse is homozygous for a mutation of the ob gen, the gene that encodes leptin. The db/db mouse is homozygous for a mutation of the db gene, the "diabetic" gene, now known to encode the leptin receptor. Thus, the ob/ob mouse is obese because it does not produce leptin, and the db/db mouse is obese because it cannot respond to leptin.
The leptin receptor belongs to the cytokine receptor family and exists in two forms, a short form and a long form.2 The long form is the likely signaling form, and the only place it is expressed in greater amounts than the short form is in the hypothalamus. The db mutation converts the long form to the short form and, thus, signaling is prevented.
An important discovery was that leptin induces weight loss in mice because of decreased appetite and food consumption and an increase in heat production and activity. An inverse relationship exists between leptin levels and the hypothalamic concentration of neuropeptide Y (NPY), a peptide that stimulates food intake, decreases heat production, and increases insulin and cortisol secretion. Thus, the mechanism for regulation of appetite and energy expenditure involves a message between fat cells and the brain, transmitted by leptin, and in the brain, control of appetite and energy expenditure, regulated by NPY, which in turn, is regulated by leptin. Fasting and exercise decrease fat, lower leptin levels, and increase NPY gene expression. Eating increases insulin and leptin levels, and decreases NPY expression. Insulin is at least one regulator of the ob gene and its secretion of leptin.
When life was tougher, leptin served the purpose of meeting the threat of starvation. During periods of food availability, individuals with defects in the leptin system could consume large amounts and store excess fat. Today with no shortage of food, these individuals who survived during food shortages in the past now become obese and succumb to the complications of obesity.
Most studies have indicated that nearly all obese adults and children have elevated leptin levels, due to an increase in ob gene expression and partly due to greater production because of larger fat cells. In obese individuals, fat cells therefore produce leptin normally, and a prevalent genetic failure has not been identified. Thus, it is hypothesized that obesity is due to resistance to leptin, and the exact mechanism is a subject of intensive study.
A small percentage of obese humans will probably have mutations in the leptin receptor or the ob gene. The first definitive demonstration of a congenital leptin deficiency in humans was recently reported in two severely obese children who were cousins. Their serum leptin levels were very low due to a homozygous deletion of a single guanine in the leptin gene.
Why is it so hard for overweight people to maintain weight loss? Weight loss in obese and lean people produces the same response, decreased leptin and insulin. The obese person tends to regain weight because the lower leptin started from a different set point and is now lower than what the body views as required to be stable in terms of the amount of fat. When energy expenditure, food intake, and body weight are in balance, leptin is at a level consistent with a set point determined by this balance. With weight loss and loss of fat, leptin decreases, causing an increase in appetite and a decrease in energy. This is great when you lose weight with an illness, but it is not good for an overweight person trying to lose weight. Thus, whenever a perturbation occurs, leptin levels change to restore the original status quo, making it difficult for overweight people to maintain weight loss.
Several observations indicate a role for leptin in reproductive physiology. Leptin administration accelerates the onset of puberty in rodents and restores fertility in ob/ob mice. Leptin levels decrease with increasing Tanner stages of puberty in girls, suggesting increasing sensitivity, perhaps allowing greater food intake for growth by lowering the satiety signal.
The leptin story has restored credibility to the critical weight hypothesis originally proposed by Rose Frisch in the 1970s. The critical weight hypothesis states that the onset and regularity of menstrual function necessitate maintaining weight above a critical level and therefore, above a critical amount of body fat. It has always been a mystery how total body fat could talk with the brain. A mystery no longer! Fat talks to the brain via leptin, and the leptin system affects reproduction.
There is a difference, however, between ordinary weight loss and stress-induced weight loss (e.g., exercise or psychologic problems such as anorexia). In ordinary weight loss, corticotropin-releasing hormone (CRH) secretion is reduced, and the hypercortisolism is believed to be mediated through NPY signals in the hypothalamus. In stress-induced weight loss, CRH secretion is increased.
Corticotropin-releasing hormone (CRH) directly inhibits hypothalamic GnRH secretion, probably by augmenting endogenous opioid secretion. Women with hypothalamic amenorrhea (including exercisers and women with eating disorders) demonstrate hypercortisolism (due to increased CRH and ACTH), suggesting that this is the pathway by which stress interrupts reproductive function.3 In regards to reproduction, the final pathway is suppression of GnRH, a response to multiple inputs indicating the availability of metabolic fuel. Even in runners with regular menstrual patterns, LH pulsatile frequency and amplitude are significantly reduced. A central inhibition of GnRH can be discerned even before there is perceptible evidence of menstrual irregularity. The clinical presentation (inadequate luteal phase, anovulation, amenorrhea) will depend upon the degree of GnRH suppression.
A unifying hypothesis focuses on energy balance.4 When available energy is excessively diverted as in exercise or when insufficient as with eating disorders, reproduction is suspended in order to support essential metabolism for survival.
Thus, reproduction may not be directly affected by the level of body fat. Rather, body fat is a marker of the metabolic energy state, and the extremely low leptin levels in anorexic patients are an appropriate attempt to restore appetite, an attempt that fails to overcome the stress-induced increase in CRH and its consequences. It is also possible that the high NPY levels in response to low leptin secretion inhibit GnRH secretion. From a teleologic point of view, there is sense to these relationships; the responses that assist the body to withstand stress also inhibit menstrual function because a stressful period is not the ideal time for reproduction.
Although the leptin mechanism offers the potential for new treatments for obesity, it is not around the corner. Leptin, a polypeptide, cannot be administered orally, and, in view of high levels in overweight people, another method must be found to attack the apparent resistance to leptin. Thus far, it appears that genetic defects in the ob gene are uncommon; nevertheless, for affected individuals, a leptin agonist may be therapeutic. Even if this complex system yields new treatments, it is unlikely that we will be able to ignore eating appropriately and exercising adequately.
References
1. Schwartz MW, Seeley RJ. N Engl J Med 1997;336: 1802-1811.
2. Tartaglia LA. J Biol Chem 1997;272:6093-6096.
3. Dorn LD, Chrousos GP. Seminars Reprod Endocrinol 1997;15:19-35.
4. Wade GN, et al. 1996;270(Endocrinol Metab 33): E1-E19.
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